In comparison to the rather clear-cut situation for nicotinic activation, the effect of muscarinic drugs on stimulus reinforcement is less clear. There is evidence that muscarinic receptor activation can decrease amphetamine-induced hyperactivity [32] and inhibit amphetamine-induced DA release in the NAc [33]. Conversely, muscarinic antagonists enhance the locomotor stimulating effects of amphetamine and cocaine [32,34,35]. Systemic administration of muscarinic agonists and partial agonists have been reported to decrease cocaine self-administration rates in mice [36], whereas co-administration with the muscarinic antagonist, scopolamine decreases cocaine self-administration in rhesus monkeys [37]. In addition, mice lacking the muscarinic M5 type receptor self-administer less cocaine and show reduced cocaine conditioned place preference compared to their wild-type counterparts [38], suggesting that muscarinic receptors may mediate some component of cocaine reward.
