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, (-)-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.

Figure 1.

Effects of LY379268 on reinstatement induced by discriminative stimuli associated with cocaine or SCM. A, Responses during cocaine (Coc/S⁺) and saline (Sal/S^–) self-administration, extinction, (EXT), reinstatement tests in the presence of the saline (S^–) versus cocaine (S⁺) cues, and LY379268 effects on conditioned reinstatement (**p < 0.0001 vs S⁺; ^††p < 0.001 vs S^– and EXT; *p < 0.05 vs vehicle). Inset, Reinstatement responses without drug or vehicle treatment 2 d after each drug test. B, Responses during SCM self-administration (SCM/S⁺) versus non-reward (no-SCM/S^–) sessions, extinction (EXT), reinstatement tests in the presence of the non-reward (S^–) versus SCM (S⁺) cues, and effects of LY379268 on conditioned reinstatement (**p < 0.0001 vs SCM/S⁺; ^†p < 0.05 vs S^– and EXT; **p < 0.001 vs vehicle).

Figure 2.

Effects of LY379268 on cocaine and SCM self-administration. A, Number of cocaine infusions after vehicle versus LY379268 administration (*p < 0.05 vs 0, 0.3, and 1.0 mg/kg). B, SCM-reinforced responses after vehicle versus LY379268 administration. Responding was not attenuated by LY379268 treatments.