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      Glutamatergic transmission in drug reward: implications for drug addiction

      review-article
      Frontiers in Neuroscience
      Frontiers Media S.A.
      cocaine, nicotine, alcohol, heroin, reward, nucleus accumbens, prefrontal cortex, microdialysis

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          Abstract

          Individuals addicted to drugs of abuse such as alcohol, nicotine, cocaine, and heroin are a significant burden on healthcare systems all over the world. The positive reinforcing (rewarding) effects of the above mentioned drugs play a major role in the initiation and maintenance of the drug-taking habit. Thus, understanding the neurochemical mechanisms underlying the reinforcing effects of drugs of abuse is critical to reducing the burden of drug addiction in society. Over the last two decades, there has been an increasing focus on the role of the excitatory neurotransmitter glutamate in drug addiction. In this review, pharmacological and genetic evidence supporting the role of glutamate in mediating the rewarding effects of the above described drugs of abuse will be discussed. Further, the review will discuss the role of glutamate transmission in two complex heterogeneous brain regions, namely the nucleus accumbens (NAcc) and the ventral tegmental area (VTA), which mediate the rewarding effects of drugs of abuse. In addition, several medications approved by the Food and Drug Administration that act by blocking glutamate transmission will be discussed in the context of drug reward. Finally, this review will discuss future studies needed to address currently unanswered gaps in knowledge, which will further elucidate the role of glutamate in the rewarding effects of drugs of abuse.

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          Most cited references293

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          Metabotropic glutamate receptors: physiology, pharmacology, and disease.

          The metabotropic glutamate receptors (mGluRs) are family C G-protein-coupled receptors that participate in the modulation of synaptic transmission and neuronal excitability throughout the central nervous system. The mGluRs bind glutamate within a large extracellular domain and transmit signals through the receptor protein to intracellular signaling partners. A great deal of progress has been made in determining the mechanisms by which mGluRs are activated, proteins with which they interact, and orthosteric and allosteric ligands that can modulate receptor activity. The widespread expression of mGluRs makes these receptors particularly attractive drug targets, and recent studies continue to validate the therapeutic utility of mGluR ligands in neurological and psychiatric disorders such as Alzheimer's disease, Parkinson's disease, anxiety, depression, and schizophrenia.
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            Glutamate neurotoxicity and diseases of the nervous system.

            D Choi (1988)
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              Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats.

              The effect of various drugs on the extracellular concentration of dopamine in two terminal dopaminergic areas, the nucleus accumbens septi (a limbic area) and the dorsal caudate nucleus (a subcortical motor area), was studied in freely moving rats by using brain dialysis. Drugs abused by humans (e.g., opiates, ethanol, nicotine, amphetamine, and cocaine) increased extracellular dopamine concentrations in both areas, but especially in the accumbens, and elicited hypermotility at low doses. On the other hand, drugs with aversive properties (e.g., agonists of kappa opioid receptors, U-50,488, tifluadom, and bremazocine) reduced dopamine release in the accumbens and in the caudate and elicited hypomotility. Haloperidol, a neuroleptic drug, increased extracellular dopamine concentrations, but this effect was not preferential for the accumbens and was associated with hypomotility and sedation. Drugs not abused by humans [e.g., imipramine (an antidepressant), atropine (an antimuscarinic drug), and diphenhydramine (an antihistamine)] failed to modify synaptic dopamine concentrations. These results provide biochemical evidence for the hypothesis that stimulation of dopamine transmission in the limbic system might be a fundamental property of drugs that are abused.
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                Author and article information

                Contributors
                Journal
                Front Neurosci
                Front Neurosci
                Front. Neurosci.
                Frontiers in Neuroscience
                Frontiers Media S.A.
                1662-4548
                1662-453X
                05 November 2015
                2015
                : 9
                : 404
                Affiliations
                Pharmaceutical and Biomedical Sciences, Raabe College of Pharmacy, Ohio Northern University Ada, OH, USA
                Author notes

                Edited by: Styliani Vlachou, Dublin City University, Ireland

                Reviewed by: Karen K. Szumlinski, University of California, Santa Barbara, USA; Eugene A. Kiyatkin, National Institute on Drug Abuse, USA

                *Correspondence: Manoranjan S. D'Souza m-dsouza@ 123456onu.edu

                This article was submitted to Neuropharmacology, a section of the journal Frontiers in Neuroscience

                Article
                10.3389/fnins.2015.00404
                4633516
                26594139
                56e57f64-c6af-405a-97f1-1420da03fb1f
                Copyright © 2015 D'Souza.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 31 July 2015
                : 12 October 2015
                Page count
                Figures: 0, Tables: 4, Equations: 0, References: 313, Pages: 27, Words: 22390
                Funding
                Funded by: Raabe College of Pharmacy
                Categories
                Pharmacology
                Review

                Neurosciences
                cocaine,nicotine,alcohol,heroin,reward,nucleus accumbens,prefrontal cortex,microdialysis
                Neurosciences
                cocaine, nicotine, alcohol, heroin, reward, nucleus accumbens, prefrontal cortex, microdialysis

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