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Mesolimbic dopamine neurons in the ventral tegmental area (VTA) play important roles in mediating the rewarding effects of opiates in addicted rats and in drug relapse. M5 muscarinic receptors (M5R) are needed for prolonged dopamine release in the nucleus accumbens induced by morphine. However, little is known about the role of M5Rs in extinction and relapse. Here, we found that the rewarding effects of morphine are similar in wild-type and M5R knockout mice (C57BL/6). Thus, we further investigated the extinction and reinstatement of morphine-conditioned reward. Within group analyses showed that morphine-induced conditioned place preference (CPP) extinguished much faster in M5R KOs (on day 5) than wild-type mice (on 10 day). And cross group and genotype analyses further confirmed this finding. More interestingly, after extinction, either morphine (1, 6 and 10 mg/kg, i.p.) or amphetamine (1 and 3 mg/kg, i. p.) priming reinstated morphineinduced CPP only in wild-type, but not in M5R KOs. Regardless of the genotype, amphetamine but not morphine priming changed the context preference of mice to the black chamber, implying a drug-specific, but M5R-independent increase of anxiety in the mice. These results allow us to conclude that M5Rs play an important role in the extinction and reinstatement of morphine-conditioned reward.

M5 Muscarinic Receptor Gene Deletion Accelerates Extinction, But Inhibits Reinstatement of Morphine-Conditioned Reward in Mice