Increased cocaine self-administration in M4 muscarinic acetylcholine receptor knockout XXXX .

@entity19 @entity2915 @entity72964 @entity734
RATIONALE: The reinforcing effects of cocaine are mediated by the mesolimbic dopamine system. Behavioral and neurochemical studies have shown that the cholinergic muscarinic @entity72964 receptor subtype plays an important role in regulation of dopaminergic neurotransmission. OBJECTIVES: Here we investigated for the first time the involvement of @entity72964 receptors in the reinforcing effects of cocaine using chronic intravenous cocaine self-administration in extensively backcrossed @entity72964 (-/-)) @entity19 . METHODS: We evaluated acquisition of cocaine self-administration in experimentally na  ve @entity19 . 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 @entity2915 were evaluated. RESULTS: @entity72964 (-/-) @entity19 earned significantly more cocaine reinforcers and reached higher breaking points than their wild-type littermates ( @entity72964 (+/+)) at intermediate doses of cocaine under both FR 1 and PR schedules of reinforcement. Under the PR schedule, @entity72964 (-/-) @entity19 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 @entity72964 (-/-) @entity19 compared to @entity72964 (+/+) @entity19 . CONCLUSIONS: Our data suggest that @entity72964 receptors play an important role in regulation of the reward circuitry and may serve as a new target in the medical treatment of @entity734 .
