An allosteric enhancer of M4 muscarinic acetylcholine receptor function inhibits behavioral and neurochemical effects of cocaine

The mesostriatal dopamine system plays a key role in mediating the reinforcing effects of psychostimulant drugs like cocaine. The muscarinic M-4 acetylcholine receptor subtype is centrally involved in the regulation of dopamine release in striatal areas. Consequently, striatal M-4 receptors could be a novel target for modulating psychostimulant effects of cocaine. For the first time, we here addressed this issue by investigating the effects of a novel selective positive allosteric modulator of M-4 receptors, VU0152100, on cocaine-induced behavioral and neurochemical effects in mice. To investigate the effect of VU0152100 on the acute reinforcing effects of cocaine, we use an acute cocaine self-administration model. We used in vivo microdialysis to investigate whether the effects of VU0152100 in the behavioral studies were mediated via effects on dopaminergic neurotransmission. In addition, the effect of VU0152100 on cocaine-induced hyperactivity and rotarod performance was evaluated. We found that VU0152100 caused a prominent reduction in cocaine self-administration, cocaine-induced hyperlocomotion, and cocaine-induced striatal dopamine increase, without affecting motor performance. Consistent with these effects of VU0152100 being mediated via M-4 receptors, its inhibitory effects on cocaine-induced increases in striatal dopamine were abolished in M-4 receptor knockout mice. Furthermore, selective deletion of the M-4 receptor gene in dopamine D-1 receptor-expressing neurons resulted in a partial reduction of the VU0152100 effect, indicating that VU0152100 partly regulates dopaminergic neurotransmission via M-4 receptors co-localized with D-1 receptors. These results show that positive allosteric modulators of the M-4 receptor deserve attention as agents in the future treatment of cocaine abuse.