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 {"type":"entrez-protein","attrs":{"text":"SCH58261","term_id":"1052882304","term_text":"SCH58261"}}SCH58261.

Key results:

When administered at individually sub-threshold doses, a combination of SR141716A (0.1 mg·kg⁻¹) and {"type":"entrez-protein","attrs":{"text":"SCH58261","term_id":"1052882304","term_text":"SCH58261"}}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 {"type":"entrez-protein","attrs":{"text":"SCH58261","term_id":"1052882304","term_text":"SCH58261"}}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, {"type":"entrez-protein","attrs":{"text":"SCH58261","term_id":"1052882304","term_text":"SCH58261"}}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.