Article

Glutamate and reinstatement.

Department of Neurosciences, Medical University of South Carolina, Charleston, SC, United States. <>
Current Opinion in Pharmacology (Impact Factor: 4.23). 02/2009; 9(1):59-64. DOI: 10.1016/j.coph.2008.12.003
Source: PubMed

ABSTRACT The importance of glutamate in the reinstatement of cocaine-seeking behavior has been established. New molecular and neurochemical adaptations in the glutamatergic system which drive cocaine relapse have been identified, such as the ability of CB1 receptor stimulation to reduce basal glutamate levels and the involvement of the GluR1 receptor subunit in reinstatement. Furthermore, it is apparent that similar glutamatergic neuroadaptations arise after self-administration of cocaine, heroin, nicotine, and alcohol. For example, reinstatement to cocaine, nicotine, and alcohol can be prevented both by the stimulation of group II mGluR receptors and by the blockade of group I mGluR receptors. The similarities in the neurochemistry behind relapse to these varied drug classes indicate that drugs that target the glutamate system could be effective at treating relapse to multiple types of drugs.

0 Followers
 · 
75 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Alcohol and other drugs of abuse, including psychostimulants and opioids, can induce epigenetic changes: a contributing factor for drug addiction, tolerance, and associated withdrawal symptoms. DNA methylation is a major epigenetic mechanism and it is one of more than 200 methylation reactions supported by methyl donor S-adenosylmethionine (SAM). Levels of SAM are controlled by cellular redox status via the folate and vitamin B12-dependent enzyme methionine synthase (MS). For example, under oxidative conditions MS is inhibited, diverting its substrate homocysteine (HCY) to the trans sulfuration pathway. Alcohol, dopamine, and morphine, can alter intracellular levels of glutathione (GSH)-based cellular redox status, subsequently affecting SAM levels and DNA methylation status. Here, existing evidence is presented in a coherent manner to propose a novel hypothesis implicating the involvement of redox-based epigenetic changes in drug addiction. Further, we discuss how a "gene priming" phenomenon can contribute to the maintenance of redox and methylation status homeostasis under various stimuli including drugs of abuse. Additionally, a new mechanistic rationale for the use of metabolic interventions/redox-replenishers as symptomatic treatment of alcohol and other drug addiction and associated withdrawal symptoms is also provided. Hence, the current review article strengthens the hypothesis that neuronal metabolism has a critical bidirectional coupling with epigenetic changes in drug addiction exemplified by the link between redox-based metabolic changes and resultant epigenetic consequences under the effect of drugs of abuse.
    Frontiers in Neuroscience 01/2014; 8:444. DOI:10.3389/fnins.2014.00444
  • Source
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Alcohol consumption and the reinstatement of alcohol-seeking rely on glutamate and GABA transmission. Modulating these neurotransmitters may be a viable treatment strategy to prevent alcohol relapse. N-acetylcysteine (NAC) and the antibiotic ceftriaxone (CEF) alter the glial reuptake and release of glutamate while the antibiotic cefazolin (CEFAZ) modulates GABA signaling without affecting glutamate. Here, we used the extinction-reinstatement model of relapse to test the ability of these compounds to attenuate the reinstatement of alcohol-seeking. Male Sprague-Dawley rats were trained to self-administer 20% (v/v) alcohol in the home cage using an intermittent schedule (24 h on, 24 h off) for 12 sessions. Subsequently, animals self-administered alcohol during daily 45-min operant sessions for 26 sessions, followed by extinction training. We tested whether chronic administration of NAC, CEF, or CEFAZ attenuated the cue-primed reinstatement of alcohol-seeking. CEF and CEFAZ attenuated cue-primed reinstatement of alcohol-seeking while NAC had no effect. We subsequently investigated whether CEF and CEFAZ alter the self-administration of sucrose and chow pellets and if CEFAZ attenuates the reinstatement of cocaine-seeking. The operant self-administration of regular chow and sucrose was not altered by either CEF or CEFAZ. CEFAZ had no effect on cocaine reinstatement, a behavior that has been strongly tied to altered glutamate homeostasis in the nucleus accumbens. Thus the ability of CEFAZ to attenuate alcohol reinstatement likely does not involve the glial modulation of glutamate levels. The dampening of GABA transmission may be a common mechanism of action of cefazolin and ceftriaxone.
    Frontiers in Pharmacology 01/2015; 6:44. DOI:10.3389/fphar.2015.00044

Preview

Download
4 Downloads
Available from