Rationale
The reinforcing effects of cocaine are mediated by the mesolimbic dopamine system. Behavioral and neurochemical studies have shown that the cholinergic muscarinic M4 receptor subtype plays an important role in regulation of dopaminergic neurotransmission.
Objectives
Here we investigated for the first time the involvement of M4 receptors in the reinforcing effects of cocaine using chronic intravenous cocaine self-administration in extensively backcrossed M4 receptor knockout (M4 -/-) mice.
Methods
We evaluated acquisition of cocaine self-administration in experimentally naïve mice. Both cocaine self-administration and food-maintained operant behavior were evaluated under fixed ratio 1 (FR 1) and progressive ratio (PR) schedules of reinforcement. In addition, cocaine-induced dopamine release and cocaine-induced hyperactivity were evaluated.
Results
M4 -/- mice earned significantly more cocaine reinforcers and reached higher breaking points than their wild-type littermates (M4 +/+) at intermediate doses of cocaine under both FR 1 and PR schedules of reinforcement. Under the PR schedule, M4 -/- mice exhibited significantly higher response rates at the lowest liquid food concentration. In accordance with these results, cocaine-induced dopamine efflux in the nucleus accumbens and hyperlocomotion were increased in M4 -/- mice compared to M4 +/+ mice.
Conclusions
Our data suggest that M4 receptors play an important role in regulation of the reward circuitry and may serve as a new target in the medical treatment of drug addiction