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·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 (mGlu₅) 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·kg⁻¹) and SCH58261 (0.5 mg·kg⁻¹ i.p.) produced a reduction (28%) in ethanol self‐administration. Combinations of threshold doses of SR141716A (0.3 mg·kg⁻¹) and SCH58261 (2.0 mg·kg⁻¹, i.p.) caused an essentially additive reduction (68%) in alcohol self‐administration. A combination of individually sub‐threshold doses of CB₁ and mGlu₅ receptor antagonists did not affect alcohol self‐administration; however, combined threshold doses of SR141716A (0.3 mg·kg⁻¹) and MTEP (1.0 mg·kg⁻¹ i.p.) did reduce ethanol self‐administration markedly (80%). Cue‐conditioned alcohol seeking was attenuated by pretreatment with MTEP (1.0 mg·kg⁻¹) co‐administered with SR141716A (0.3 mg·kg⁻¹ i.p.). In contrast, SCH58261 (2.0 mg·kg⁻¹) co‐administered with SR141716A (0.3 mg·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 mGlu₅ and CB₁ receptors did prevent relapse‐like alcohol seeking after abstinence, suggesting a prominent role for mGlu₅ receptors in this paradigm.