Glutamate and reinstatement

Department of Neurosciences, Medical University of South Carolina, Charleston, SC, United States. <>
Current Opinion in Pharmacology (Impact Factor: 4.6). 02/2009; 9(1):59-64. DOI: 10.1016/j.coph.2008.12.003
Source: PubMed


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.

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    • "Reinstatement of responding for drug can be elicited by stress, low priming doses of drug, and by the presentation of drug-associated cues (Bossert et al., 2005, Capriles et al., 2003, De Wit & Stewart, 1981, De Wit & Stewart, 1983, Fuchs et al., 2004, Fuchs et al., 2008, Fuchs et al., 1998, Knackstedt & Kalivas, 2009, Marchant et al., 2013b, Shalev et al., 2002, Torregrossa & Kalivas, 2008, Zhou & Kalivas, 2008). In the extinction-reinstatement paradigm (Rocha & Kalivas, 2010), animals experience a series of extinction sessions following a short period of drug self-administration; this results in a progressive decline in responding. "
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    ABSTRACT: Drug addiction is widely recognised to afflict some but not all individuals by virtue of underlying risk markers and traits involving multifaceted interactions between polygenic and external factors. Remarkably, only a small proportion of individuals exposed to licit and illicit drugs develop compulsive drug seeking behavior, maintained in the face of adverse consequences, and associated detrimental patterns of drug intake involving extended and repeated bouts of binge intoxication, withdrawal, and relapse. As a consequence research has increasingly endeavoured to identify distinctive neurobehavioral mechanisms and endophenotypes that predispose individuals to compulsive drug use. However, research in active drug users is hampered by the difficulty in categorising putatively causal behavioral traits prior to the initiation of drug use. By contrast, research in experimental animals is often hindered by the validity of approaches used to investigate the neural and psychological mechanisms of compulsive drug-seeking habits in humans. Herein, we survey and discuss the principal findings emanating from preclinical animal research on addiction and highlight how specific behavioral endophenotypes of presumed genetic origin (e.g. trait anxiety, novelty preference and impulsivity) differentially contribute to compulsive forms of drug seeking and taking and, in particular, how these differentiate between different classes of stimulant and non-stimulant drugs of abuse.
    Genes Brain and Behavior 10/2015; DOI:10.1111/gbb.12265 · 3.66 Impact Factor
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    • "respond) for drugs and is a measure of their reinforcing efficacy (Markou et al., 1993; Richardson and Roberts, 1996); consistently, WSE also reduced performance on this measure of ethanol self-administration. In addition, WSE also decreased the deprivation effect and the reinstatement of ethanol-seeking behaviours, two experimental paradigms (Davis and Smith, 1976; De Wit and Stewart, 1981) recognized to have face validity to model human relapse (Knackstedt and Kalivas, 2009). "

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    • "The mesocorticolimbic dopamine system possesses neural connections from the VTA to the PFC and NAc and was crowned as the key circuit for reward and reinstatement of drug-seeking behaviors (Schultz, 1998; Horvitz, 2000; Robinson and Berridge, 2000; Comoli et al., 2003; Steketee , 2005). Most importantly, it is believed that the release of the neurotransmitters such as dopamine, glutamate, and corticotrophin-releasing factor in the key brain regions associated with relapse are essential for the behavioral outcomes of the drug (Wise, 1998; Di Chiara, 1999; Koob, 1999; Lu et al., 2003; Knackstedt and Kalivas, 2009). Furthermore, recent evidence supports the hypothesis that elevated anxiety, low mood, and increased sensitivity to stress (collectively labeled as negative affect) is the driving force behind the transition to addiction (George et al., 2014). "

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