mGluR5 positive allosteric modulation enhances extinction learning following cocaine self-administration.

Abstract

Extinction of classically and instrumentally conditioned behaviors, such as conditioned fear and drug-seeking behavior, is a process of active learning, and recent studies indicate that potentiation of glutamatergic transmission facilitates extinction learning. In this study we investigated the effects of the type 5 metabotropic glutamate receptors (mGluR5) positive allosteric modulator 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) on the extinction of cocaine-seeking behavior in rats with a history of intravenous cocaine self-administration. To assess its effects on acquisition and consolidation of extinction learning, CDPPB (60 mg/kg) or vehicle was administered either 20 min prior to, or immediately following, each of 10 extinction sessions, respectively. When administered prior to each extinction session, CDPPB produced a significant reduction in the number of active lever presses on all 10 days of extinction training as compared to vehicle-treated animals. When administered following each extinction session, a significant reduction in the number of active lever presses was observed on the 2nd through 10th day of extinction. Both treatment regimens also reduced the number of extinction training sessions required to meet extinction criteria. Pre- or post-extinction training administration of CDPPB did not alter responding on the inactive lever and had no effects on open field locomotor activity. These data indicate that positive allosteric modulation of mGluR5 receptors facilitates the acquisition and consolidation of extinction learning following cocaine self-administration, and may provide a novel pharmacological approach to enhancing extinction learning when combined with cue exposure therapy for the treatment of cocaine addiction.

Adolescent Alcohol Exposure Reduces Behavioral Flexibility, Promotes Disinhibition, and Increases Resistance to Extinction of Ethanol Self-Administration in Adulthood

“…In addition, extinction of fear and drug memories represents a simpler form of flexibility entailing the formation of a new memory that competes with the original drug or fear memory. In agreement with previous studies showing that CDPPB can facilitate the extinction of cocaine memories (Cleva et al , 2011; Gass et al , 2009), we observed that CDPPB facilitates the extinction of ethanol self-administration, including the reversal of resistance to extinction observed in adult AIE exposed rats. In light of the fact that both set shifting and extinction are critically-dependent on intact medial PFC function, our results suggest that the procognitive actions of CDPPB relate, at least in part, to actions within the PFC that enhance cognitive control of behavior.…”

“…In light of the fact that both set shifting and extinction are critically-dependent on intact medial PFC function, our results suggest that the procognitive actions of CDPPB relate, at least in part, to actions within the PFC that enhance cognitive control of behavior. Importantly, the ability of CDPPB to reverse behavioral deficits induced by AIE does not appear to result from alterations in locomotor activity as previous research in our laboratory (Cleva et al , 2011) and others (Kufahl et al , 2012; Reichel et al , 2011) has shown that this dose of CDPPB does not alter motor behavior.…”

“…The dose of CDPPB was based on our previous studies (Cleva et al , 2011; Gass and Olive, 2009) as well as other studies (Kufahl et al , 2012; Reichel et al , 2011) that showed facilitation of extinction learning, pro-cognitive effects, and no effects on motor behavior. Rats were placed in the self-administration apparatus and extinction criteria was considered to have been met when the number of active lever presses exhibited by an individual rat was <20% (for two consecutive days) of those observed on the average of the last two days of active drug self-administration for that particular rat.…”

Imaging Glutamate Homeostasis in Cocaine Addiction with the Metabotropic Glutamate Receptor 5 Positron Emission Tomography Radiotracer [11C]ABP688 and Magnetic Resonance Spectroscopy

“…In monkeys, mGluR5 antagonist administration attenuates cocaine self-administration, cocaine-induced reinstatement of drug seeking behavior, and the discriminative stimulus effects of cocaine (8, 9). However, recent studies in rodents have also shown that activation of the mGluR5 improves the acquisition and consolidation of extinction learning following cocaine exposure (10, 34). Thus, while these studies show that mGluR5 antagonism reduces cocaine self-administration in animal models, activation of the receptor appears to improve extinction learning.…”

“…The administration of an mGluR5 antagonist to rodents reduces the reinforcing properties of cocaine (2–7) and similar results have been reported in rhesus monkeys (8, 9). On the other hand, activation of the mGluR5 with the administration of a positive allosteric modulator has been shown to improve extinction learning following cocaine self-administration in rodents (10). …”