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International Journal of Medicinal Chemistry
Volume 2011 (2011), Article ID 403039, 16 pages
http://dx.doi.org/10.1155/2011/403039
Review Article

Dopamine Receptors and Parkinson's Disease

Department of Neurology, Sapporo Medical University, Sapporo 060-8556, Japan

Received 27 December 2010; Revised 4 March 2011; Accepted 12 April 2011

Academic Editor: Maarten Reith

Copyright © 2011 Shin Hisahara and Shun Shimohama. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Parkinson's disease (PD) is a progressive extrapyramidal motor disorder. Pathologically, this disease is characterized by the selective dopaminergic (DAergic) neuronal degeneration in the substantia nigra. Correcting the DA deficiency in PD with levodopa (L-dopa) significantly attenuates the motor symptoms; however, its effectiveness often declines, and L-dopa-related adverse effects emerge after long-term treatment. Nowadays, DA receptor agonists are useful medication even regarded as first choice to delay the starting of L-dopa therapy. In advanced stage of PD, they are also used as adjunct therapy together with L-dopa. DA receptor agonists act by stimulation of presynaptic and postsynaptic DA receptors. Despite the usefulness, they could be causative drugs for valvulopathy and nonmotor complication such as DA dysregulation syndrome (DDS). In this paper, physiological characteristics of DA receptor familyare discussed. We also discuss the validity, benefits, and specific adverse effects of pharmaceutical DA receptor agonist.

1. Introduction

Parkinson’s disease (PD) is a common progressive neurodegenerative disorder that can be accurately diagnosed. A recent meta-analysis study indicated that standardized all-age prevalence of 51.3 to 176.9 per 100 000 in door-to-door surveys and prevalence in record-based studies ranged from 35.8 to 68.3 per 100 000 in Asia [1]. The standardized incidence rates were 8.7 per 100 000 person-years in door-to-door surveys and 6.7 to 8.3 per 100 000 person-years in record-based surveys [1]. Clinical symptoms in PD comprise both motor and nonmotor symptoms. PD patients show slowness of initiation of voluntary movements with progressive reduction in speech (bradykinesia), muscular rigidity, resting tremor, and postural instability. Additionally, it is known that almost 90% of PD patients experience nonmotor symptoms during the course of disease [2]. The spectrum of nonmotor symptoms is also very broad and comprises neuropsychiatric conditions, such as depression, dementia, and hallucinations as well as autonomic, sensory, and REM sleep behavior disorders.

A region-specific selective loss of dopaminergic (DAergic) neuromelanin-containing neurons from the pars compacta of the substantia nigra (SNpc) is the pathological hallmark of PD. However, cell loss in the locuscoeruleus, dorsal nuclei of the vagus, raphe nuclei, nucleusbasalis of Meynert, and some other catecholaminergic brain stem structures including the ventrotegmental area also exists [3]. This neuronal cell loss is accompanied by intraneuronal inclusions: the Lewy body (LB). α-synuclein represents one of the most abundant proteins found in LBs, and it may play a pivotal role in the progression of PD. Since the degree of DAergic neuronal loss correlates with the severity of PD, levodopa (L-dopa), a chemical precursor of dopamine (DA) is the most effective drug for the symptomatic treatment of PD. Unfortunately, the clinical efficacy often declines after long-term levodopa replacement therapy (DA replacement therapy; DRT), and additionally, disabling adverse effects appear, most notably motor fluctuation such as the wearing-off or on-off phenomenon and dyskinesia [4].

Nowadays, DA receptor agonists are even regarded as first choice in de novo and young PD patients to delay onset of levodopa therapy. They are also used as combination therapy together with levodopa to retard the development of motor complications in advanced stages of PD. DA receptor agonists appear to act by not only direct stimulation of postsynaptic DA receptors but also presynaptic receptors. However, DA receptor agonists may be slightly less potent medicines than levodopa and may be poorly tolerated by older PD patients. Additionally, long-term therapy with traditional ergot DA receptor agonists may result in valvular heart disease [58]. A lack of spontaneity or reduced motivation (i.e., anhedonia) is the most troublesome issue in the therapy of advanced stage of PD patients. Medicines with high affinity for the DA receptors potentially improve these symptoms [9, 10]; however, hedonistic dysregulation syndrome or DA dysregulation syndrome (DDS) has emerged as a serious issue in PD with long-term DRT [11].

In this paper, we describe the physiology of DA receptors, the characteristics of animal models that have undergone genetic manipulation of DA receptors, the significance of DA receptors stimulants in therapeutic strategies of PD, and the issues of motor and nonmotor complications with long-term treatment.

2. Physiological Characterization of DA Receptors

DA is a prototypical slow neurotransmitter that plays significant roles in a variety of not only motor functions but also cognitive, motivational, and neuroendocrine [18]. All members of receptors share a number of structural characteristics such as (1) seven hydrophobic transmembrane stretches, (2) significant amount of amino acid sequence identity between different subfamily within these transmembrane regions and posttranslational modifications such as glycosylation and phosphorylation, and (3) conserved amino acid residues that are involved in interaction of G-protein and in binding agonists [19] (Table 1). On the basis of biochemical, pharmacological, and physiological criteria, DA receptors have been classified into two subfamilies, termed D1 and D2 [20, 21]. Genes encoding members of the DA receptor family are part of a larger superfamily of genes comprising the G protein-coupled superfamily receptors (GPCRs) [12, 19]. G protein-related actions of GPCRs are mediated by a subset of the heteromeric G protein subtypes. In general, G proteins consist of three protein subunits α, β, and γ. The α-subunits are functionally classified into several classes such as Gαs, Gαi, Gαo, Gαolf, Gαt, Gαq, and Gα12 and determine actions of GPCRs. Upon ligand binding, Gα proteins release GDP and newly bind GTP, then βγ-complex dissociates from α-subunit. Both the α-subunit and the βγ-complex can transduce the signal to activate a number of effector systems. For example, the activation of Gαs subunit stimulates adenylate cyclase (AC), whereas the activation of Gαi subunit inhibits AC. The D1 subfamily, including D1 and D5, are generally coupled to Gαs, and Gαolf and stimulate the production of cAMP and activate protein kinase A (PKA) [12] (Table 1). The D2 subfamily, including D2, D3, and D4, are coupled to Gαi and Gαo and downregulate the production of cAMP via inhibiting AC, resulting in a decrease in PKA activity [12] (Table 1). One of a PKA substrate, DA and cAMP-regulated phosphoprotein 32-kDa (DARPP-32) is known to be involved in DA receptor signaling. DARPP-32 is a multifunctional phosphoprotein and acts as an integrator involved in the modulation of cell signaling in response to multiple neurotransmitters, including DA [22]. Activated DARPP-32 inhibits protein phosphatase 1 (PP1) and results in activation of mitogen-activated protein (MAP) kinases, such as extracellular signal-regulated kinase (ERK) and MAP/ERK kinase (MEK). MAP kinases play a pivotal role in the regulation of synaptic plasticity and have been shown to be signaling intermediates that are involved in the regulation of DA-associated behavior [23].

tab1
Table 1: Dopamine receptor family.

Activation of D1 receptor/PKA/DARPP-32 signaling cascade leads to the inactivation of PP1 and allows for the activation of MEK and its downstream kinase ERK. D1 DA receptor-mediated ERK activation might involve the behavioral responses to drugs to abuse. Moreover, D1 subfamily can also couple to Gαq that regulates phospholipase C (PLC) activation. Activated PLC leads to the production of inositol triphosphate (IP3) and diacylglycerol and activation of protein kinase C (PKC). PKC increases mobilization of intracellular calcium in response to IP3. D1 subfamily agonist SKF-82526 can activate PLC, and this reaction is completely lost in the hippocampal, cortical, and striatal tissues of D5 receptor knockout mice, indicating D5 receptor plays a role for molecular signaling through Gαq [24, 25]. Lee et al. demonstrated that coactivation of D1 and D2 receptors elevates intracellular calcium with PLC and PKC activation via coupling to the Gαq pathway [26]. Several studies indicate that D1 and D2 receptors can coexpress in the brain [27, 28]; thus, it is possible that D1/D2 DA receptor heterodimers exist in vivo and regulate Gαq signaling pathway (Table 1).

D2 subfamily regulate Gαi and Gαo/PKA/DARPP-32 signaling cascade and also act on ion channels or by triggering the release of intracellular calcium [12]. D2 receptors regulate Gβγ subunits signaling. This subunit complex activates PLC and produces IP3, resulting in increasing the cytoplasmic calcium concentration [29]. Gβγ subunits can reduce the level of activity of the L/N-type of calcium channels [30]. Through these diverse cAMP- and Ca2+-dependent mechanisms, DA influences neuronal activity, synaptic activity, and behavior [3134]. Importantly, D2 receptor-mediated Gβγ subunits signaling regulates not only calcium channels but also potassium channels and G protein-coupled inwardly rectifying potassium channels (GIRK) [3537]. D2 receptors also regulate β-arrestin. The scaffolding proteins β-arrestin 1 and β-arrestin 2 have been traditionally associated with the termination of GPCR signaling and with receptor internalization. Following GPCR activation and their phosphorylation by GPCR kinases (GRKs), β-arrestins bind to the receptors to uncouple them from G proteins and participate in the recruitment of the endocytic protein complex, thus leading to an attenuation of GPCR signaling. β-arrestin 2 is a signaling intermediate implicated in the cAMP-independent regulation of Akt and glycogen synthase kinase 3 (GSK-3) by DA [13, 38]. Beaulieu et al. demonstrated that D2 DA receptor-mediated Akt/GSK-3 signaling is disrupted in mice lacking β-arrestin 2 [38] (Table 1).

The D1 receptor subfamily is expressed in multiple brain regions, including the cortex, hippocampus, amygdala, and most intensively, the striatum, olfactory bulb, and substantia nigra [39]. In the cortex and hippocampus, D1 receptors are expressed in a subpopulation of interneurons [40], but are primarily expressed in pyramidal neurons, with a predominant subcellular localization in the spines of apical dendrites [41]. D5 receptors coexpresses with D1 receptors in cortical pyramidal neurons, and are predominately localized in shafts [41] (Table 1).

The expression and localization of D2 receptor subfamily have also been investigated at the cellularand subcellular levels [39, 4246]. There are two major D2 receptor variants that have been termed D2-long (D2L) and D2-short (D2S) [47, 48]. D2L contains an additional 29 amino acids in the third cytoplasmic loop. D2L and D2S expressed mainly postsynaptically and presynaptically, respectively. D2S might function as autoreceptor that decreases DA release, resulting in decreased locomotor activity; however, activation of postsynaptic D2 receptors stimulates locomotion. D2 receptors, the predominant subtype of thisclass, are expressed in the pituitary gland and basal ganglia (striatum and substantia nigra) and localized in both pre- and postsynaptic structures. Presynaptically, D2 receptors areassociated with both forebrain projecting DAergic afferents and glutamatergic terminalsin the striatum and prefrontal cortex (PFC). Postsynaptically, D2 receptors are concentrated inshafts and spines of both cortical pyramidal neurons and striatopallidal neurons. While both D1 and D2 receptors are abundant in the striatum, the expression pattern of D1 and D2 receptors in the axon terminals, dendrites, and spines are obviously different by electron microscopic analysis [42]. These findings indicate segregated circuit via D1 and D2 receptors in the striatum. D3 receptors are expressed in the olfactory tubercle, nucleus accumbens, striatum, and substantia nigra. Importantly, D3 receptors are also found in limbic system such as hippocampus, septum, or mammillary nuclei of the hypothalamus. The D4 receptors, known to have an unusually high affinity for the atypicalneuroleptic clozapine, are localized in thefrontal cortex, medulla, amygdala, hypothalamus, mesencephalon, and nucleusaccumbens. It has been shown that lower level of D4 receptor expression is detected in the basal ganglia. In the rat central nervous system, the relative abundance of the DA receptors is D1 > D2 > D3 > D5 > D4 [49].

Consistent with the degeneration and loss of DA neurons in PD, the density of postsynaptic DA receptors increases in association with developing DA denervation supersensitivity. In 1970s and 1980s, many reports have indicated that D1 and D2 receptors are increased in the untreated PD using radioisotope-labeled high-affinity ligands and return to normal level upon levodopa therapy [5052]. Interestingly, GIRK2 knockout mice exhibited hyperactivity, which was inhibited by the D1/D5 receptor antagonist SCH-23390 [53]. SCH-23390, D1 agonists SKF-38393, and SKF-81297 can reversibly inhibit GIRK channel, and prior application of a GIRK channel blocker eliminated the depolarizing effect of D1 agonists [54, 55]. Witkowski et al. conclude that activation of D1DA receptors may lead to inhibition of GIRK channel currents [55]. A selective D3 agonist PD-128907 is one of the most useful compounds for investigating behavioral change. PD-128907 reduced spontaneous locomotor activity in a novel environment [56, 57]. Eticlopride and raclopride are selective D2 receptor antagonists. Eticlopride has been shown to robustly block the reinforcing effects of cocaine [5860]. Increased densities of D1 and D2 DA receptors may account for the clinical sensitivity to DA agonists in the PD patients, especially in early stage. Scherfler et al. demonstrated that raclopride-binding potential is significantly decreased in striatal, thalamic, and cortical areas (temporal, orbitofrontal, and parietal cortex) in parkin-linked PD patients compared with young onset PD patients, matched for age, severity, and duration [61]. They discussed that the decrease in D2 binding found in parkin-linked PD compared with young onset PD patients could be a direct consequence of the parkin genetic defect itself or a greater susceptibility to receptor downregulation following long-term DAergic agent exposure. Boileau et al. performed positron emission tomography with D3 receptor preferring ligand propyl-hexahydro-naphtho-oxazin (PHNO) in brain of nondepressed, nondemented, DAergic drug-naïve patients with early-stage PD [62]. They demonstrated that decreased binding ratio correlated with motor deficits and lowered mood. These results indicate that DA receptors and their binding potential may gradually decrease in the progression of PD.

It has long been suggested that DA dysfunction plays a major role in the pathogenesis of schizophrenia. Antipsychotics such as chlorpromazine and haloperidol act primarily as D2 receptor antagonists [63] (Table 1). These D2 receptor blockades are effective in attenuating positive symptoms of schizophrenia (e.g., hallucinations and delusions) associated with acute episodes as well as preventing psychotic relapse. Wong et al. demonstrated that D2 receptor density in the caudate nucleus is elevated in drug-naïve schizophrenia patients with positron emission tomography (PET) study [64]. Breier et al. also showed that patients with schizophrenia compared with healthy volunteers had significantly greater amphetamine-related reductions in radioligand [11C] raclopride-specific binding ratio with PET [65]. This result indicates that schizophrenia is associated with elevated amphetamine-induced synaptic DA concentrations [65] (Table 1). Studies also showed that increased striatal DA synthesis capacity in unmedicated schizophrenia patients [66, 67]. These results indicated that the pool of releasable DA is increased in patients with schizophrenic psychosis. Kramer et al. demonstrated that a selective D4 receptor agonist L-745870 is ineffective in patients with schizophrenia [68].

3. Genetic Manipulation of DA Receptors and Pathophysiology of PD

The facts regarding the contribution of D1- and D2-type DA receptors in the genesis of the behavioral and neurochemical Parkinsonian phenotype have been provided byclassic pharmacological approaches. Recently, genetically modified mice of DA receptors are also clarifying the significance of specific effects of DA-related neuronal physiology and pathophysiology.

In 1994, Xu et al. and Drago et al. generated D1 receptor-deficient mice [69, 70]. Xu et al. demonstrated that these mice also appear to exhibit a general behavioral hyperactivity during both phases of light-dark cycle [69]; however, Drago et al. described that the locomotor activity of knockout mice did not differ significantly from that of normal control except for displaying a significant decrease in rearing behavior [70]. Test for akinesia were normal. Moreover, Gantois et al. used a Cre/Lox transgenic approach to generate ananimal model in which D1 receptor-expressing cells are progressively ablated in the postnatal brain [71]. Whereas no differences in locomotor activity were found between the mutated mice and control, mutant showed hyperactivity in a novel environment. Abnormal oral behaviors such as chewing and sifting, limb-clasping dystonic posture, and spontaneous seizure are also found in mutant mice. Increased locomotor activity of D1 receptor-deficient mice is cancelled with a D1/D5 receptor antagonist SCH 23390, indicating that D1 and D5 receptors can exert distinct and complex physiological actions in locomotor activity [72].

In contrast to disruption of D1 receptor subfamily, spontaneous PD-like locomotor impairment is found in D2 receptor subfamily knockout mice. D2 receptor-deficient mice exhibit significantly reduced spontaneous movements in behavioral tests [73]. However, Kelly et al. demonstrated that striatal tissue content of monoamines and their metabolites from C57BL/6 congenic strain of D2 receptor mutant mice did not differ from those of wild type, and they found no evidence for supersensitive D1, D3, or D4 DA receptors in the D2 receptor knockout mice [74]. Recently, Tinsley et al. showed that LB-like cytoplasmic inclusions containing α-synuclein and ubiquitin were present in substantia nigra neurons of older D2 receptor knockout mice (>18 months old) [75]. Diffuse cytosolic α-synuclein immunoreactivity in nigral neurons increased with age in both wild-type and knockout mice, most likely because of redistribution of α-synuclein from striatal terminals to substantia nigra cell bodies. Gene and protein expression studies showed endoplasmic reticulum (ER) stress and changes in trafficking and autophagic pathways, indicating that these changes were accompanied by a loss of DA terminals in the dorsal striatum [75]. Wang et al. showed behavioral alteration in the D2L receptor-deficient mice [76]. The knockout mice display reduced locomotor activity and rearing behavior and reduced sensitivity to haloperidol-induced catalepsy. These results indicate that D2L might have a bigger impact on certain types of motor functions, and blockade of D2L might contribute more than blockade of D2S to the extrapyramidal side effects (or parkinsonism) that are commonly associated with typical antipsychotic drugs [76]. In addition, D2 receptor plays a pivotal role in the striatal processing of motor information received from the cortex in the generation of striatal synaptic plasticity. Whereas tetanic stimulation of corticostriatal fibers produced long-term potentiation (LTP) in the D2 receptor-null mice, long-term depression (LTD) is usually recorded in wild-type mice [77]. The LTP in knockout mice is blocked by an NMDA receptor antagonist, indicating that D2 receptor is involved in the formation of striatal LTD and exerts a negative control in the expression of an NMDA-mediated long-term LTP at corticostriatal synapses. Adenosine A2A receptors (A2AR) are known to coexpress D2 receptors in striatopallidal neurons, and A2AR-D2 receptor interaction modulates DA-mediated signaling [78]. A2AR selective antagonist, (E)-1,3-diethyl-8-(3,4-dimethoxystyryl)-7-methyl-3,7-dihydro-1Hpurine-2,6-dione (KW-6002, Istradefylline), exhibits anti-Parkinsonian activities [79]. Aoyama et al. demonstrated that locomotor impairment can be relieved by KW-6002 treatment in D2 receptor knockout mice [80]. Furthermore, the level of the expression of enkephalin and substance P is elevated to normal levels after A2AR antagonist treatment. These results show that A2AR and D2 receptor have antagonistic and independent activities in controlling neuronal and motor functions in the basal ganglia [80].

Although D3 receptor-deficient mice do not exhibit parkinsonism, it is quite important to elucidate specific behavioral alteration in the knockout mice for understanding clinical features of pharmacotherapeutic DA receptor agonists in the treatment of PD. D3 mutant mice exhibit hyperactivity in novel and exploratory environment and rearing behavior [8183]. These mutant mice demonstrated that both D1- and D2-receptor-binding sites are present in the dorsal and ventral striatum and the distributions and the densities of both binding sites in the mutants and controls are qualitatively and quantitatively similar [82]. Importantly, hyperactivity of mutant mice is caused by response to combinations of D1 and D2 receptor subfamily agonists, cocaine, and amphetamine. Carta et al. also showed that acute administration of cocaine resulted in increasing mRNA level of c-fos and dynorphin in the dorsal and ventral striatum of D3 receptor knockout mice, indicating D3 receptor plays a role on gene regulation in the DA system [84]. Moreover, Schmauss found that c-fos mRNA levels expressed in response to D1 agonist or methamphetamine administration is significantly blunted in D3 receptor-deficient (and also D2 receptor-deficient) mice [85]. D3 receptor mutants exhibit deficits in their spatial working memory, and methamphetamine pretreatment does not rescue this memory deficit of D3 mutants [85, 86]. These results indicate that the constitutive inactivation of D3 receptors leads to a decrease in agonist-promoted D1 receptor activity. D’Agata et al. have investigated parkin expression profile in D3 knockout mice [87]. parkin is known as one of the causative genes of autosomal recessive juvenile Parkinson’s disease. Parkin protein has an E3 ubiquitin-ligase activity, and loss of parkin function may result in accumulation of unnecessary molecules that lead to the degeneration of neurons. Real-time PCR analysis showed a different quantitative expression of parkin gene in mutant compared to control mice. Furthermore, immunoreactivity of parkin showed a higher intensity in D3 receptor knockout mice compared to wild type by Western blot analysis using parkin mouse monoclonal antibody [87]. Karasinska et al. generated mice lacking both D1 and D3 receptors and investigated psychostimulant-induced behavior [88]. Administration of cocaine increased locomotor activity in wild-type and D3 knockout mice, failed to stimulate activityin D1 knockout mice, and reduced activity in D1/D3 knockout mice. Karasinska et al. discussed the significance of expression level of phosphorylated cAMP-responsive element-binding protein (pCREB) in the striatum. CREB is activated by phosphorylation in striatal regions following DA receptor activation. Striatal pCREB levels following acute cocaine were increased in D3 mutant mice and decreased in D1 and D1/D3 mutant mice [88]. The change of locomotor activity of D3 mutant mice is controversial. Jung et al. demonstrated that the activity of D2/D3 double mutants is significantly reduced not only when compared to wild type but also when compared to single D2 receptor mutants [89]. They indicated that a relatively long observation period for locomotor activity is needed in D3 mutant mice because of their rapidly habituating hyperactivity [89].

D4 knockout mice show significantly reduced exploration behavior and rearing activity [90, 91]. Extent of improvement of locomotor activity is dramatically increased in D4 receptor-deficient mice than that of wild type of littermate following the administration of ethanol, cocaine, and amphetamine, indicating that knockout mice are more responsive to the locomotor stimulants than wild type [90]. Falzone et al. described that the absence of D4 receptor increases avoidance behavior to unconditioned stimuli and does not impair behavioral reactions to fear-conditioned stimuli in two different approach/avoidance conflict paradigms [92]. These results indicate that D4 receptor could play a pivotal role in the DAergic modulation of cortical signals triggered by environmental stimuli, because D4 receptor is physiologically expressed at highest levels in the prefrontal cortex and is the predominant D2-like receptor localized in this brain area (Table 1).

4. Treatment for PD with DA Receptor Agonists

As a result of significant advances in experimental therapeutics in vitro and in vivo, progression of treatment for PD has been made, and many promising therapies are emerging. L-dopa is classical, but it remains the most potent medication for controlling PD symptoms [96]. Unfortunately, despite adjustments of the timing and dose frequency of L-dopa, motor fluctuation (such as wearing-off and on-off phenomena) and involuntary movements (such as dyskinesia and dystonia) could tend to appear in the PD patients who are treated long duration of L-dopa medication. There is ongoing debate as to when it is most appropriate to initiate L-dopa therapy in the course of PD. Most physicians and neurologists pay attention to timing for starting of L-dopa therapy in order to delay the onset of related motor complications. DA receptor agonists are now known to have beneficial effects to delay onset adverse effects of L-dopa and recommended as first choice treatment in the relatively young-onset PD patients.

DA receptor agonists exert their pharmacologic effect by directly activating DA receptors, bypassing the presynaptic synthesis of DA (Table 2). In general, half-lives of agonists are remarkably longer than L-dopa; therefore, they can produce more persistent period of DA receptor stimulation than L-dopa. In addition, metabolites of receptor agonists do not generate free radicals that are toxic on DA neurons [97]. DA receptor agonists also have been suggested to be neuroprotective acting as free-radical scavengers, reducing DA synthesis, DA release and metabolism via activating presynaptic autoreceptors, ameliorate excitotoxicity by suppressing subthalamic nucleus overactivity, and exert antiapoptotic effects (review in [98101]). Experimental (as described above) and clinical studies have provided evidence that activation of the D2 receptors (D2 and D3 receptor) is beneficial for treatment of PD; however, pharmaceutical receptor agonists also stimulate D1 receptor to some extent.

tab2
Table 2: Pharmacological features of ergoline DA agonists.

DA receptor agonists are classified by their chemical structural formula as ergoline derivatives including bromocriptine, pergolide, cabergoline, lisuride, and α-dihydroergocriptine (DHEC) and nonergoline derivatives including pramipexole, ropinirole, rotigotine, and apomorphine. Ergolines are derivative of ergot alkaloids that have a longer history in PD therapy and are as effective as nonergolines. Nonergolines have been developed later in the hope that they could provide the benefits of the ergolines without their adverse effects.

4.1. Bromocriptine (Parlodel and Cycloset)

Bromocriptine is the first therapeutic DA receptor agonist (Table 2). It has been shown to protect mice against 6-hydoxydopamine (6-OHDA) and can scavenge methamphetamine-induced free radicals [102104]. The pharmacological neuroprotective effects of bromocriptine comprise not only D2 receptor agonist but also antioxidant free-radical scavenger. It also exerted a neuroprotective effect against glutamate-induced cytotoxicity in rat mesencephalic and cortical neurons [105, 106]. Kihara et al. indicated that bromocriptine could upregulate Bcl-2 expression via phosphatidylinositol 3 kinase cascade [106].

4.2. Pergolide (Permax)

Pergolide is rapidly absorbed following oral dosing, reaching peak plasma concentrations within 2-3 hours, and it is completely eliminated within 4-5 days (review in [107]) (Table 2). Pergolide has a long half-life of about 21 hours. This has interesting implications, as it should produce a more physiological or continuous stimulation of DA receptors, avoiding or delaying the induction of dyskinesia [107]. Similar to bromocriptine, pergolide also has been shown to have the neuroprotective effect in vitro and in vivo [97, 108, 109]. Long-term oral administration of pergolide results in preventing age-related diminution of DA cell bodies in the rat substantia nigra [108]. Asanuma et al. also reported that repeated pretreatment with pergolide significantly protected against 6-OHDA-induced reduction in striatal DA content [109]. The neuroprotective effect of pergolide has been shown to be mediated by free-radical scavenging activity [110].

4.3. Cabergoline (Cabaser and Dostinex)

Cabergoline has a very long elimination half-life of 65–110 hours (Table 2). Arai et al. showed that combined therapy with low doses of L-dopa and cabergoline is beneficial for treating patients with PD [111]. This combination is highly effective in controlling motor disability without inducing dyskinesia in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine- (MPTP-) lesioned Parkinsonian cynomolgus monkeys [111]. Administration of cabergoline also attenuates 6-OHDA-indced DAergic neuronal loss in mice [112]. Daily administration of cabergoline to mice significantly increased striatal glutathione (GSH) levels by activation of RNA expression of GSH-related enzymes, indicating scavenging free radicals by activation of the GSH system [112]. Cabergoline is also an inducer of glial cell line-derived neurotrophic factor (GDNF) that may have neuroprotective and neurorestorative properties in DAergic nigral neurons [113].

4.4. Lisuride (Dopergin, Proclacam, and Revanil)

Lisuride is used to lower prolactin and to prevent migraine attacks. It has not only a D2 receptor agonist properties but also has 5-hydroxytryptamine (5-HT and serotonin) agonist activity. Terminal half-life for elimination of lisuride from the plasma is around 2 hours, which is shorter than most other DA agonists (Table 2). Lisuride has solubility properties similar to apomorphine and therefore, can be given subcutaneously and intravenously. Nomoto et al. studied the effects of lisuride in the dermal application on MPTP-treated common marmosets and on 5 patients with PD [114]. The agent relieved akinesia and Parkinsonism of MPTP-treated monkeys and increased the duration of “on” period in the patient of PD. The other important feature of lisuride is that it has no affinity to 5-HT2B receptors [115, 116]. Therefore, lisuride might not a causative agent for valvular heart disease and fibrotic reactions that could be related to other ergot DA receptor agonists described below.

4.5. α-dihydroergocriptine (DHEC)

DHEC is a dihydro-derivative of ergocryptine acting as a D2agonist and a partial D1 agonist. Therefore, DHEC has a pharmacodynamic profile quite comparable to that of bromocriptine. DHEC improves the symptoms and neuronal degeneration of the MPTP-treated monkey model of PD [117, 118]. In cellular models, DHEC protected cultured granule cells against age-dependent neuronal cell death and increased the survival of DAergic cells when coadministered with L-dopa and DA [119, 120].

4.6. Pramipexole (Mirapex, Mirapexin, and Sifrol)

Pramipexole is one of a representative nonergot DA receptor agonist that has a potent activity to D2 and D3 receptors [121] (Table 2). It has been shown to be a safe and effective drug when used as monotherapy in early-to-moderate stages and adjunct therapy with L-dopa in advanced stage of PD [122124]. Importantly, pramipexole reduced not only motor symptoms of PD but also significantly reduced anhedonia in patients who had associated depression [124]. Recent studies exhibited that pramipexole improves both subjective symptoms of restless legs syndrome (RLS), mainly characterized by discomfort at rest and urge to move focused on the legs, and objective sleep parameters [125, 126]. Zou et al. showed that the neuroprotective effect of pramipexole is the result of antioxidant property [127, 128]. Pramipexole also interferes with the activation of caspase-mediated cell death pathways in rotenone- and MPTP-administered human neuroblastoma cell line SH-SY5Y [129, 130]. Interestingly, The protective effect was not prevented by DA receptor blockade using sulpiride or clozapine, indicating that pramipexole acts by other protective mechanism that is not dependent on DA receptor occupation [130]. Izumi et al. revealed that pramipexole protects DAergic neurons from glutamate cytotoxicity by the reduction of intracellular DA content [131]. Ramirez et al. reported that pramipexole plays a role for D3 receptor-mediated neuroprotection against MPTP-induced neurotoxicity with D3 receptor knockout mice [132]. Furthermore, the DA D3 receptor selective antagonist A-437203 partially inhibited the neuroprotective effect of pramipexole in D3 receptor expressing mice but not in knockout mice. These results indicate that D3-dependent and D3-independent pramipexole-mediated neuroprotection seem to act against MPTP neurotoxicity.

4.7. Ropinirole (Requip, Ropark, Adartrel, and Ropinotergotirole)

Ropinirole is a nonergoline agonist and has a high affinity for D2 and D3 DA receptors (Table 2). It has been also demonstrated to be effective in early and advanced PD [133135]. Monotherapy is also effective in early stage of PD with resting tremor [136]. Similar to pramipexole, ropinirole is also well tolerated in patients with RLS [137, 138]. Recent report indicates that ropiniroleis more effective for acute therapeutic efficacy with regard to periodic leg movement in RLS than gabapentin [139]. In animal model of PD, ropinirole reverses motor and behavioral deficits induced by MPTP in marmosets [140] and protects striatal DAergic neurons against 6-OHDA in mice via increased GSH, catalase, and superoxide dismutase [141]. Matsukawa et al. revealed that lentiviral overexpression of both D2 and D3 receptor in 6-OHDA-administered rats results in the enhancement of efficacy of ropinirole for motor symptoms [142].

4.8. Rotigotine (Neupro)

Rotigotine is a unique nonergoline DA receptor agonist for D1 through D5 receptors, particularly in the highest affinity for D3 receptor [93] (Table 2). It has been formulated for transdermal delivery that ensures continuous drug release and stable plasma concentration over a period of 24 hours [143]. Various formulations of L-dopa have been developed to delay levodopa degradation in peripheral tissues and prolong its half-life, and thus minimize plasma peaks and troughs of drugs. In addition to their symptomatic benefits and in delaying the initiation of L-dopa therapy, agonists have also been used to provide more continuous DAergic stimulation. Randomized, blind, controlled trials of transdermal rotigotine revealed efficacy and safety in the treatment of early and advanced PD [144, 145]. Transdermal rotigotine is also effective in moderate-to-severe RLS [146, 147]. In rodent and primate PD models, rotigotine treatment demonstrated its protective effects from MPTP toxicity and efficacy of behavioral symptoms improvement [148, 149].

4.9. Piribedil (Trivastal, Pronoran, Trastal, and Trivastan)

Piribedil is a centrally acting DA agonist with an affinity for D2 and D3 receptors [150, 151] (Table 2). Ziegler et al. demonstrated that a 6-month oral administration of piribedil in combination with L-dopa is well tolerated and significantly improves motor symptoms compared with placebo in PD nonfluctuating patients [152]. In 6-OHDA-induced rat animal models, combination therapy with piribedil and L-dopa can improve cognitive functions while reducing risk of motor complications [153]. Moreover, piribedil monotherapy is shown to be effective for the improvement of motor symptoms and safe with early stage of PD [154]. A recent study of a single-dose placebo-controlled, randomized, double-blind study indicates that a novel orodispersible formulation of the piribedil (S90049) is promising to provide relief on motor signs and aborting “off” episodes of PD [155]. Smith et al. generated common marmoset PD model induced by MPTP and treated with L-dopa to improve motor deficits but with mild dyskinesia [156]. Then, switching treatment from L-dopa to piribedil resulted in decreasing dyskinesia without symptomatic deterioration, indicating that piribedil could suppress dyskinesia induced by long-term treatment with L-dopa.

4.10. Apomorphine (Apokyn, Ixense, Spontane, and Uprima)

Apomorphine is a nonergoline and a nonselective DA receptor agonist [157] (Table 2). Historically, it was the first DA receptor agonist used for treating PD since 1950s. It is first known since 1845 for its emetic properties, and it has been utilized for different clinical situations, such as analgesia, insomnia, alcohol dependence, schizophrenia, and erectile dysfunction. Since apomorphine has a rapid absorption and a short half-life, the best mode of administration is subcutaneous intermittent injection or continuous infusion. Continuous infusion can be used as monotherapy or in concomitance with extremely low doses of L-dopa. Apomorphine also can reduce “off” periods, improve motor symptoms of PD, and suppress dyskinesia (reviewed in [158]). Like other DA receptor agonists, there are several reports describing the neuroprotective potential of apomorphine in animal models. Pretreatment with apomorphine administered subcutaneously in mice protects against MPTP-induced loss of nigrostriatal DA neurons as indicated by striatal DA content [159]. Similarly, Battaglia et al. revealed that continuous subcutaneous infusion of apomorphine rescues loss of striatal immunoreactivity for tyrosine hydroxylase and DA transporter in MPTP-injected mice [160]. Apomorphine treatment significantly attenuated the 6-OHDA-induced striatal DA depletion, and dihydroxyphenyl acetic acid (DOPAC)/DA ratios, a neurochemical indicator for neuroprotection, were normalized [161]. The neuroprotective effect of apomorphine could be a consequence of antioxidant activity, potent iron chelating action, inhibition of lipid peroxidation, induction of neurotrophic factors, and anti-inflammatory effects [159, 162166].

4.11. Adverse Effects Associated with DA Receptor Agonists

Despite the fact that DA receptor agonists have the advantage of providing symptom control without increasing amount of L-dopa and dyskinesia or wearing-off effect that occurs with long-term L-dopa treatment, physicians and neurologists noticed several PD patients treated with DA receptor agonists developed critical side effects. Fibrotic valvular heart disease and DRT-induced pathological behaviors (DDS) are representative features of agonists. Physicians must consider balance the benefits of continued therapy with agonists against these possible risks. Further investigations are necessary to assist with treatment decisions.

4.12. Fibrotic Valvular Heart Disease

Fibrotic heart disease is mainly induced by ergoline derivatives. Pritchett et al. first described three pergolide-treated PD patients who developed unexplained tricuspid regurgitation in 2002 [167]. The other cases that indicate other ergot DA receptor agonists such as cabergoline and bromocriptine seem to be causative agents [168, 169]. No patients given lisuride have developed valvulopathy. Several studies of echocardiographic prevalence have shown moderate to severe valvular disease in about ~31% of patients taking pergolide and in about ~69% taking cabergoline [8, 170173]. These studies have not performed echocardiographic analysis before starting ergoline DA receptor agonists; therefore, preexisting valvular heart disease cannot be excluded. Schade et al. investigated population-based cohort study with data from the United Kingdom General Practice Research Database [174]. After excluding subjects that have preexisting valvular heart disease, of 31 cases from comprising 11,417 patients who had received anti-Parkinsonian drugs newly developed valvular regurgitation. 31 cases from comprising 11,417 patients who had received anti-Parkinsonian drugs newly developed valvular regurgitation. 12 patients have been taking pergolide or cabergoline. The rate of cardiac-valve regurgitation is increased with current use of pergolide (adjusted incidence-rate ratio, 7.1) and cabergoline (4.9) [174].

It remains controversial whether a high daily dose of prescribing agonists or cumulative dose of drugs is true risk for prevalence of valvulopathy. Van Camp et al. discussed that 5 mg or high daily dose of pergolide administration promotes heightened risk for development heart disease; however, this result was not statistically significant [175]. Other study indicates that 3 mg or high daily dose of pergolide and cabergoline raised risk although it is still increased in patients who are received 3 mg or less of either drugs [174]. On the other hand, the risk of valvulopathy might be small in patients treated with low dose of agonists. Kim et al. indicated no significant difference in the frequency of valvulopathy in the subjects receiving a mean daily dose of 1.13 mg of pergolide for mean duration of 53 months compared with controls [171]. Yamamoto et al. also showed that there was no significant high risk in the frequency of moderate-to-severe valvular regurgitation in the PD patients receiving a mean daily dose of 1.4 mg of pergolide [170]. Few studies showed natural history of pergolide/cabergoline-induced valvular heart disease. Pinero et al. described a patient who developed severe mitral valve regurgitation after 4 months treatment with cabergoline [176]. Moreover, some of these drug-induced valvulopathy case showed partial improvement after stopping pergolide/cabergoline treatment [172, 175].

The pathogenesis of DA receptor agonist-induced valvulopathy is associated with 5-HT2 and 5-HT2 receptor-mediated signaling. 5-HT2 has a significant mitogenic effect on smooth muscle cells and fibroblast with upregulation of transforming growth factor β (TGF-β) [177179]. 5-HT2B receptor is abundant on cardiac valves and ergoline DA receptor agonists could stimulate these receptors, resulting in mitogenesis and thickening of valves [180]. Moreover, 5-HT transporter- (5-HTT-) deficient mice showed marked valvular fibrosis and 5-HT2 administration results in downregulating gene expression of 5-HTT [181, 182]. These results indicate that modulation of 5-HTT expression also plays a pivotal role for pathogenesis of valvulopathy.

Whereas pergolide has been withdrawn from the US market, most ergoline DA receptor agonists still remains in use in the rest of the world. In many countries, guidelines recommended relatively low daily dose of pergolide/cabergoline to decrease the prevalence of valvular heart disease. It is also recommended to perform echocardiography before starting treatment and regularly thereafter.

4.13. DRT-Induced Pathological Behaviors (DDS)

Anti Parkinsonian drug-induced nonmotor complications have been significant problem in PD patients. Giovannoni et al. described four patients and proposed diagnostic criteria for DDS as follows [11]: L-dopa responsive PD; need for excessive dose of DRT to relieve symptoms, drug hoarding and seeking, impairment of social or occupational functioning, development of affective syndrome related to DRT, development of a withdrawal state on reducing the level of DRT, and duration of disturbance of at least six months. DDS observed in PD patients could be characterized as impulsive, compulsive, and stereotyped behavior such as punding, pathologicalInternet use, compulsive skin picking, pathological (compulsive) gambling, compulsive buying, binge eating, and hypersexuality.

Punding behavior is characterized as compulsive hobbyism. An intense inappropriate and unproductive fascination for common objects with repetitive meaningless movements such as endless computer use, cleaning and tidying, gardening, collecting, and sorting common objects [183]. PD patients with punding are found to take higher dose of DRT and to endure more severe dyskinesia than those who do not pund [184]. Reduction of amount of DRT and/or treatment with antidepressant drugs such as selective serotonergic reuptake inhibitors are effective for improvement of punding.

Pathological gambling and shopping are failure to resist compulsive gambling/buying that are associated with adjunctive DA agonist therapy but not with DA agonist monotherapy [185, 186]. Voon et al. estimated that lifetime prevalence of pathologic gambling was 3.4% and on any DA agonist was 7.2% [185]. It was associated with earlier PD onset and with DA agonists but not with agonist subtype or doses. Reduction or stopping of these drugs improves this pathological behavior.

Hypersexuality is defined as a preoccupation with sexual feelings and thoughts, nymphomania or satyriasis may occur in 2%–4% of the patients [185, 187, 188]. It is associated with DA receptor agonists; however, it has been reported in patients on L-dopa monotherapy and after subthalamic deep brain stimulation [187189]. Although this abnormal behavior easily disrupts social and marital life, it is rather refractory and often difficult to improve after ceasing the DA receptor agonists and/or adding antipsychotic drugs.

Potential mechanism for DDS associated with DA receptor agonists are not fully understood. DA is not only implicated in voluntary movement control but also plays a significant role in the brain’s reward system, learning and decision making mechanism, and the modulation of behaviors. The ventral part of striatum receives input from the amygdala, hippocampus, and anterior cingulate cortex, whereas the dorsal part outputs information of motor circuits [190, 191]. In PD, striatal DA deficiency results in general striatal dysregulation, both motor (dorsal part) and nonmotor (ventral part) symptoms. Exaggerated amplification of a normal limbic input in the dorsal part of striatum could result in stereotyped motor output (punding). Overactivation of the ventral part of the striatum is suggested to be associated with increased compulsive and stereotyped behaviors.

5. Concluding Remarks

In the late 20th century, many outstanding studies of the basic genetic and structural features of DA receptors have brought about remarkable progression for therapeutic strategy of several disorders caused by malfunction of DA receptors and DA signaling such as PD and schizophrenia. More recently, many studies have revealed information on the regulatory and signaling mechanisms that are involved in DA receptor signaling. Signaling events that are caused by the activation of each DA receptor are significantly complex and these mechanisms depend on the many molecules such as ligands and kinases. On the other hand, further studies are needed to clarify the characteristics of D3, D4, and D5 receptors. Discovery of new features of these receptors may provide better understanding roles of DA outside of the basal ganglia and give rise to innovations of pharmacotherapeutic strategy of PD treatment. Nonmotor complications and DDS are still major issues for management of the patients with PD. Further investigations of normal and abnormal DA receptor signaling in vivo will continue to evolve in exciting ways in the future.

Conflict of Interests

The authors declare no conflict of interests.

References

  1. W. Muangpaisan, H. Hori, and C. Brayne, “Systematic review of the prevalence and incidence of Parkinson's disease in Asia,” Journal of Epidemiology, vol. 19, no. 6, pp. 281–293, 2009. View at Publisher · View at Google Scholar · View at Scopus
  2. L. M. Shulman, R. L. Taback, J. Bean, and W. J. Weiner, “Comorbity of the nonmotor symptoms of Parkinson's disease,” Movement Disorders, vol. 16, no. 3, pp. 507–510, 2001. View at Publisher · View at Google Scholar · View at Scopus
  3. P. Damier, E. C. Hirsch, Y. Agid, and A. M. Graybiel, “The substantia nigra of the human brain: II. Patterns of loss of dopamine-containing neurons in Parkinson's disease,” Brain, vol. 122, no. 8, pp. 1437–1448, 1999. View at Publisher · View at Google Scholar · View at Scopus
  4. T. N. Chase, M. M. Mouradian, and T. M. Engber, “Motor response complications and the function of striatal efferent systems,” Neurology, vol. 43, no. 12, supplement 6, pp. S23–S27, 1993. View at Scopus
  5. K. R. Chaudhari, V. Dhawan, S. Basu, G. Jackson, and P. Odin, “Valvular heart disease and fibrotic reactions may be related to ergot dopamine agonists, but non-ergot agonists may also not be spared,” Movement Disorders, vol. 19, no. 12, pp. 1522–1523, 2004. View at Publisher · View at Google Scholar · View at PubMed
  6. R. Tintner, P. Manian, P. Gauthier, and J. Jankovic, “Pleuropulmonary fibrosis after long-term treatment with the dopamine agonist pergolide for Parkinson disease,” Archives of Neurology, vol. 62, no. 8, pp. 1290–1295, 2005. View at Publisher · View at Google Scholar · View at PubMed
  7. B. L. Roth, “Focus on research: drugs and valvular heart disease,” The New England Journal of Medicine, vol. 356, no. 1, pp. 6–9, 2007. View at Scopus
  8. R. Zanettini, A. Antonini, G. Gatto, R. Gentile, S. Tesei, and G. Pezzoli, “Valvular heart disease and the use of dopamine agonists for Parkinson's disease,” The New England Journal of Medicine, vol. 356, no. 1, pp. 39–46, 2007. View at Scopus
  9. I. Rektorová, I. Rektor, M. Bareš et al., “Pramipexole and pergolide in the treatment of depression in Parkinson's disease: a national multicentre prospective randomized study,” European Journal of Neurology, vol. 10, no. 4, pp. 399–406, 2003. View at Publisher · View at Google Scholar · View at Scopus
  10. M. R. Lemke, H. M. Brecht, J. Koester, P. H. Kraus, and H. Reichmann, “Anhedonia, depression, and motor functionong in Parkinson's disease during treatment with pramipexole,” Journal of Neuropsychiatry and Clinical Neurosciences, vol. 17, no. 2, pp. 214–220, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  11. G. Giovannoni, J. D. O'Sullivan, K. Turner, A. J. Manson, and A. J. L. Lees, “Hedonistic homeostatic dysregulation in patients with Parkinson's disease on dopamine replacement therapies,” Journal of Neurology Neurosurgery and Psychiatry, vol. 68, no. 4, pp. 423–428, 2000. View at Publisher · View at Google Scholar · View at Scopus
  12. C. Missale, S. Russel Nash, S. W. Robinson, M. Jaber, and M. G. Caron, “Dopamine receptors: from structure to function,” Physiological Reviews, vol. 78, no. 1, pp. 189–225, 1998. View at Scopus
  13. J. M. Beaulieu, R. R. Gainetdinov, and M. G. Caron, “The Akt-GSK-3 signaling cascade in the actions of dopamine,” Trends in Pharmacological Sciences, vol. 28, no. 4, pp. 166–172, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  14. D. Vallone, R. Picetti, and E. Borrelli, “Structure and function of dopamine receptors,” Neuroscience and Biobehavioral Reviews, vol. 24, no. 1, pp. 125–132, 2000. View at Publisher · View at Google Scholar · View at Scopus
  15. J. Yuan, X. Chen, R. Brodbeck et al., “NGB 2904 NGB 2849: two highly selective dopamine D3 receptor antagonists,” Bioorganic and Medicinal Chemistry Letters, vol. 8, no. 19, pp. 2715–2718, 1998. View at Publisher · View at Google Scholar · View at Scopus
  16. P. Grundt, E. E. Carlson, J. Cao et al., “Novel heterocyclic trans olefin analogues of N-{4-[4-(2,3-dichlorophenyl) piperazin-1-yl]butyl}arylcarboxamides as selective probes with high affinity for the dopamine D3 receptor,” Journal of Medicinal Chemistry, vol. 48, no. 3, pp. 839–848, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  17. T. J. Banasikowski, A. Bespalov, K. Drescher et al., “Double dissociation of the effects of haloperidol and the dopamine D3 receptor antagonist ABT-127 on acquisition vs. expression of cocaine-conditioned activity in rats,” Journal of Pharmacology and Experimental Therapeutics, vol. 335, no. 2, pp. 506–515, 2010. View at Publisher · View at Google Scholar · View at PubMed
  18. A. Carlsson, “A paradigm shift in brain research,” Science, vol. 294, no. 5544, pp. 1021–1024, 2001. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  19. H. B. Niznik and H. H. M. Van Tol, “Dopamine receptor genes: new tools for molecular psychiatry,” Journal of Psychiatry and Neuroscience, vol. 17, no. 4, pp. 158–180, 1992. View at Scopus
  20. J. W. Kebabian and D. B. Calne, “Multiple receptors for dopamine,” Nature, vol. 277, no. 5692, pp. 93–96, 1979. View at Scopus
  21. P. Seeman, “Brain dopamine receptors,” Pharmacological Reviews, vol. 32, no. 3, pp. 229–313, 1980.
  22. P. Svenningsson, A. Nishi, G. Fisone, J. A. Girault, A. C. Nairn, and P. Greengard, “DARPP-32: an integrator of neurotransmission,” Annual Review of Pharmacology and Toxicology, vol. 44, pp. 269–296, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  23. M. T. Berhow, N. Hiroi, and E. J. Nestler, “Regulation of ERK (extracellular signal regulated kinase), part of the neurotrophin signal transduction cascade, in the rat mesolimbic dopamine system by chronic exposure to morphine or cocaine,” Journal of Neuroscience, vol. 16, no. 15, pp. 4707–4715, 1996. View at Scopus
  24. C. C. Felder, P. A. Jose, and J. Axelrod, “The dopamine-1 agonist, SKF 82526, stimulates phospholipase-C activity independent of adenylate cyclase,” Journal of Pharmacology and Experimental Therapeutics, vol. 248, no. 1, pp. 171–175, 1989. View at Scopus
  25. A. Sahu, K. R. Tyeryar, H. O. Vongtau, D. R. Sibley, and A. S. Undieh, “D5 dopamine receptors are required for dopaminergic activation of phospholipase C,” Molecular Pharmacology, vol. 75, no. 3, pp. 447–453, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  26. S. P. Lee, C. H. So, A. J. Rashid et al., “Dopamine D1 and D2 receptor co-activation generates a novel phospholipase C-mediated calcium signal,” Journal of Biological Chemistry, vol. 279, no. 34, pp. 35671–35678, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  27. A. J. Rashid, C. H. So, M. M. C. Kong et al., “D1-D2 dopamine receptor heterooligomers with unique pharmacology are coupled to rapid activation of Gq/11 in the striatum,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 2, pp. 654–659, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  28. Z. W. Zhang, M. W. Burke, N. Calakos, J. M. Beaulieu, and E. Vaucher, “Confocal analysis of cholinergic and dopaminergic inputs onto pyramidal cells in the prefrontal cortex of rodents,” Frontiers in Neuroanatomy, vol. 4, p. 21, 2010.
  29. S. Hernádez-López, T. Tkatch, E. Perez-Garci et al., “D2 dopamine receptors in striatal medium spiny neurons reduce L-type Ca2+ currents and excitability via a novel PLCβ1-IP3-Calcineurin-signaling cascade,” Journal of Neuroscience, vol. 20, no. 24, pp. 8987–8995, 2000.
  30. Z. Yan, W. J. Song, and D. J. Surmeier, “D2 dopamine receptors reduce N-type Ca2+ currents in rat neostriatal cholinergic interneurons through a membrane-delimited, protein-kinase-C-insensitive pathway,” Journal of Neurophysiology, vol. 77, no. 2, pp. 1003–1015, 1997. View at Scopus
  31. S. M. Nicola, D. James Surmeier, and R. C. Malenka, “Dopaminergic modulation of neuronal excitability in the striatum and nucleus accumbens,” Annual Review of Neuroscience, vol. 23, pp. 185–215, 2000. View at Publisher · View at Google Scholar · View at PubMed
  32. J. K. Seamans and C. R. Yang, “The principal features and mechanisms of dopamine modulation in the prefrontal cortex,” Progress in Neurobiology, vol. 74, no. 1, pp. 1–58, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  33. D. J. Surmeier, J. Ding, M. Day, Z. Wang, and W. Shen, “D1 and D2 dopamine-receptor modulation of striatal glutamatergic signaling in striatal medium spiny neurons,” Trends in Neurosciences, vol. 30, no. 5, pp. 228–235, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  34. P. Calabresi, B. Picconi, A. Tozzi, and M. Di Filippo, “Dopamine-mediated regulation of corticostriatal synaptic plasticity,” Trends in Neurosciences, vol. 30, no. 5, pp. 211–219, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  35. E. V. Kuzhikandathil, W. Yu, and G. S. Oxford, “Human dopamine D3 and D2L receptors couple to inward rectifier potassium channels in mammalian cell lines,” Molecular and Cellular Neurosciences, vol. 12, no. 6, pp. 390–402, 1998. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  36. N. Lavine, N. Ethier, J. N. Oak et al., “G protein-coupled receptors form stable complexes with inwardly rectifying potassium channels and adenylyl cyclase,” Journal of Biological Chemistry, vol. 277, no. 48, pp. 46010–46019, 2002. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  37. C. Lüscher and P. A. Slesinger, “Emerging roles for G protein-gated inwardly rectifying potassium (GIRK) channels in health and disease,” Nature Reviews Neuroscience, vol. 11, no. 5, pp. 301–315, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  38. J. M. Beaulieu, T. D. Sotnikova, S. Marion, R. J. Lefkowitz, R. R. Gainetdinov, and M. G. Caron, “An Akt/β-arrestin 2/PP2A signaling complex mediates dopaminergic neurotransmission and behavior,” Cell, vol. 122, no. 2, pp. 261–273, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  39. A. I. Levey, S. M. Hersch, D. B. Rye et al., “Localization of D1 and D2 dopamine receptors in brain with subtype-specific antibodies,” Proceedings of the National Academy of Sciences of the United States of America, vol. 90, no. 19, pp. 8861–8865, 1993. View at Publisher · View at Google Scholar · View at Scopus
  40. E. C. Muly, K. Szigeti, and P. S. Goldman-Rakic, “D1 receptor in interneurons of macaque prefrontal cortex: distribution and subcellular localization,” Journal of Neuroscience, vol. 18, no. 24, pp. 10553–10565, 1998. View at Scopus
  41. C. Bergson, L. Mrzljak, J. F. Smiley, M. Pappy, R. Levenson, and P. S. Goldman-Rakic, “Regional, cellular, and subcellular variations in the distribution of D1 and D5 dopamine receptors in primate brain,” Journal of Neuroscience, vol. 15, no. 12, pp. 7821–7836, 1995. View at Scopus
  42. S. M. Hersch, B. J. Ciliax, C. A. Gutekunst et al., “Electron microscopic analysis of D1 and D2 dopamine receptor proteins in the dorsal striatum and their synaptic relationships with motor corticostriatal afferents,” Journal of Neuroscience, vol. 15, no. 7, pp. 5222–5237, 1995. View at Scopus
  43. K. K. L. Yung, J. P. Bolam, A. D. Smith, S. M. Hersch, B. J. Ciliax, and A. I. Levey, “Immunocytochemical localization of D1 and D2 dopamine receptors in the basal ganglia of the rat: light and electron microscopy,” Neuroscience, vol. 65, no. 3, pp. 709–730, 1995. View at Publisher · View at Google Scholar
  44. S. R. Sesack, C. Aoki, and V. M. Pickel, “Ultrastructural localization of D2 receptor-like immunoreactivity in midbrain dopamine neurons and their striatal targets,” Journal of Neuroscience, vol. 14, no. 1, pp. 88–106, 1994. View at Scopus
  45. H. Wang and V. M. Pickel, “Dopamine D2 receptors are present in prefrontal cortical afferents and their targets in patches of the rat caudate-putamen nucleus,” Journal of Comparative Neurology, vol. 442, no. 4, pp. 392–404, 2002. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  46. C. R. Gerfen, “The neostriatal mosaic: multiple levels of compartmental organization in the basal ganglia,” Annual Review of Neuroscience, vol. 15, pp. 285–320, 1992. View at Scopus
  47. B. Giros, P. Sokoloff, M. P. Martres, J. F. Riou, L. J. Emorine, and J. C. Schwartz, “Alternative splicing directs the expression of two D2 dopamine receptor isoforms,” Nature, vol. 342, no. 6252, pp. 923–926, 1989. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  48. F. J. Monsma, L. D. McVittie, C. R. Gerfen, L. C. Mahan, and D. R. Sibley, “Multiple D2 dopamine receptors produced by alternative RNA splicing,” Nature, vol. 342, no. 6252, pp. 926–929, 1989. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  49. M. Jaber, S. W. Robinson, C. Missale, and M. G. Caron, “Dopamine receptors and brain function,” Neuropharmacology, vol. 35, no. 11, pp. 1503–1519, 1996. View at Publisher · View at Google Scholar · View at Scopus
  50. T. Lee, P. Seeman, and A. Rajput, “Receptor basis for dopaminergic supersensitivity in Parkinson's disease,” Nature, vol. 273, no. 5657, pp. 59–61, 1978. View at Scopus
  51. R. Raisman, R. Cash, and M. Ruberg, “Binding of [3H]SCH 23390 to D-1 receptors in the putamen of control and Parkinsonian subjects,” European Journal of Pharmacology, vol. 113, no. 3, pp. 467–468, 1985. View at Scopus
  52. P. Seeman and H. B. Niznik, “Dopamine receptors and transporters in Parkinson's disease and schizophrenia,” FASEB Journal, vol. 4, no. 10, pp. 2737–2744, 1990. View at Scopus
  53. Y. Blednov, M. Stoffel, R. Cooper, D. Wallace, N. Mane, and R. Harris, “Hyperactivity and dopamine D1 receptor activation in mice lacking girk2 channels,” Psychopharmacology, vol. 159, no. 4, pp. 370–378, 2002. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  54. E. V. Kuzhikandathil and G. S. Oxford, “Classic D1 dopamine receptor antagonist R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH23390) directly inhibits G protein-coupled inwardly rectifying potassium channels,” Molecular Pharmacology, vol. 62, no. 1, pp. 119–126, 2002. View at Publisher · View at Google Scholar · View at Scopus
  55. G. Witkowski, B. Szulczyk, R. Rola, and P. Szulczyk, “D1 dopaminergic control of G protein-dependent inward rectifier K+ (GIRK)-like channel current in pyramidal neurons of the medial prefrontal cortex,” Neuroscience, vol. 155, no. 1, pp. 53–63, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  56. L. J. Bristow, G. P. Cook, J. C. Gay et al., “The behavioural and neurochemical profile of the putative dopamine D3 receptor agonist, (+)-PD 128907, in the rat,” Neuropharmacology, vol. 35, no. 3, pp. 285–294, 1996. View at Publisher · View at Google Scholar · View at Scopus
  57. M. Guitart-Masip, B. Johansson, A. Fernández-Teruel, A. Tobeña, and L. Giménez-Llort, “Divergent effect of the selective D3 receptor agonist pd-128,907 on locomotor activity in Roman high- and low-avoidance rats: relationship to NGFI-A gene expression in the Calleja islands,” Psychopharmacology, vol. 196, no. 1, pp. 39–49, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  58. G. Winger, “Dopamine antagonist effects on behavior maintained by cocaine and alfentanil in rhesus monkeys,” Behavioural Pharmacology, vol. 5, no. 2, pp. 141–152, 1994. View at Scopus
  59. M. A. Nader, K. L. Green, R. R. Luedtke, and R. H. Mach, “The effects of benzamide analogues on cocaine self-administration in rhesus monkeys,” Psychopharmacology, vol. 147, no. 2, pp. 143–152, 1999. View at Scopus
  60. J. L. Martelle and M. A. Nader, “A review of the discovery, pharmacological characterization, and behavioral effects of the dopamine D2-like receptor antagonist eticlopride,” CNS Neuroscience and Therapeutics, vol. 14, no. 3, pp. 248–262, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  61. C. Scherfler, N. L. Khan, N. Pavese et al., “Striatal and cortical pre- and postsynaptic dopaminergic dysfunction in sporadic parkin-linked parkinsonism,” Brain, vol. 127, no. 6, pp. 1332–1342, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  62. I. Boileau, M. Guttman, P. Rusjan et al., “Decreased binding of the D3 dopamine receptor-preferring ligand [11C]-(+)-PHNO in drug-nave Parkinsons disease,” Brain, vol. 132, no. 5, pp. 1366–1375, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  63. A. Carlsson and M. Lindqvist, “Effect of chlorpromazine or haloperidol on formation of 3methoxytyramine and normetanephrine in mouse brain,” Acta Pharmacologica et Toxicologica, vol. 20, pp. 140–144, 1963.
  64. D. F. Wong, H. N. Wagner Jr., L. E. Tune, et al., “Positron emission tomography reveals elevated D2 dopamine receptors in drug-naive schizophrenics,” Science, vol. 234, no. 4783, pp. 1558–1563, 1986. View at Scopus
  65. A. Breier, T. P. Su, R. Saunders et al., “Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: evidence from a novel positron emission tomography method,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 6, pp. 2569–2574, 1997. View at Publisher · View at Google Scholar · View at Scopus
  66. J. Hietala, E. Syvalahti, K. Vuorio et al., “Presynaptic dopamine function in striatum of neuroleptic-naive schizophrenic patients,” The Lancet, vol. 346, no. 8983, pp. 1130–1131, 1995. View at Scopus
  67. G. Gründer, I. Vernaleken, M. J. Müller et al., “Subchronic haloperidol downregulates dopamine synthesis capacity in the brain of schizophrenic patients in vivo,” Neuropsychopharmacology, vol. 28, no. 4, pp. 787–794, 2003. View at Scopus
  68. M. S. Kramer, B. Last, A. Getson, and S. A. Reines, “The effects of a selective D4 dopamine receptor antagonist (L-745,870) in acutely psychotic inpatients with schizophrenia,” Archives of General Psychiatry, vol. 54, no. 6, pp. 567–572, 1997. View at Scopus
  69. M. Xu, R. Moratalla, L. H. Gold et al., “Dopamine D1 receptor mutant mice are deficient in striatal expression of dynorphin and in dopamine-mediated behavioral responses,” Cell, vol. 79, no. 4, pp. 729–742, 1994. View at Publisher · View at Google Scholar · View at Scopus
  70. J. Drago, C. R. Gerfen, J. E. Lachowicz et al., “Altered striatal function in a mutant mouse lacking D1A dopamine receptors,” Proceedings of the National Academy of Sciences of the United States of America, vol. 91, no. 26, pp. 12564–12568, 1994. View at Publisher · View at Google Scholar · View at Scopus
  71. I. Gantois, K. Fang, L. Jiang et al., “Ablation of D1 dopamine receptor-expressing cells generates mice with seizures, dystonia, hyperactivity, and impaired oral behavior,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 10, pp. 4182–4187, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  72. D. Centonze, C. Grande, E. Saulle et al., “Distinct roles of D1 and D5 dopamine receptors in motor activity and striatal synaptic plasticity,” Journal of Neuroscience, vol. 23, no. 24, pp. 8506–8512, 2003. View at Scopus
  73. J. H. Baik, R. Picetti, A. Saiardi et al., “Parkinsonian-like locomotor impairment in mice lacking dopamine D2 receptors,” Nature, vol. 377, no. 6548, pp. 424–428, 1995. View at Scopus
  74. M. A. Kelly, M. Rubinstein, T. J. Phillips et al., “Locomotor activity in D2 dopamine receptor-deficient mice is determined by gene dosage, genetic background, and developmental adaptations,” Journal of Neuroscience, vol. 18, no. 9, pp. 3470–3479, 1998. View at Scopus
  75. R. B. Tinsley, C. R. Bye, C. L. Parish et al., “Dopamine D2 receptor knockout mice develop features of Parkinson disease,” Annals of Neurology, vol. 66, no. 4, pp. 472–484, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  76. Y. Wang, R. Xu, T. Sasaoka, S. Tonegawa, M. P. Kung, and E. B. Sankoorikal, “Dopamine D2 long receptor-deficient mice display alterations in striatum-dependent functions,” Journal of Neuroscience, vol. 20, no. 22, pp. 8305–8314, 2000. View at Scopus
  77. P. Calabresi, A. Saiardi, A. Pisani et al., “Abnormal synaptic plasticity in the striatum of mice lacking dopamine D2 receptors,” Journal of Neuroscience, vol. 17, no. 12, pp. 4536–4544, 1997. View at Scopus
  78. J. S. Fink, D. R. Weaver, S. A. Rivkees et al., “Molecular cloning of the rat A2 adenosine receptor: selective co-expression with D2 dopamine receptors in rat striatum,” Molecular Brain Research, vol. 14, no. 3, pp. 186–195, 1992. View at Publisher · View at Google Scholar · View at Scopus
  79. T. Kanda, T. Tashiro, Y. Kuwana, and P. Jenner, “Adenosine A2A receptors modify motor function in MPTP-treated common marmosets,” NeuroReport, vol. 9, no. 12, pp. 2857–2860, 1998. View at Scopus
  80. S. Aoyama, H. Kase, and E. Borrelli, “Rescue of locomotor impairment in dopamine D2 receptor-deficient mice by an Adenosine A2A receptor antagonist,” Journal of Neuroscience, vol. 20, no. 15, pp. 5848–5852, 2000. View at Scopus
  81. D. Acilli, C. S. Fishburn, J. Drago et al., “A targeted mutation of the D3 dopamine receptor gene is associated with hyperactivity in mice,” Proceedings of the National Academy of Sciences of the United States of America, vol. 93, no. 5, pp. 1945–1949, 1996. View at Publisher · View at Google Scholar · View at Scopus
  82. M. Xu, T. E. Koeltzow, G. T. Santiago et al., “Dopamine D3 receptor mutant mice exhibit increased behavioral sensitivity to concurrent stimulation of D1 and D2 receptors,” Neuron, vol. 19, no. 4, pp. 837–848, 1997. View at Publisher · View at Google Scholar · View at Scopus
  83. T. Li, Y. Hou, C.-X. Yan, T. Chen, Y. Zhao, and S.-B. Li, “Dopamine D3 receptor knock-out mice display deficits in locomotor sensitization after chronic morphine administration,” Neuroscience Letters, vol. 485, no. 3, pp. 256–260, 2010. View at Publisher · View at Google Scholar · View at PubMed
  84. A. R. Carta, C. R. Gerfen, and H. Steiner, “Cocaine effects on gene regulation in the striatum and behavior: increased sensitivity in D3 dopamine receptor-deficient mice,” NeuroReport, vol. 11, no. 11, pp. 2395–2399, 2000. View at Scopus
  85. C. Schmauss, “A single dose of methamphetamine leads to a long term reversal of the blunted dopamine D1 receptor-mediated neocortical c-fos responses in mice deficient for D2 and D3 receptors,” Journal of Biological Chemistry, vol. 275, no. 49, pp. 38944–38948, 2000. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  86. S. B. Glickstein, P. R. Hof, and C. Schmauss, “Mice lacking dopamine D2 and D3 receptors have spatial working memory deficits,” Journal of Neuroscience, vol. 22, no. 13, pp. 5619–5629, 2002. View at Scopus
  87. V. D'Agata, A. Tiralongo, A. Castorina et al., “Parkin expression profile in dopamine D3 receptor knock-out mice brains,” Neurochemical Research, vol. 34, no. 2, pp. 327–332, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  88. J. M. Karasinska, S. R. George, R. Cheng, and B. F. O'Dowd, “Deletion of dopamine D1 and D3 receptors differentially affects spontaneous behaviour and cocaine-induced locomotor activity, reward and CREB phosphorylation,” European Journal of Neuroscience, vol. 22, no. 7, pp. 1741–1750, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  89. M. Y. Jung, B. V. Skryabin, M. Arai et al., “Potentiation of the D2 mutant motor phenotype in mice lacking dopamine D2 and D3 receptors,” Neuroscience, vol. 91, no. 3, pp. 911–924, 1999. View at Publisher · View at Google Scholar · View at Scopus
  90. M. Rubinstein, T. J. Phillips, J. R. Bunzow et al., “Mice lacking dopamine D4 receptors are supersensitive to ethanol, cocaine, and methamphetamine,” Cell, vol. 90, no. 6, pp. 991–1001, 1997. View at Publisher · View at Google Scholar · View at Scopus
  91. S. C. Dulawa, D. K. Grandy, M. J. Low, M. P. Paulus, and M. A. Geyer, “Dopamine D4 receptor-knock-out mice exhibit reduced exploration of novel stimuli,” Journal of Neuroscience, vol. 19, no. 21, pp. 9550–9556, 1999. View at Scopus
  92. T. L. Falzone, D. M. Gelman, J. I. Young, D. K. Grandy, M. J. Low, and M. Rubinstein, “Absence of dopamine D4 receptors results in enhanced reactivity to unconditioned, but not conditioned, fear,” European Journal of Neuroscience, vol. 15, no. 1, pp. 158–164, 2002. View at Publisher · View at Google Scholar · View at Scopus
  93. D. Scheller, C. Ullmer, R. Berkels, M. Gwarek, and H. Lübbert, “The in vitro receptor profile of rotigotine: a new agent for the treatment of Parkinson's disease,” Naunyn-Schmiedeberg's Archives of Pharmacology, vol. 379, no. 1, pp. 73–86, 2009. View at Publisher · View at Google Scholar · View at PubMed
  94. M. J. Millan, L. Maiofiss, D. Cussac, V. Audinot, J. A. Boutin, and A. Newman-Tancredi, “Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. I. A multivariate analysis of the binding profiles of 14 drugs at 21 native and cloned human receptor subtypes,” Journal of Pharmacology and Experimental Therapeutics, vol. 303, no. 2, pp. 791–804, 2002. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  95. W. Krause, R. Dorow, B. Nieuweboer, and S. H. Hasan, “Pharmacokinetics and pharmacodynamics of the ergot derivative, transdihydrolisuride, in man,” European Journal of Clinical Pharmacology, vol. 27, no. 3, pp. 335–339, 1984. View at Scopus
  96. J. Jankovic, “Parkinson's disease: clinical features and diagnosis,” Journal of Neurology, Neurosurgery and Psychiatry, vol. 79, no. 4, pp. 368–376, 2008. View at Publisher · View at Google Scholar · View at PubMed
  97. G. Gille, W. D. Rausch, S. T. Hung et al., “Pergolide protects dopaminergic neurons in primary culture under stress conditions,” Journal of Neural Transmission, vol. 109, no. 5-6, pp. 633–643, 2002. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  98. W.-D. Le and J. Jankovic, “Are dopamine receptor agonists neuroprotective in Parkinson's disease?” Drugs and Aging, vol. 18, no. 6, pp. 389–396, 2001.
  99. A. H. V. Schapira, “Neuroprotection in PD—a role for dopamine agonists?” Neurology, vol. 61, no. 6, supplement 3, pp. S34–S42, 2003.
  100. Y. Kitamura, T. Taniguchi, S. Shimohama, A. Akaike, and Y. Nomura, “Neuroprotective mechanisms of antiparkinsonian dopamine D2-receptor subfamily agonists,” Neurochemical Research, vol. 28, no. 7, pp. 1035–1040, 2003. View at Publisher · View at Google Scholar · View at Scopus
  101. Z. Pirtošek and D. Flisar, “Neuroprotection and dopamine agonists,” Advances in Experimental Medicine and Biology, vol. 541, pp. 55–74, 2003.
  102. N. Ogawa, K. I. Tanaka, M. Asanuma et al., “Bromocriptine protects mice against 6-hydroxydopamine and scavenges hydroxyl free radicals in vitro,” Brain Research, vol. 657, no. 1-2, pp. 207–213, 1994. View at Scopus
  103. T. Kondo, T. Ito, and Y. Sugita, “Bromocriptine scavenges methamphetamine-induced hydroxyl radicals and attenuates dopamine depletion in mouse striatum,” Annals of the New York Academy of Sciences, vol. 738, pp. 222–229, 1994. View at Scopus
  104. T. Yoshikawa, Y. Minamiyama, Y. Naito, and M. Kondo, “Antioxidant properties of bromocriptine, a dopamine agonist,” Journal of Neurochemistry, vol. 62, no. 3, pp. 1034–1038, 1994. View at Scopus
  105. H. Sawada, M. Ibi, T. Kihara et al., “Dopamine D2-type agonists protect mesencephalic neurons from glutamate neurotoxicity: mechanisms of neuroprotective treatment against oxidative stress,” Annals of Neurology, vol. 44, no. 1, pp. 110–119, 1998. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  106. T. Kihara, S. Shimohama, H. Sawada et al., “Protective effect of dopamine D2 agonists in cortical neurons via the phosphatidylinositol 3 kinase cascade,” Journal of Neuroscience Research, vol. 70, no. 3, pp. 274–282, 2002. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  107. O. Blin, “The pharmacokinetics of pergolide in Parkinson's disease,” Current Opinion in Neurology, vol. 16, supplement 1, pp. S9–S12, 2003.
  108. D. L. Felten, S. Y. Felten, R. W. Fuller, T. D. Romano, E. B. Smalstig, and D. T. Wong, “Chronic dietary pergolide preserves nigrostriatal neuronal integrity in aged-Fischer-344 rats,” Neurobiology of Aging, vol. 13, no. 2, pp. 339–351, 1992. View at Publisher · View at Google Scholar
  109. M. Asanuma, N. Ogawa, S. Nishibayashi, M. Kawai, Y. Kondo, and E. Iwata, “Protective effects of pergolide on dopamine levels in the 6-hydroxydopamine-lesioned mouse brain,” Archives Internationales de Pharmacodynamie et de Therapie, vol. 329, no. 2, pp. 221–230, 1995.
  110. J. Opacka-Juffry, A. W. Wilson, and S. B. Blunt, “Effects of pergolide treatment on in vivo hydroxyl free radical formation during infusion of 6-hydroxydopamine in rat striatum,” Brain Research, vol. 810, no. 1-2, pp. 27–33, 1998. View at Publisher · View at Google Scholar · View at Scopus
  111. N. Arai, M. Isaji, M. Kojima, E. Mizuta, and S. Kuno, “Combined effects of cabergoline and L-dopa on parkinsonism in MPTP-treated cynomolgus monkeys,” Journal of Neural Transmission, vol. 103, no. 11, pp. 1307–1316, 1996. View at Scopus
  112. M. Yoshioka, K.-I. Tanaka, I. Miyazaki et al., “The dopamine agonist cabergoline provides neuroprotection by activation of the glutathione system and scavenging free radicals,” Neuroscience Research, vol. 43, no. 3, pp. 259–267, 2002. View at Publisher · View at Google Scholar
  113. K. Ohta, A. Fujinami, S. Kuno et al., “Cabergoline stimulates synthesis and secretion of nerve growth factor, brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor by mouse astrocytes in primary culture,” Pharmacology, vol. 71, no. 3, pp. 162–168, 2004. View at Publisher · View at Google Scholar · View at PubMed
  114. M. Nomoto, S.-I. Iwata, M. Irifune, S. Kaseda, M. Osame, and T. Fukuda, “Dermal application of lisuride on parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the common marmoset and on cases with Parkinson's disease,” Nihon Shinkei Seishin Yakurigaku Zasshi, vol. 18, no. 3, pp. 81–87, 1998.
  115. R. Horowski, S. Jähnichen, and H. H. Pertz, “Fibrotic valvular heart disease is not related to chemical class but to biological function: 5-HT2B receptor activation plays crucial role,” Movement Disorders, vol. 19, no. 12, pp. 1523–1524, 2004. View at Publisher · View at Google Scholar · View at PubMed
  116. S. Jähnichen, R. Horowski, and H. H. Pertz, “Agonism at 5-HT2B receptors is not a class effect of the ergolines,” European Journal of Pharmacology, vol. 513, no. 3, pp. 225–228, 2005. View at Publisher · View at Google Scholar · View at PubMed
  117. G. Bernocchi, G. Gerzeli, E. Scherini, and C. Vignola, “Neuroprotective effects of α-dihydroergocryptine against damages in the substantia nigra caused by severe treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine,” Acta Neuropathologica, vol. 85, no. 4, pp. 404–413, 1993.
  118. G. Coppi, “Neuroprotective activity of α-dihydroergocryptine in animal models,” Journal of Neural Transmission. Supplementum, no. 45, pp. 307–318, 1995. View at Scopus
  119. A. Favit, M. A. Sortino, G. Aleppo, U. Scapagnini, and P. L. Canonico, “The inhibition of peroxide formation as a possible substrate for the neuroprotective action of dihydroergocryptine,” Journal of Neural Transmission. Supplementum, no. 45, pp. 297–305, 1995.
  120. G. Gille, K. Radad, H. Reichmann, and W.-D. Rausch, “Synergistic effect of α-dihydroergocryptine and L-dopa or dopamine on dopaminergic neurons in primary culture,” Journal of Neural Transmission, vol. 113, no. 9, pp. 1107–1118, 2006. View at Publisher · View at Google Scholar · View at PubMed
  121. J. Mierau and G. Schingnitz, “Biochemical and pharmacological studies on pramipexole, a potent and selective dopamine D2 receptor agonist,” European Journal of Pharmacology, vol. 215, no. 2-3, pp. 161–170, 1992. View at Publisher · View at Google Scholar
  122. W. J. Weiner, S. A. Factor, J. Jankovic et al., “The long-term safety and efficacy of pramipexole in advanced Parkinson's disease,” Parkinsonism and Related Disorders, vol. 7, no. 2, pp. 115–120, 2001. View at Publisher · View at Google Scholar · View at Scopus
  123. K. Marek, J. Seibyl, I. Shoulson et al., “Dopamine transporter brain imaging to assess the effects of pramipexole vs levodopa on Parkinson disease progression,” Journal of the American Medical Association, vol. 287, no. 13, pp. 1653–1661, 2002. View at Scopus
  124. H. Reichmann, M. H. Brecht, J. Köster, P. H. Kraus, and M. R. Lemke, “Pramipexole in routine clinical practice: a prospective observational trial in Parkinson's disease,” CNS Drugs, vol. 17, no. 13, pp. 965–973, 2003. View at Publisher · View at Google Scholar · View at Scopus
  125. J. W. Winkelman, K. D. Sethi, C. A. Kushida et al., “Efficacy and safety of pramipexole in restless legs syndrome,” Neurology, vol. 67, no. 6, pp. 1034–1039, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  126. W. H. Oertel, K. Stiasny-Kolster, B. Bergtholdt et al., “Efficacy of pramipexole in restless legs syndrome: a six-week, multicenter, randomized, double-blind study (effect-RLS study),” Movement Disorders, vol. 22, no. 2, pp. 213–219, 2007. View at Publisher · View at Google Scholar · View at PubMed
  127. L. Zou, J. Jankovic, D. B. Rowe, W. Xie, S. H. Appel, and W. Le, “Neuroprotection by pramipexole against dopamine- and levodopa-induced cytotoxicity,” Life Sciences, vol. 64, no. 15, pp. 1275–1285, 1999. View at Publisher · View at Google Scholar · View at Scopus
  128. B. Ferger, P. Teismann, and J. Mierau, “The dopamine agonist pramipexole scavenges hydroxyl free radicals induced by striatal application of 6-hydroxydopamine in rats: an in vivo microdialysis study,” Brain Research, vol. 883, no. 2, pp. 216–223, 2000. View at Publisher · View at Google Scholar · View at Scopus
  129. N. A. Abramova, D. S. Cassarino, S. M. Khan, T. W. Painter, and J. P. Bennett Jr., “Inhibition by R(+) or S(-) pramipexole of caspase activation and cell death induced by methylpyridinium ion or beta amyloid peptide in SH-SY5Y neuroblastoma,” Journal of Neuroscience Research, vol. 67, no. 4, pp. 494–500, 2002. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  130. M. Gu, M. Irvani, J. M. Cooper, D. King, P. Jenner, and A. H.V. Schapira, “Pramipexole protects against apoptotic cell death by non-dopaminergic mechanisms,” Journal of Neurochemistry, vol. 91, no. 5, pp. 1075–1081, 2004. View at Publisher · View at Google Scholar · View at PubMed
  131. Y. Izumi, H. Sawada, N. Yamamoto et al., “Novel neuroprotective mechanisms of pramipexole, an anti-Parkinson drug, against endogenous dopamine-mediated excitotoxicity,” European Journal of Pharmacology, vol. 557, no. 2-3, pp. 132–140, 2007. View at Publisher · View at Google Scholar · View at PubMed
  132. A. D. Ramirez, S. K. F. Wong, and F. S. Menniti, “Pramipexole inhibits MPTP toxicity in mice by dopamine D3 receptor dependent and independent mechanisms,” European Journal of Pharmacology, vol. 475, no. 1-3, pp. 29–35, 2003. View at Publisher · View at Google Scholar · View at Scopus
  133. A. D. Korczyn, E. R. Brunt, J. P. Larsen, Z. Nagy, H. Poewe, and S. Ruggieri, “A 3-year randomized trial of ropinirole and bromocriptine in early Parkinson's disease,” Neurology, vol. 53, no. 2, pp. 364–370, 1999.
  134. O. Rascol, D. J. Brooks, A. D. Korczyn, P. P. De Deyn, C. E. Clarke, and A. E. Lang, “A five-year study of the incidence of dyskinesia in patients with early Parkinson's disease who were treated with ropinirole or levodopa. 056 Study Group,” The New England Journal of Medicine, vol. 342, no. 20, pp. 1484–1491, 2000. View at Publisher · View at Google Scholar · View at PubMed
  135. S. Cristina, R. Zangaglia, F. Mancini, E. Martignoni, G. Nappi, and C. Pacchetti, “High-dose ropinirole in advanced Parkinson's disease with severe dyskinesias,” Clinical Neuropharmacology, vol. 26, no. 3, pp. 146–150, 2003. View at Publisher · View at Google Scholar
  136. A. Schrag, J. Keens, and J. Warner, “Ropinirole for the treatment of tremor in early Parkinson's disease,” European Journal of Neurology, vol. 9, no. 3, pp. 253–257, 2002. View at Publisher · View at Google Scholar · View at Scopus
  137. R. Allen, P. M. Becker, R. Bogan et al., “Ropinirole decreases periodic leg movements and improves sleep parameters in patients with restless legs syndrome,” Sleep, vol. 27, no. 5, pp. 907–914, 2004. View at Scopus
  138. S. M. Cheer, L. M. Bang, and G. M. Keating, “Ropinirole: for the treatment of restless legs syndrome,” CNS Drugs, vol. 18, no. 11, pp. 747–754, 2004. View at Publisher · View at Google Scholar · View at Scopus
  139. M. Saletu, P. Anderer, G. M. Saletu-Zyhlarz et al., “Comparative placebo-controlled polysomnographic and psychometric studies on the acute effects of gabapentin versus ropinirole in restless legs syndrome,” Journal of Neural Transmission, vol. 117, no. 4, pp. 463–473, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  140. R. J. Eden, B. Costall, A. M. Domeney et al., “Preclinical pharmacology of ropinirole (SK and F 101468-A) a novel dopamine D2 agonist,” Pharmacology Biochemistry and Behavior, vol. 38, no. 1, pp. 147–154, 1991. View at Publisher · View at Google Scholar · View at Scopus
  141. M. Iida, I. Miyazaki, K. I. Tanaka, H. Kabuto, E. Iwata-Ichikawa, and N. Ogawa, “Dopamine D2 receptor-mediated antioxidant and neuroprotective effects of ropinirole, a dopamine agonist,” Brain Research, vol. 838, no. 1-2, pp. 51–59, 1999. View at Publisher · View at Google Scholar · View at Scopus
  142. N. Matsukawa, M. Maki, T. Yasuhara et al., “Overexpression of D2/D3 receptors increases efficacy of ropinirole in chronically 6-OHDA-lesioned Parkinsonian rats,” Brain Research, vol. 1160, no. 1, pp. 113–123, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  143. D. R. Black and C. N. Sang, “Advances and limitations in the evaluation of analgesic combination therapy,” Neurology, vol. 65, no. 12, supplement 4, pp. S3–S6, 2005.
  144. R. L. Watts, J. Jankovic, C. Waters, A. Rajput, B. Boroojerdi, and J. Rao, “Randomized, blind, controlled trial of transdermal rotigotine in early Parkinson disease,” Neurology, vol. 68, no. 4, pp. 272–276, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  145. W. H. Poewe, O. Rascol, N. Quinn et al., “Efficacy of pramipexole and transdermal rotigotine in advanced Parkinson's disease: a double-blind, double-dummy, randomised controlled trial,” The Lancet Neurology, vol. 6, no. 6, pp. 513–520, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  146. W. H. Oertel, H. Benes, D. Garcia-Borreguero et al., “Efficacy of rotigotine transdermal system in severe restless legs syndrome: a randomized, double-blind, placebo-controlled, six-week dose-finding trial in Europe,” Sleep Medicine, vol. 9, no. 3, pp. 228–239, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  147. C. Trenkwalder, H. Beneš, W. Poewe et al., “Efficacy of rotigotine for treatment of moderate-to-severe restless legs syndrome: a randomised, double-blind, placebo-controlled trial,” The Lancet Neurology, vol. 7, no. 7, pp. 595–604, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  148. J. D. Belluzzi, E. F. Domino, J. M. May, K. S. Bankiewicz, and D. A. McAfee, “N-0923, a selective dopamine D2 receptor agonist, is efficacious in rat and monkey models of Parkinson's disease,” Movement Disorders, vol. 9, no. 2, pp. 147–154, 1994. View at Scopus
  149. D. Scheller, P. Chan, Q. Li et al., “Rotigotine treatment partially protects from MPTP toxicity in a progressive macaque model of Parkinson's disease,” Experimental Neurology, vol. 203, no. 2, pp. 415–422, 2007. View at Publisher · View at Google Scholar · View at PubMed
  150. A. Gobert, J.-M. Rivet, V. Audinot et al., “Functional correlates of dopamine D3 receptor activation in the rat in vivo and their modulation by the selective antagonist, (+)-S 14297: II. Both D2 and ‘silent’ D3 autoreceptors control synthesis and release in mesolimbic, mesocortical and nigrostriatal pathways,” Journal of Pharmacology and Experimental Therapeutics, vol. 275, no. 2, pp. 899–913, 1995.
  151. M. J. Millan, J.-L. Peglion, J. Vian et al., “Functional correlates of dopamine D3 receptor activation in the rat in vivo and their modulation by the selective antagonist, (+)-S 14297: I. Activation of postsynaptic D3 receptors mediates hypothermia, whereas blockade of D2 receptors elicits prolactin secretion and catalepsy,” Journal of Pharmacology and Experimental Therapeutics, vol. 275, no. 2, pp. 885–898, 1995.
  152. M. Ziegler, A. Castro-Caldas, S. Del Signore, and O. Rascol, “Efficacy of piribedil as early combination to levodopa in patients with stable parkinson's disease: a 6-month, randomized, placebo-controlled study,” Movement Disorders, vol. 18, no. 4, pp. 418–425, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  153. N. Turle-Lorenzo, B. Maurin, C. Puma et al., “The dopamine agonist piribedil with L-DOPA improves attentional dysfunction: relevance for Parkinson's disease,” Journal of Pharmacology and Experimental Therapeutics, vol. 319, no. 2, pp. 914–923, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  154. O. Rascol, B. Dubois, A. C. Caldas, S. Senn, S. Del Signore, and A. Lees, “Early piribedil monotherapy of parkinson's disease: a planned seven-month report of the REGAIN study,” Movement Disorders, vol. 21, no. 12, pp. 2110–2115, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  155. O. Rascol, J.-P. Azulay, O. Blin et al., “Orodispersible sublingual piribedil to abort OFF episodes: a single dose placebo-controlled, randomized, double-blind, cross-over study,” Movement Disorders, vol. 25, no. 3, pp. 368–376, 2010. View at Publisher · View at Google Scholar · View at PubMed
  156. L. A. Smith, M. J. Jackson, L. Johnston et al., “Switching from levodopa to the long-acting dopamine D2/D3 agonist piribedil reduces the expression of dyskinesia while maintaining effective motor activity in MPTP-treated primates,” Clinical Neuropharmacology, vol. 29, no. 3, pp. 112–125, 2006. View at Publisher · View at Google Scholar · View at PubMed
  157. D. Deleu, Y. Hanssens, and M. G. Northway, “Subcutaneous apomorphine: an evidence-based review of its use in Parkinson's disease,” Drugs and Aging, vol. 21, no. 11, pp. 687–709, 2004. View at Publisher · View at Google Scholar · View at Scopus
  158. C. G. Goetz, W. Poewe, O. Rascol, and C. Sampaio, “Evidence-based medical review update: pharmacological and surgical treatments of Parkinson's disease: 2001 to 2004,” Movement Disorders, vol. 20, no. 5, pp. 523–539, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  159. E. Grünblatt, S. Mandel, T. Berkuzki, and M. B. H. Youdim, “Apomorphine protects against MPTP-induced neurotoxicity in mice,” Movement Disorders, vol. 14, no. 4, pp. 612–618, 1999. View at Publisher · View at Google Scholar · View at Scopus
  160. G. Battaglia, C. L. Busceti, L. Cuomo et al., “Continuous subcutaneous infusion of apomorphine rescues nigro-striatal dopaminergic terminals following MPTP injection in mice,” Neuropharmacology, vol. 42, no. 3, pp. 367–373, 2002. View at Publisher · View at Google Scholar · View at Scopus
  161. H. Yuan, S. Sarre, G. Ebinger, and Y. Michotte, “Neuroprotective and neurotrophic effect of apomorphine in the striatal 6-OHDA-lesion rat model of Parkinson's disease,” Brain Research, vol. 1026, no. 1, pp. 95–107, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  162. M. Gassen, Y. Glinka, B. Pinchasi, and M. B. H. Youdim, “Apomorphine is a highly potent free radical scavenger in rat brain mitochondrial fraction,” European Journal of Pharmacology, vol. 308, no. 2, pp. 219–225, 1996. View at Publisher · View at Google Scholar · View at Scopus
  163. E. E. Sam and N. Verbeke, “Free radical scavenging properties of apomorphine enanantiomers and dopamine: possible implication in their mechanism of action in parkinsonism,” Journal of Neural Transmission—Parkinson's Disease and Dementia Section, vol. 10, no. 2-3, pp. 115–127, 1995. View at Publisher · View at Google Scholar
  164. A. Ubeda, C. Montesinos, M. Paya, and M. J. Alcaraz, “Iron-reducing and free-radical-scavenging properties of apomorphine and some related benzylisoquinolines,” Free Radical Biology and Medicine, vol. 15, no. 2, pp. 159–167, 1993. View at Publisher · View at Google Scholar · View at Scopus
  165. M. B. H. Youdim, E. Grünblatt, and S. Mandel, “The pivotal role of iron in NF-κB activation and nigrostriatal dopaminergic neurodegeneration. Prospects for neuroprotection in Parkinson's disease with iron chelators,” Annals of the New York Academy of Sciences, vol. 890, pp. 7–25, 1999. View at Scopus
  166. M. Roceri, R. Molteni, F. Fumagalli et al., “Stimulatory role of dopamine on fibroblast growth factor-2 expression in rat striatum,” Journal of Neurochemistry, vol. 76, no. 4, pp. 990–997, 2001. View at Publisher · View at Google Scholar · View at Scopus
  167. A. M. Pritchett, J. F. Morrison, W. D. Edwards, H. V. Schaff, H. M. Connolly, and R. E. Espinosa, “Valvular heart disease in patients taking pergolide,” Mayo Clinic Proceedings, vol. 77, no. 12, pp. 1280–1286, 2002. View at Scopus
  168. J. Serratrice, P. Disdier, G. Habib, F. Viallet, and P. J. Weiller, “Fibrotic valvular heart disease subsequent to bromocriptine treatment,” Cardiology in Review, vol. 10, no. 6, pp. 334–336, 2002. View at Scopus
  169. J. Horvath, R. D. Fross, G. Kleiner-Fisman et al., “Severe multivalvular heart disease: a new complication of the ergot derivative dopamine agonists,” Movement Disorders, vol. 19, no. 6, pp. 656–662, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  170. M. Yamamoto, T. Uesugi, and T. Nakayama, “Dopamine agonists and cardiac valvulopathy in Parkinson disease: a case-control study,” Neurology, vol. 67, no. 7, pp. 1225–1229, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  171. J. Y. Kim, E. J. Chung, S. W. Park, and W. Y. Lee, “Valvular heart disease in Parkinson's disease treated with ergot derivative dopamine agonists,” Movement Disorders, vol. 21, no. 8, pp. 1261–1264, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  172. C. Peralta, E. Wolf, H. Alber et al., “Valvular heart disease in Parkinson's disease vs. controls: an echocardiographic study,” Movement Disorders, vol. 21, no. 8, pp. 1109–1113, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  173. S. Junghanns, J. T. Fuhrmann, G. Simonis et al., “Valvular heart disease in Parkinson's disease patients treated with dopamine agonists: a reader-blinded monocenter echocardiography study,” Movement Disorders, vol. 22, no. 2, pp. 234–238, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  174. R. Schade, F. Andersohn, S. Suissa, W. Haverkamp, and E. Garbe, “Dopamine agonists and the risk of cardiac-valve regurgitation,” The New England Journal of Medicine, vol. 356, no. 1, pp. 29–38, 2007. View at Scopus
  175. G. Van Camp, A. Flamez, B. Cosyns et al., “Treatment of Parkinson's disease with pergolide and relation to restrictive valvular heart disease,” The Lancet, vol. 363, no. 9416, pp. 1179–1183, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  176. A. Pinero, P. Marcos-Alberca, and J. Fortes, “Cabergoline-related severe restrictive mitral regurgitation,” The New England Journal of Medicine, vol. 353, no. 18, pp. 1976–1977, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  177. G. M. Nemecek, S. R. Coughlin, D. A. Handley, and M. A. Moskowitz, “Stimulation of aortic smooth muscle cell mitogenesis by serotonin,” Proceedings of the National Academy of Sciences of the United States of America, vol. 83, no. 3, pp. 674–678, 1986. View at Scopus
  178. K. Seuwen, I. Magnaldo, and J. Pouyssegur, “Serotonin stimulates DNA synthesis in fibroblasts acting through 5-HT1B receptors coupled to a Gi-protein,” Nature, vol. 335, no. 6187, pp. 254–256, 1988. View at Scopus
  179. B. Jian, J. Xu, J. Connolly et al., “Serotonin mechanisms in heart valve disease I: serotonin-induced up-regulation of transforming growth factor-β1 via G-protein signal transduction in aortic valve interstitial cells,” American Journal of Pathology, vol. 161, no. 6, pp. 2111–2121, 2002. View at Scopus
  180. A. Newman-Tancredi, D. Cussac, Y. Quentric et al., “Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. III. Agonist and antagonist properties at serotonin, 5-HT1 and 5-H2, receptor subtypes,” Journal of Pharmacology and Experimental Therapeutics, vol. 303, no. 2, pp. 815–822, 2002. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  181. A. Mekontso-Dessap, F. Brouri, O. Pascal et al., “Deficiency of the 5-hydroxytryptamine transporter gene leads to cardiac fibrosis and valvulopathy in mice,” Circulation, vol. 113, no. 1, pp. 81–89, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  182. C. S. Elangbam, L. E. Job, L. M. Zadrozny et al., “5-hydroxytryptamine (5HT)-induced valvulopathy: compositional valvular alterations are associated with 5HT2B receptor and 5HT transporter transcript changes in Sprague-Dawley rats,” Experimental and Toxicologic Pathology, vol. 60, no. 4-5, pp. 253–262, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  183. S. S. O'Sullivan, A. H. Evans, and A. J. Lees, “Punding in Parkinson's disease,” Practical Neurology, vol. 7, no. 6, pp. 397–399, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  184. L. Silveira-Moriyama, A. H. Evans, R. Katzenschlager, and A. J. Lees, “Punding and dyskinesias,” Movement Disorders, vol. 21, no. 12, pp. 2214–2217, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  185. V. Voon, K. Hassan, M. Zurowski et al., “Prospective prevalence of pathologic gambling and medication association in Parkinson disease,” Neurology, vol. 66, no. 11, pp. 1750–1752, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  186. V. Voon, T. Thomsen, J. M. Miyasaki et al., “Factors associated with dopaminergic drug-related pathological gambling in Parkinson disease,” Archives of Neurology, vol. 64, no. 2, pp. 212–216, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  187. K. J. Klos, J. H. Bower, K. A. Josephs, J. Y. Matsumoto, and J. E. Ahlskog, “Pathological hypersexuality predominantly linked to adjuvant dopamine agonist therapy in Parkinson's disease and multiple system atrophy,” Parkinsonism and Related Disorders, vol. 11, no. 6, pp. 381–386, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  188. V. Voon, K. Hassan, M. Zurowski et al., “Prevalence of repetitive and reward-seeking behaviors in Parkinson disease,” Neurology, vol. 67, no. 7, pp. 1254–1257, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  189. L. M. Romito, M. Raja, A. Daniele et al., “Transient mania with hypersexuality after surgery for high-frequency stimulation of the subthalamic nucleus in Parkinson's disease,” Movement Disorders, vol. 17, no. 6, pp. 1371–1374, 2002. View at Publisher · View at Google Scholar · View at PubMed
  190. H. J. Groenewegen, H. W. Berendse, J. G. Wolters, and A. H. M. Lohman, “The anatomical relationship of the prefrontal cortex with the striatopallidal system, the thalamus and the amygdala: evidence for a parallel organization,” Progress in Brain Research, vol. 85, pp. 95–118, 1990.
  191. S. N. Haber, J. L. Fudge, and N. R. McFarland, “Striatonigrostriatal pathways in primates form an ascending spiral from the shell to the dorsolateral striatum,” Journal of Neuroscience, vol. 20, no. 6, pp. 2369–2382, 2000. View at Scopus