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


OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
These results show that positive allosteric modulators of the M₄ receptor deserve attention as agents in the future treatment of cocaine abuse.
Laboratory of Neuropsychiatry, Psychiatric Centre Copenhagen, Copenhagen University Hospital, 9 Blegdamsvej, 2100 Copenhagen, Denmark.
Ditte
D
Dencker
Pia
P
Weikop
Gunnar
G
Sørensen
David P D
DP
Woldbye
Gitta
G
Wörtwein
Jürgen
J
Wess
Anders
A
Fink-Jensen
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003042:Cocaine / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000188:drug therapy*; D003342:Corpus Striatum / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D043588:Receptor, Muscarinic M4 / Q000819:agonists*; D012054:Reinforcement, Psychology; D012646:Self Administration; D013876:Thiophenes / Q000008:administration & dosage / Q000494:pharmacology*
C579414:3-amino-N-(4-methoxybenzyl)-4,6-dimethylthieno(2,3-b)pyridine-2-carboxamide; D000697:Central Nervous System Stimulants; D011725:Pyridines; D043588:Receptor, Muscarinic M4; D013876:Thiophenes; D003042:Cocaine; D004298:Dopamine