Abstract
Recent studies have implicated glutamate neurotransmission as an important substrate for the extinction of conditioned behaviors, including responding for drug reinforcement. Positive allosteric modulation of the type-5 metabotropic glutamate receptor (mGluR5) in particular has emerged as a treatment strategy for the enhancement of extinction of drug-motivated behaviors. Here, we investigated the effects of the mGluR5 positive allosteric modulator CDPPB, a compound known for its cognitive enhancing effects in rodents, on extinction learning in rats with different histories of methamphetamine (METH) training. Rats were trained to self-administer METH under two conditions: 16 daily sessions of short access (90 min/day, ShA), or eight daily sessions of short access followed by eight sessions of long access (6 h/day, LgA). Control rats self-administered sucrose pellets in daily 30 min sessions. Next, rats were administered vehicle or 30 mg/kg CDPPB prior to seven consecutive daily extinction sessions, subjected to additional extinction sessions to re-establish a post-treatment baseline, and then tested for reinstatement of behavior in the presence of METH- or sucrose-paired cues. Rats were then subjected to a second series of extinction sessions, preceded by vehicle or 30 mg/kg CDPPB, and an additional test for cue-triggered reinstatement. CDPPB treatment resulted in a more rapid extinction of responding on the active lever, especially in the early sessions of the first extinction sequence. However, treatment effects were minimal during subsequent cue reinstatement tests and non-existent during the second series of extinction sessions. Rats with histories of ShA, LgA, and sucrose training expressed similar behavioral sensitivities to CDPPB, with LgA rats demonstrating a modestly higher treatment effect. Positive allosteric modulation of mGluR5 may therefore have some beneficial effects on efforts to facilitate extinction learning and reduce methamphetamine seeking.
Highlights
Addiction to methamphetamine (METH) is marked by continued use in spite of adverse consequences, as well as chronic relapse to drug-taking after extended periods of abstinence
analysis of variance (ANOVA) of the daily METH infusions revealed a significant effect of training day (F 15, 315 = 8.9, p < 0.0001), and post hoc comparisons confirmed that a greater number of reinforcements were delivered during Days 7 and 9–16 than Days 1–3 (26.3 ± 1.8; Newman–Keuls tests, p < 0.05)
Repeated injections of CDPPB prior to extinction training sessions resulted in enhanced extinction of operant responding previously associated with METH reinforcement
Summary
Addiction to methamphetamine (METH) is marked by continued use in spite of adverse consequences, as well as chronic relapse to drug-taking after extended periods of abstinence. Experimental or casual METH taking brings about maladaptive changes in the brain beyond the reward circuitry, involving systems associated with learning and memory functions (Childress et al, 1999; Volkow et al, 2008; Koob and Volkow, 2010). Accumulating evidence of these alterations in preclinical studies and human brain neuroimaging experiments has led to the conceptualization of drug addiction as a disorder of learning and memory systems (Kelley, 2004; Hyman et al, 2006). Though several models of addiction as a learning disorder have been proposed, they tend to share the common argument that the progression of the disease is characterized by two forms of aberrant learning: drug-associated environmental cues attaining, through a Pavlovian conditioning process, a persistent incentive salience capable of triggering craving, and relapse behaviors (associative overlearning), and drug-taking behavior growing into a compulsive habit (instrumental overlearning, a form of associative learning; Volkow et al, 2002; Ciccocioppo et al, 2004)
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