Attenuation of ethanol self-administration and of conditioned reinstatement of alcohol-seeking behaviour by the antiopioid peptide nociceptin/orphanin FQ in alcohol-preferring rats

Abstract

Rationale: Nociceptin/orphanin FQ (N/OFQ), the endogenous ligand of the opioid-like orphan receptor NOP, was shown to reduce home-cage ethanol consumption, ethanol-induced conditioned place preference and stress-induced reinstatement of alcohol-seeking behaviour.

Objectives: The present study, using genetically selected Marchigian Sardinian alcohol-preferring (msP) rats, was designed to evaluate the effect of this opioid peptide on 10% ethanol and 10% sucrose self-administration, under a fixed-ratio 1 (FR 1) or a progressive-ratio (PR) schedule of reinforcement. Furthermore, using an experimental model of relapse in which rats were trained to lever press for ethanol in the presence of the discriminative stimulus of an orange odour (S(+)) and a 1-s cue light (CS(+)) or for water in the presence of anise odour (S(-)) and 1-s white noise (CS(-)), the effect of N/oFQ on cue-induced reinstatement of extinguished ethanol responding was investigated.

Results: Sub-chronic (6 days) intracerebroventricular (i.c.v.) injection of 0.5 microg or 1.0 microg N/OFQ per rat significantly reduced alcohol self-administration under both the FR 1 and PR schedules of reinforcement. Conversely, i.c.v. administration of 0.5, 1.0 or 4.0 microg of the peptide per rat did not affect sucrose self-administration. In addition, i.c.v. N/OFQ (1.0-2.0 microg per rat) significantly inhibited the reinstatement of extinguished ethanol responding under an S(+)/CS(+) condition, whereas lever pressing under S(-)/CS(-) was not altered.

Conclusions: The present study demonstrates that the reinforcing effects of ethanol are markedly blunted by activation of the opioidergic N/OFQ receptor system. Moreover, the data provide evidence of the efficacy of N/OFQ to prevent reinstatement of ethanol-seeking behaviour elicited by environmental conditioned stimuli.

Fig. 1

Fixed ratio 1 10% ethanol self-administration in Marchigian Sardinian alcohol-preferring rats (n=9/group) treated i.c.v. for six consecutive days with 0.5 μg and 1.0 μg per rat of N/OFQ or its vehicle (Veh). *P<0.05 versus vehicle

Fig. 2

Performance on a progressive ratio schedule of reinforcement of rats (n=8) treated i.c.v. with 0.5 μg and 1.0 μg per rat of N/OFQ or its vehicle (Veh) in a counterbalanced order (Latin square). A Mean (±SEM) number of rewards earned. B Mean (±SEM) number of responses emitted at breaking point. *P<0.05 versus vehicle

Fig. 3

Training: responses on the last day of the discrimination training phase in the presence of distinct discriminative stimuli predictive of the availability of 10% (w/v) ethanol (S⁺/CS⁺) or water (S⁻/CS⁻). Extinction: extinction responses during the 20 days of this phase. Reinstatement: responses in rats exposed to the S⁺/CS⁺ and S⁻/CS⁻ conditions (in the absence of ethanol or water) and treated i.c.v. with 2.0 μg and 4.0 μg per rat of N/OFQ or its vehicle (Veh). Responding in the S⁺/CS⁺ test differed from S⁻/CS⁻ responses (P<0.01). Treatment with N/OFQ 4.0 μg per rat significantly reduced responses under S⁺/CS⁺ but not under S⁻/CS⁻ conditions. Values represent the mean (±SEM) of 7–9 subjects per group. Difference from vehicle *P<0.05

Fig. 4

Fixed ratio 1 10% sucrose self-administration in Marchigian Sardinian alcohol-preferring rats (n=25) treated i.c.v. for six consecutive days with 0.5, 1.0 and 4.0 μg per rat of N/OFQ or its vehicle (Veh)

Fig. 5

Performance on a progressive ratio schedule of reinforcement of rats (n=7) treated i.c.v. with 0.5, 1.0 and 4.0 μg per rat of N/OFQ or its vehicle (Veh) in a counterbalanced order (Latin square). A Mean (±SEM) number of rewards earned. B Mean (±SEM) number of responses emitted at breaking point