Enhanced Sensitivity to Attenuation of Conditioned Reinstatement by the mGluR2/3 Agonist LY379268 and Increased Functional Activity of mGluR2/3 in Rats with a History of Ethanol Dependence

Recent findings implicate group II metabotropic glutamate receptors (mGluR_2/3) in the reinforcing and dependence-inducing actions of ethanol and identify these receptors as treatment targets for alcoholism. Here, we investigated the effects of mGLuR_2/3 activation on conditioned reinstatement in rats with different ethanol-dependence histories and examined dependence-associated changes in the functional activity of mGluR_2/3. Following ethanol self-administration training and conditioning procedures, rats were made ethanol dependent, using ethanol vapor inhalation, under three conditions: a single intoxication and withdrawal episode (SW), repeated cycles of intoxication and withdrawal (RW), or no intoxication (CTRL). At 1 week after removal from ethanol vapor, self-administration resumed until stable baseline performance was reached, followed by extinction of operant responding and reinstatement tests. Post-withdrawal self-administration was increased in the RW group, but all groups showed conditioned reinstatement. The mGluR_2/3 agonist {"type":"entrez-nucleotide","attrs":{"text":"LY379268","term_id":"1257807854","term_text":"LY379268"}}LY379268 dose -dependently reduced reinstatement in all groups, but was more effective at low doses in the SW and RW groups. The highest dose of {"type":"entrez-nucleotide","attrs":{"text":"LY379268","term_id":"1257807854","term_text":"LY379268"}}LY379268 tested reduced spontaneous locomotor activity and operant responding maintained by a non-drug reinforcer, without differences among groups. The heightened sensitivity to the effects of {"type":"entrez-nucleotide","attrs":{"text":"LY379268","term_id":"1257807854","term_text":"LY379268"}}LY379268 in rats with an ethanol-dependence history was therefore specific to behavior motivated by ethanol-related stimuli. Both the SW and RW groups showed elevated [³⁵S]GTPγS binding in the central nucleus of the amygdala (CeA) and bed nucleus of stria terminalis (BNST), relative to the CTRL group. The findings implicate changes in mGluR_2/3 functional activity as a factor in ethanol dependence and support treatment target potential of mGlu_2/3 receptors for craving and relapse prevention.