Cue-conditioned alcohol seeking in rats following abstinence: involvement of metabotropic glutamate 5 receptors

Background and purpose: The current study was designed to: (i) examine whether functional interactions occur between receptors known to regulate alcohol self-administration; and (ii) characterize relapse to alcohol seeking following abstinence. Experimental approach: The selective cannabinoid CB1 receptor antagonist SR141716A (0.03-1.0 mg center dot kg-1 i.p.) resulted in a dose-dependent reduction in ethanol self-administration in ethanol-preferring Indiana-preferring rats. SR141716A was then co-administered with either the selective glutamate metabotropic glutamate 5 (mGlu(5)) receptor antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) or the selective adenosine A(2A) receptor antagonist SCH58261. Key results: When administered at individually sub-threshold doses, a combination of SR141716A (0.1 mg center dot kg-1) and SCH58261 (0.5 mg center dot kg-1 i.p.) produced a reduction (28%) in ethanol self-administration. Combinations of threshold doses of SR141716A (0.3 mg center dot kg-1) and SCH58261 (2.0 mg center dot kg-1, i.p.) caused an essentially additive reduction (68%) in alcohol self-administration. A combination of individually sub-threshold doses of CB1 and mGlu(5) receptor antagonists did not affect alcohol self-administration; however, combined threshold doses of SR141716A (0.3 mg center dot kg-1) and MTEP (1.0 mg center dot kg-1 i.p.) did reduce ethanol self-administration markedly (80%). Cue-conditioned alcohol seeking was attenuated by pretreatment with MTEP (1.0 mg center dot kg-1) co-administered with SR141716A (0.3 mg center dot kg-1 i.p.). In contrast, SCH58261 (2.0 mg center dot kg-1) co-administered with SR141716A (0.3 mg center dot kg-1 i.p.) did not reduce cue-conditioned alcohol seeking. Conclusions and implications: Adenosine A(2A) and cannabinoid CB1 receptors regulated alcohol self-administration additively, but combined low-dose antagonism of these receptors did not prevent cue-conditioned alcohol seeking after abstinence. In contrast, combined low-dose antagonism of mGlu(5) and CB1 receptors did prevent relapse-like alcohol seeking after abstinence, suggesting a prominent role for mGlu(5) receptors in this paradigm.