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

Abstract

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 CB(1) 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 (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.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 CB(1) and mGlu(5) 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 CB(1) 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 CB(1) receptors did prevent relapse-like alcohol seeking after abstinence, suggesting a prominent role for mGlu(5) receptors in this paradigm.

Figure 1

The effect of SR141716A and MTEP on operant ethanol self-administration in iP rats (n= 10). Ethanol self-administration was significantly reduced by SR141716A administration at 1.0 mg·kg⁻¹ (P= 0.003) and 0.3 mg·kg⁻¹ (P= 0.006) i.p. When co-administered at a low dose, SR141716A and MTEP had no effect on ethanol self-administration at 0.1 and 0.25 mg·kg⁻¹, respectively, but did significantly reduce ethanol self-administration when co-administered at 0.3 and 1 mg·kg⁻¹ i.p. (P= 0.001). Water responses were significantly reduced by SR141716A at 1 mg·kg⁻¹ (P= 0.009) and SR141716A, and MTEP co-administered at 0.1 and 0.25 mg·kg⁻¹ i.p. (P= 0.011). V, Vehicle; SR0.1 or 0.3, SR141716A at 0.1 or 0.3 mg·kg⁻¹ i.p.; MTEP 0.25 or 1.0, MTEP at 0.25 or 1.0 mg·kg⁻¹ i.p. *Significantly different to vehicle.

Figure 2

The effect of SCH58261 and SR141716A on operant ethanol self-administration in iP rats (n= 10). Ethanol self-administration was not significantly altered by SCH58261 at 0.5 mg·kg⁻¹ i.p., although water responding was reduced (P= 0.035). SR141716A at 0.1 mg·kg⁻¹ i.p. did not alter responding. When co-administered, SR141716A and SCH58261 significantly reduced responding for ethanol without affecting responding for water at 0.1 and 0.5 mg·kg⁻¹ (P= 0.030), and 0.3 and 2 mg·kg⁻¹ (P= 0.005) respectively. V, Vehicle; SCH0.5 or 2, SCH58261 at 0.5 or 2.0 mg·kg⁻¹ i.p.; SR0.1 or 0.3, SR141716A at 0.1 or 0.3 mg·kg⁻¹ i.p. *Significantly different to vehicle.

Figure 3

The effect of SCH58261 and MTEP, co-administered with SR141716A, on cue-conditioned alcohol seeking in iP rats (n= 10 per treatment). MTEP (1.0 mg·kg⁻¹) and SR141716A (0.3 mg·kg⁻¹) significantly reduced cue-conditioned alcohol seeking compared with vehicle (P < 0.001). SCH58261 (2.0 mg·kg⁻¹) and SR141716A (0.3 mg·kg⁻¹) co-administered i.p. had no effect on cue-conditioned alcohol seeking. Veh, Vehicle; SCH2.0, SCH58261 at 2.0 mg·kg⁻¹ i.p.; SR0.3, SR141716A at 0.3 mg·kg⁻¹ i.p.; MTEP1.0, MTEP at 1.0 mg·kg⁻¹ i.p. *Significantly different to vehicle (P < 0.001).

Figure 4

Summary figures describing the effects of SCH58261, MTEP and SR141716A on operant ethanol self-administration in iP rats. Open bars represent the percentage change in deliveries of 10% v/v ethanol on an FR3 schedule. The dotted, horizontal line represents the theoretical additive effect of each combination. The solid bar represents the actual percentage reduction in ethanol self-administration achieved with co-administration. (A) The combination of SCH58261 (0.5 mg·kg⁻¹) and MTEP (0.25 mg·kg⁻¹) injected i.p. produces a synergistic reduction in ethanol self-administration in iP rats. Primary data for Figure 4a have been reported previously (Adams et al., 2008). (B) The combination of SR141716A (0.1 mg·kg⁻¹) and MTEP (0.25 mg·kg⁻¹ both i.p.) and (C) the combination of SR141716A (0.1 mg·kg⁻¹) and SCH58261 (0.5 mg·kg⁻¹ i.p.) produced essentially additive effects on ethanol self-administration. SCH: SCH58261, SR: SR141716A.