By analyzing the functional role of adenosine receptor heteromers, we review a series of new concepts that should modify our classical views of neurotransmission in the central nervous system (CNS). Neurotransmitter receptors cannot be considered as single functional units anymore. Heteromerization of neurotransmitter receptors confers functional entities that possess different biochemical characteristics with respect to the individual components of the heteromer. Some of these characteristics can be used as a “biochemical fingerprint” to identify neurotransmitter receptor heteromers in the CNS. This is exemplified by changes in binding characteristics that are dependent on coactivation of the receptor units of different adenosine receptor heteromers. Neurotransmitter receptor heteromers can act as “processors” of computations that modulate cell signaling, sometimes critically involved in the control of pre- and postsynaptic neurotransmission. For instance, the adenosine A1-A2A receptor heteromer acts as a concentration-dependent switch that controls striatal glutamatergic neurotransmission. Neurotransmitter receptor heteromers play a particularly important integrative role in the “local module” (the minimal portion of one or more neurons and/or one or more glial cells that operates as an independent integrative unit), where they act as processors mediating computations that convey information from diverse volume-transmitted signals. For instance, the adenosine A2A-dopamine D2 receptor heteromers work as integrators of two different neurotransmitters in the striatal spine module.

Sergi Ferré

Francisco Ciruela

César Quiroz

Rafael Luján

Patrizia Popoli

Rodrigo A. Cunha

Luigi F. Agnati

Kjell Fuxe

Amina S. Woods

Carme Lluis

Rafael Franco

Adenosine Receptor Heteromers and their Integrative Role in Striatal Function

This review will introduce the concept of toll-like receptor (TLR)–mediated glial activation as central to all of the following: neuropathic pain, compromised acute opioid analgesia, and unwanted opioid side effects (tolerance, dependence, and reward). Attenuation of glial activation has previously been demonstrated both to alleviate exaggerated pain states induced by experimental pain models and to reduce the development of opioid tolerance. Here we demonstrate that selective acute antagonism of TLR4 results in reversal of neuropathic pain as well as potentiation of opioid analgesia. Attenuating central nervous system glial activation was also found to reduce the development of opioid dependence, and opioid reward at a behavioral (conditioned place preference) and neurochemical (nucleus accumbens microdialysis of morphine-induced elevations in dopamine) level of analysis. Moreover, a novel antagonism of TLR4 by (+)- and (˗)-isomer opioid antagonists has now been characterized, and both antiallodynic and morphine analgesia potentiating activity shown. Opioid agonists were found to also possess TLR4 agonistic activity, predictive of glial activation. Targeting glial activation is a novel and as yet clinically unexploited method for treatment of neuropathic pain. Moreover, these data indicate that attenuation of glial activation, by general or selective TLR antagonistic mechanisms, may also be a clinical method for separating the beneficial (analgesia) and unwanted (tolerance, dependence, and reward) actions of opioids, thereby improving the safety and efficacy of their use.

Mark R. Hutchinson

Sondra T. Bland

Kirk W. Johnson

Kenner C. Rice

Steven F. Maier

Linda R. Watkins

Opioid-Induced Glial Activation: Mechanisms of Activation and Implications for Opioid Analgesia, Dependence, and Reward

Until recently, heptahelical G-protein-coupled receptors (GPCRs) were considered to be expressed as monomers on the cell surface of neuronal and non-neuronal cells. It is now becoming evident that this view must be overtly changed since these receptors can form homodimers, heterodimers, and higher-order oligomers on the plasma membrane. Here we discuss some of the basics and some new concepts of receptor homo- and heteromerization. Dimers-oligomers modify pharmacology, trafficking, and signaling of receptors. First of all, GPCR dimers must be considered as the main molecules that are targeted by neurotransmitters or by drugs. Thus, binding data must be fitted to dimer-based models. In these models, it is considered that the conformational changes transmitted within the dimer molecule lead to cooperativity. Cooperativity must be taken into account in the binding of agonists-antagonists-drugs and also in the binding of the so-called allosteric modulators. Cooperativity results from the intramolecular cross-talk in the homodimer. As an intramolecular cross-talk in the heterodimer, the binding of one neurotransmitter to one receptor often affects the binding of the second neurotransmitter to the partner receptor. Coactivation of the two receptors in a heterodimer can change completely the signaling pathway triggered by the neurotransmitter as well as the trafficking of the receptors. Heterodimer-specific drugs or dual drugs able to activate the two receptors in the heterodimer simultaneously emerge as novel and promising drugs for a variety of central nervous system (CNS) therapeutic applications.

Vicent Casadó

Antoni Cortés

Carla Ferrada

Josefa Mallol

Amina Woods

Enric I. Canela

Basic Concepts in G-Protein-Coupled Receptor Homo- and Heterodimerization

Circadian rhythms prepare organisms for predictable events during the Earth's 24-h day.  These rhythms are entrained by a variety of stimuli.  Light is the most ubiquitous and best known zeitgeber, but a number of others have been identified, including food, social cues, locomotor activity, and, most recently drugs of abuse.  Given the diversity of zeitgebers, it is probably not surprising that genes capable of clock functions are located throughout almost all organs and tissues.  Recent evidence suggests that drugs of abuse can directly entrain some circadian rhythms.  We have report here that entrainment by drugs of abuse is independent of the suprachiasmatic nucleus and the light/dark cycle, is not dependent on direct locomotor stimulation, and is shared by a variety of classes of drugs of abuse.  We suggest that drug-entrained rhythms reflect variations in underlying neurophysiological states.  This could be the basis for known daily variations in drug metabolism, tolerance, and sensitivity to drug reward.  These rhythms could also take the form of daily periods of increased motivation to seek and take drugs, and thus contribute to abuse, addiction and relapse.

Ann E. K. Kosobud

Andrea G. Gillman

Joseph K. Leffel

Norman C. Pecoraro

G. V. Rebec

William Timberlake

Drugs of Abuse Can Entrain Circadian Rhythms

Diane M. P. Lawrence

David A. Thomas

Da-Yu Wu

Glial Cells and the Neurobiology of Addiction

Numerous reports have documented a high occurrence of sleep difficulties in drug-dependent populations, prompting researchers to characterize sleep profiles and physiology in drug abusing populations. This mini-review examines studies indicating that drug-dependent populations exhibit alterations in sleep homeostatic and restoration processes in response to sleep deprivation. Sleep deprivation is a principal sleep research tool that results in marked physiological challenge, which provides a means to examine sleep homeostatic processes in response to extended wakefulness. A report from our laboratory demonstrated that following recovery sleep from sleep deprivation, brain high-energy phosphates particularly beta–nucleoside triphosphate (beta-NTP) are markedly increased as measured with phosphorus magnetic resonance spectroscopy (MRS). A more recent study examined the effects of sleep deprivation in opiate-dependent methadone-maintained (MM) subjects. The study demonstrated increases in brain beta-NTP following recovery sleep. Interestingly, these increases were of a markedly greater magnitude in MM subjects compared to control subjects. A similar study examined sleep deprivation in cocaine-dependent subjects demonstrating that cocaine-dependent subjects exhibit greater increases in brain beta-NTP following recovery sleep when compared to control subjects. The studies suggest that sleep deprivation in both MM subjects and cocaine-dependent subjects is characterized by greater changes in brain ATP levels than control subjects. Greater enhancements in brain ATP following recovery sleep may reflect a greater disruption to or impact of sleep deprivation in drug dependent subjects, whereby sleep restoration processes may be unable to properly regulate brain ATP and maintain brain high-energy equilibrium. These studies support the notion of a greater susceptibility to sleep loss in drug dependent populations. Additional sleep studies in drug abusing populations are needed, particularly those that examine potential differential effects of sleep deprivation.

George H. Trksak

J. Eric Jensen

Perry F. Renshaw

Scott E. Lukas

Brain Phosphorus Magnetic Resonance Spectroscopy Imaging of Sleep Homeostasis and Restoration in Drug Dependence

Contemporary biology has been revolutionized by a recently discovered class of small regulatory RNA molecules, microRNAs (miRNAs). Missed by researchers for decades due to their tiny size, usually mapping to non-protein-coding regions of genomes, miRNAs and miRNA-mediated regulatory networks have been the “dark matter” of molecular biology. Deciphering miRNA pathways and functions in the CNS of complex organisms is tightly linked to understanding miRNA expression patterns. To facilitate these emerging studies, I here review the basic principles of medium- and high-throughput technologies available for miRNA expression profiling.

Anna M. Krichevsky

MicroRNA Profiling: From Dark Matter to White Matter, or Identifying New Players in Neurobiology

Drug addiction is a devastating disease that affects millions of individuals worldwide. Through better understanding of the genetic variations that create a vulnerability for addiction and the molecular mechanisms that underlie the progression of addiction, better treatment options can be created for those that suffer from this condition. Recent studies point to a link between abnormal or disrupted circadian rhythms and the development of addiction. In addition, studies suggest a role for specific genes that make up the molecular clock in the regulation of drug sensitivity, sensitization, and reward. The influence of circadian genes and rhythms on drug-induced behaviors may be mediated through the mesolimbic dopaminergic system. This system has long been implicated in the development of addiction, and recent evidence supports a regulatory role for the brain's central pacemaker and circadian gene expression in the regulation of dopaminergic transmission. This review highlights the association between circadian genes and drug addiction, and the possible role of the mesolimbic dopaminergic system in this association.

Colleen A. McClung

Circadian Rhythms, the Mesolimbic Dopaminergic Circuit, and Drug Addiction

The ability of G protein coupled receptors to heterooligomerize and create novel signaling complexes has demonstrated the tremendous potential of these receptors to access diverse signaling cascades, as well as to modulate the nature of the transduced signal. In the dopamine receptor field, the existence of a D1-like receptor in brain that activated phospatidylinositol turnover has been shown, but definition of the molecular entity remained elusive. We discovered that the D1 and D2 receptors form a heterooligomer, which on activation of both receptors, coupled to Gq to activate phospholipase C and generate intracellular calcium release. The activation of Gq by the D1-D2 heterooligomer has been shown to occur in cells expressing both receptors, as well as in striatum, distinct from Gs/olf or Gi/o activation by the D1 and D2 receptor homooligomers, respectively. The activation of the D1-D2 receptor heterooligomer in brain led to a calcium signal–mediated increase in phosphorylation of calmodulin kinase lla. The calcium signal rapidly desensitized and the receptors cointernalized after occupancy of either the D1 or D2 binding pocket. Thus, the D1-D2 heterooligomer directly links the action of dopamine to rapid calcium signaling and likely has important effects on dopamine-mediated synaptic plasticity and its functional correlates in brain.

Susan R. George

Brian F. O'Dowd

A Novel Dopamine Receptor Signaling Unit in Brain: Heterooligomers of D1 And D2 Dopamine Receptors

Dendritic spines are morphologically specialized structures that receive the vast majority of central excitatory synaptic inputs. Studies have implicated changes in the size, shape, and number of dendritic spines in activity-dependent plasticity, and have further demonstrated that spine morphology is highly dependent on the dynamic organizational and scaffolding properties of its postsynaptic density (PSD). In vitro and in vivo models of experience-dependent plasticity have linked changes in the localization of glutamate receptors at the PSD with a molecular reorganization of the PSD and alterations in spine morphology. Chronic ethanol consumption results in adaptive changes in neuronal function that manifest as tolerance, physical dependence, and addiction. A potential mechanism supporting these adaptive changes that we recently identified is the homeostatic targeting of NR2B-containing NMDA receptors to the synapse. This increase is associated with and dependent on a corresponding increase in the localization of the scaffolding protein PSD-95 at the PSD, and with an actin-dependent increase in the size of dendritic spines. These observations led us to propose a molecular model for ethanol-induced plasticity at excitatory synapses in which increases in NR2B-containing NMDA receptors and PSD-95 at the PSD provide an expanded scaffolding platform for the recruitment and activation of signaling molecules that regulate spine actin dynamics, protein translation, and synaptic plasticity. This model is consistent with accumulating evidence that glutamatergic modulation of spine actin by the PSD plays a role in the aberrant plasticity of addiction.

Patrick J. Mulholland

L. Judson Chandler

The Thorny Side of Addiction: Adaptive Plasticity and Dendritic Spines

About this journal

The Scientific World Journal publishes original research and review articles&nbsp;covering a wide range of subjects in science, technology, and medicine.

Journal profile

Meet the editorial board

The Scientific World Journal maintains an Editorial Board of practicing researchers from around the world, to ensure manuscripts are handled by editors who are experts in the field of study.

Editor spotlight

Submit your proposal

Do you think there is an emerging area of research that really needs to be highlighted? Or an existing research area that has been overlooked or would benefit from deeper investigation? Raise the profile of a research area by leading a Special Issue.

Special Issues

Author guidelines

Editorial board

Databases and indexing

title

The Scientific World Journal publishes original research and review articles covering a wide range of subjects in science, technology, and medicine.

description

https://images.hindawi.com/journals/tswj/tswj.banner.jpg

twitter:card

twitter:description

twitter:site

twitter:title

twitter:url

twitter:image

The Scientific World Journal | Hindawi

The Scientific World Journal

This Issue is now open for submissions.
Papers are published upon acceptance, regardless of the Special Issue publication date.