Cholinergic M receptors are involved in morphine-induced expression of behavioral sensitization by regulating dopamine function in the nucleus accumbens of rats.

Repeated administration of morphine profoundly influences the dopaminergic and cholinergic systems in the nucleus accumbens [including the shell of the nucleus accumbens (NAcS)]. Further, dopamine release is regulated by the cholinergic system, especially the M receptor. Drug priming is one of the main factors that induces relapse in drug addiction. The present study first investigated how activation of the M receptor in the NAcS affects the expression of morphine-induced behavioral sensitization, through the administration of an M agonist (LY2033298) and antagonist (tropicamide), as well as a combination of an acetylcholinesterase inhibitor and M antagonist (huperzine-A + tropicamide). Additionally, the influence of a dopamine receptor agonist, in conjunction with an M agonist (i.e., SKF38393 + LY2033298), was also examined. Behavioral sensitization was established by exposure to 5 mg/kg morphine once every three days for a total of three exposures. The expression of behavioral sensitization was challenged by 5 mg/kg morphine. Results showed that (1) microinjection of the M receptor agonist LY2033298 (0.2 μg/side), but not the antagonist tropicamide (5, 10, or 20 μM/side) into the NAcS blocked the expression of behavioral sensitization; (2) tropicamide (20 μM/side) reversed the inhibition effect of huperzine-A on this behavior; and (3) SKF38393 (1 μg/side) reversed the inhibitory effect of LY2033298 on the expression of morphine-induced behavioral sensitization. These results suggest that the cholinergic M receptor in the NAcS plays an important role in the morphine-induced expression of behavioral sensitization through the regulation of dopamine function in rats.