| Corticotropin-releasing
factor | CRF is a 41-amino-acid neuropeptide that binds the G-protein-coupled receptors CRF1 and CRF2. The association between CRF/CRF1 system and stress-related disorders is well known [23, 37–39]. CRF is mainly implicated in the regulation of the HPA axis, the abnormalities (increased cerebral spinal fluid CRF, hyperreactivity of the HPA axis, basal hypercortisolemia, increased release of adrenocorticotropin hormone (ACTH) by CRF in subjects treated with dexamethasone, and reduced corticosteroid receptor mediated feedback inhibition of the HPA axis) of which have been frequently associated with psychiatric conditions [40]. It has been demonstrated that antidepressant treatment may restore HPA-axis abnormalities [41], particularly in the paraventricular nucleus of the hypothalamus [42], enhancing the corticosteroid receptor (CR) hypothesis based on the impaired CR function in the pathophysiology of major depression [43]. The hyperactivity and dysregulation of CRF system may trigger and/or involve the maintenance of these alterations as chronic stress or depression have been associated with increased limbic levels of CRF [44–46]. The hyperactivity of CRF system has been associated with reduced hypophyseal CRF binding in depressed patients [47] and reduced corticosteroid feedback inhibition [48]. Moreover, CRF is also implicated in emotional regulation, learning and memory, and autonomic and monoaminergic modulation which are involved in the pathogenesis of major depression [37, 49]. Relevantly, CRF antagonism modulates alterations in many other neuropeptides and hormones systems [30]. Overall, there is a large body of evidence suggesting the involvement of CRF in the pathophysiology of major affective disorders [50–53] but not all studies replicated these findings [54]. |
| Arginine
vasopressin | AVP is a nine-amino-acid neuropeptide released by the magnocellular terminals into the posterior pituitary mediating the resorption of water in the kidney. AVP interacts with CRF in the parvocellular neurons with the final aim to modulate HPA-axis activity. AVP transmission is also involved in different functions such as learning and memory, aggression, and sociality [55]. AVP binds V1a, V1b, and V3 G protein-coupled receptors which are associated with vasoconstriction, ACTH release, and antidiuresis. Parvocellular AVP and CRF are known to regulate the HPA axis.
Several findings including those derived by postmortem analyses suggested that AVP was increased in either the brain or plasma of depressed patients [56, 57]. Stressful stimuli lead to persistent increase of AVP in CRF neurons without inducing CRF changes [58]. ACTH release and responsiveness induced by CRF effects are enhanced by AVP [59]. Dinan and Scott [60] suggested that prolonged AVP transmission is a critical mechanism in determining HPA axis hyperactivity in depressed patients. There is evidence that genetic variation of AVP as well as its genetic inactivation in animals [61, 62] was related to childhood-onset mood disorders and anxiety-related behaviors. Furthermore, AVP antagonists have demonstrated efficacy in anxious and depressive human conditions showing anxiolytic and antidepressant properties [63, 64]. Overall, there are consistent evidence suggesting an active involvement of AVP in the pathogenesis of major affective disorders and recently several AVP antagonists showed promising results as possible antidepressant and anxiolytic medications [65]. |
| | Oxytocin | Oxytocin is a nonapeptide binding to a single G-protein coupled receptor and mainly implicated in behaviors such as childbirth, lactation and sexual behaviors, social memory, and cognition. Oxytocin is synthesized in the paraventricular and supraoptic nuclei of the hypothalamus, transported to the posterior pituitary and released to amygdala, hypothalamus, hippocampus, and nucleus accumbens. According to animal studies, the infusion of oxytocin stimulates maternal behavior and the administration of antagonists inhibits this behavior [66]. Social memory has been demonstrated to be influenced by the oxytocin system in laboratory animals and humans. Oxytocin antagonist may inhibit social recognition in rats that was enhanced by the infusion of an oxytocin agonist into the lateral ventricles [67]. Findings from animal studies suggested that oxytocin represents a critical modulating neuropeptide in the regulation of social interaction. Recently, it has been demonstrated that recognition memory for faces but not nonsocial stimuli has been enhanced in humans by intranasal administration of oxytocin [68]. Furthermore, oxytocin both in rodents [69] and human subjects [70] may influence the stress response modulating the HPA axis and reducing the release of stress hormone. The anxiolytic activity of oxytocin and oxytocin agonists that may be inhibited by oxytocin antagonists has been also reported in several preclinical tests [71, 72]. Intranasal oxytocin has been suggested to reduce the activation of the amygdala in response to fearful or threatening scenes in human individuals [73]. Reduced plasma levels of oxytocin have been found in patients with MDD [74] and in the cerebrospinal fluid (CSF) of schizophrenic patients [75]. Oxytocin agonists have also been reported to be effective in preclinical tests of antidepressant activity such as the tail suspension test [72]. However, CSF oxytocin has also been suggested as an important modulator of suicidal intent and interpersonal violence. Jokinen et al. [76] found that 28 medication-free suicide attempters had lower CSF oxytocin levels compared to 19 healthy controls. Among the suicide attempters, CSF oxytocin levels correlated significantly and negatively with the planning subscale of the Beck Suicide Intent Scale (SIS). After regression analyses, suicide intent was a significant predictor of CSF oxytocin corrected for age and gender whereas lifetime violent behaviour showed a trend to be a predictor of CSF oxytocin. Moreover, oxytocin agonists have been reported to restore prepulse inhibition that is disrupted by N-methyl-D-aspartate (NMDA) antagonists or dopamine agonists in rats [72, 77]. Intranasal administration of oxytocin was also reported to be useful as an adjunctive treatment in patients with schizophrenia who were treated with antipsychotic medications [78]. Finally, reduced oxytocin plasma levels have been demonstrated in autistic children [79] and several single nucleotide polymorphisms in the oxytocin system have been associated with autism [80]. Speech comprehension and social recognition [81] as well as repetitive behaviors [82] may be improved in autistic patients with administration of oxytocin. |
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