Preferential Effects of the Metabotropic Glutamate 2/3 Receptor Agonist LY379268 on Conditioned Reinstatement versus Primary Reinforcement: Comparison between Cocaine and a Potent Conventional Reinforcer

Abstract

Metabotropic glutamate receptors (mGluRs) have been implicated in regulating anxiety, stress responses, and the neurobehavioral effects of psychostimulants. The present study sought to determine whether group II mGluR activation by the potent mGlu2/3 receptor agonist, (Ϫ)-2-oxa-4-aminobicylco hexane-4,6-dicarboxylic acid (LY379268), antagonizes reinstatement of cocaine-seeking induced by cocaine-related stimuli and whether this effect extends to behavior induced by stimuli conditioned to a potent conventional reinforcer, sweetened condensed milk (SCM). Also, we tested whether the suppressant effects of LY379268 on conditioned reinstatement extend to the primary reinforcing effects of cocaine or SCM. Rats were trained to associate discriminative stimuli (S D ) with the availability of cocaine or SCM versus non-reward and then subjected to repeated extinction sessions during which the respective reinforcers and S D were withheld. Subsequent reexposure to the cocaine or SCM S D , but not the non-reward S D , produced recovery of responding at the previously active lever. LY379268 (0.3-3.0 mg/kg, s.c.) dose-dependently attenuated recovery of cocaine seeking but reduced conditioned reinstatement by the SCM S D only at the highest dose. LY379268 did not alter responding reinforced directly by SCM, and only the highest LY379268 dose reduced cocaine self-administration. The results suggest that the effects of LY379268 are selective for behavior maintained by cocaine as opposed to palatable conventional reinforcers. More importantly, the results show that LY379268 suppresses behavior motivated by stimuli conditioned to cocaine or SCM more effectively than consummatory behavior maintained by the unconditioned effects of these substances. As such, the results identify group II mGluRs as a pharmacotherapeutic target for craving and relapse prevention associated with cocaine cue exposure.

Rats with Extended Access to Cocaine Exhibit Increased Stress Reactivity and Sensitivity to the Anxiolytic-Like Effects of the mGluR 2/3 Agonist LY379268 during Abstinence

“…These findings also illustrate the importance of developing therapeutic interventions aimed at reducing stress as a strategy for reducing relapse risk. Consistent with recent reports showing a reduction in the response-reinstating effects of cocaine (Peters and Kalivas, 2006;Adewale et al, 2006), drug-associated stimuli (Baptista et al, 2004;Bossert et al, 2004Bossert et al, , 2006Zhao et al, 2006), and stressful stimuli (Zhao et al, 2006), the present data indicate that mGlu2/3 receptors may be promising treatment targets.…”

“…Recent animal studies have indicated pharmacotherapeutic potential of the mGlu2/3 receptor agonist LY379268 in treating relapse risk associated with cocaine (Peters and Kalivas, 2006;Adewale et al, 2006), drug-associated stimuli (Baptista et al, 2004;Bossert et al, 2004Bossert et al, , 2006Zhao et al, 2006), and stressful stimuli (Zhao et al, 2006). However, an important question is to what extent chronic drug use induces increased susceptibility to stress and thereby contributes to the maintenance or resumption of drug use.…”

Activation of Group II Metabotropic Glutamate Receptors in the Nucleus Accumbens Shell Attenuates Context-Induced Relapse to Heroin Seeking

“…Finally, the present findings on the effect of intra-NAc LY379268 injections in a rat relapse model extend those from our previous study on the effect of systemic and intra-VTA injections of the drug on context-induced reinstatement of heroin seeking (Bossert et al, 2004). It was also reported that systemic injections of LY379268 attenuate (1) discrete cue-induced reinstatement of heroin seeking , (2) discriminative cue-induced reinstatement of cocaine seeking (Baptista et al, 2004), (3) cocaine priming-induced reinstatement (Peters et al, 2004), (4) enhanced amphetamine-taking behavior by prior sensitizing exposure to the drug (Kim et al, 2005), and (5) other behavioral effects of abused drugs (Kenny and Markou, 2004). Together, these results from preclinical studies suggest that pharmacological manipulations that target group II metabotropic glutamate receptors should be considered in the treatment of drug addiction.…”

Activation of Group II Metabotropic Glutamate Receptors Inhibits the Discriminative Stimulus Effects of Alcohol via Selective Activity Within the Amygdala

“…To date, there is a growing interest in the role of metabotropic glutamate receptors, subtypes 2 and 3 (mGlu2/3), in modulating drug taking and seeking behavior. For example, systemic administration of mGlu2/3 receptor agonists has been shown to inhibit cocaine and nicotine self-administration (Baptista et al, 2004;Adewale et al, 2006;Liechti et al, 2007). In relation to alcohol, systemic mGlu2/3 receptor activation can reduce alcohol self-administration (Backstrom and Hyytia, 2005;Sidhpura and Weiss, 2010; but see Rodd et al, 2006) and relapse-like behavior (Rodd et al, 2006;Zhao et al, 2006;Sidhpura and Weiss, 2010).…”