Abstract
Extinction of drug-seeking behavior is a form of new and active learning. Facilitation of extinction learning is of clinical interest since cue exposure therapies for the treatment of addiction have largely been unsuccessful in preventing relapse, primarily due to the context specificity of extinction learning. Recently, several studies have shown that potentiation of glutamatergic transmission can facilitate extinction learning in rodent models of cocaine addiction. In this study we investigated the effects of the type 5 metabotropic glutamate receptor (mGluR5) positive allosteric modulator (PAM) 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) on the extinction and contextual reinstatement of methamphetamine-seeking behavior. Rats were trained and allowed to self-administer methamphetamine (0.1 mg/kg/infusion) in 2 hr daily sessions in Context A where self-administration chambers had distinct tactile, visual, auditory, and olfactory cues. Next, CDPPB (60 mg/kg) or vehicle was administered prior to subsequent extinction training sessions that were conducted in modified self-administration chambers (Context B) that were Context A. Following 16 days of extinction training in Context B, animals were placed back in Context A for assessment of contextual reinstatement of methamphetamine-seeking behavior. CDPPB failed to produce significant reductions in extinction responding or in the magnitude of contextual reinstatement of methamphetamine-seeking compared to vehicle treated controls. We postulate that numerous factors, including methamphetamine-induced changes in mGluR5 receptor expression or function, may have contributed to the observed lack of effects. Although these findings initially suggest that mGluR5 PAMs may be ineffective in facilitating extinction learning or preventing context-induced relapse in methamphetamine addiction, additional studies are warranted examining effects of other mGluR5 PAMs, particularly those with improved pharmacological properties and devoid of potential side effects at higher doses.
Highlights
Two of the most problematic obstacles to the successful treatment of drug addiction are the persistence of drug-seeking behavior during attempts at abstinence and the motivational salience of drug-associated cues and contexts
Results from the present study show that the mGluR5 positive allosteric modulator (PAM) CDPPB did not facilitate the acquisition of extinction learning following methamphetamine self-administration, nor did treatment with this compound alter context-induced reinstatement of methamphetamineseeking behavior
It could be speculated that mGluR5 PAMs may be of limited therapeutic benefit in cue exposure-based therapies for the treatment of addiction to methamphetamine, which is characterized by high rates of relapse and a lack of approved medications for the treatment of this disorder [38,39,40]
Summary
Two of the most problematic obstacles to the successful treatment of drug addiction are the persistence of drug-seeking behavior during attempts at abstinence and the motivational salience of drug-associated cues and contexts. Various studies have demonstrated that pharmacological potentiation of glutamatergic transmission with ligands such as the N-methyl-D-aspartate (NMDA) partial agonist D-cycloserine (DCS), α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptor potentiators, or the cystine prodrug N-acetylcysteine reduce extinction responding following active drug self-administration, reduce re-acquisition of drug intake, and/or facilitate the extinction of a drug-induced conditioned place preference (CPP) [10,11,12,13,14,15,16] These data suggest that potentiators of glutamatergic transmission may represent a novel class of adjunctive therapeutics that may facilitate extinction learning in the context of drug addiction, but other psychiatric disorders such as pathological anxiety [17,18,19,20,21]
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