3-amino-n-(4-methoxybenzyl)-4-6-dimethylthieno(2-3-b)pyridine-2-carboxamide and Cocaine-Related-Disorders

Cocaine addiction is a chronic brain disease affecting neurotransmission. Muscarinic cholinergic receptors modulate dopaminergic signaling in the reward system, and muscarinic receptor stimulation can block direct reinforcing effects of cocaine. Here, we tested the hypothesis that specific muscarinic M. We tested the M. VU0152100 attenuated the discriminative stimulus effect of cocaine in wild-type mice and M. These findings further support the notion that M

Topics: Animals; Cocaine; Cocaine-Related Disorders; Corpus Striatum; Hyperkinesis; Male; Mice; Mice, Knockout; Pyridazines; Pyridines; Reinforcement, Psychology; Reward; Thiophenes

The mesostriatal dopamine system plays a key role in mediating the reinforcing effects of psychostimulant drugs like cocaine. The muscarinic M₄ acetylcholine receptor subtype is centrally involved in the regulation of dopamine release in striatal areas. Consequently, striatal M₄ 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 M₄ 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 M₄ receptors, its inhibitory effects on cocaine-induced increases in striatal dopamine were abolished in M₄ receptor knockout mice. Furthermore, selective deletion of the M₄ receptor gene in dopamine D₁ receptor-expressing neurons resulted in a partial reduction of the VU0152100 effect, indicating that VU0152100 partly regulates dopaminergic neurotransmission via M₄ receptors co-localized with D₁ receptors.. These results show that positive allosteric modulators of the M₄ receptor deserve attention as agents in the future treatment of cocaine abuse.

Topics: Animals; Behavior, Animal; Central Nervous System Stimulants; Cocaine; Cocaine-Related Disorders; Corpus Striatum; Dopamine; Dose-Response Relationship, Drug; Male; Mice; Mice, Knockout; Motor Activity; Pyridines; Receptor, Muscarinic M4; Reinforcement, Psychology; Self Administration; Thiophenes