TY - JOUR
T1 - An allosteric enhancer of M4 muscarinic acetylcholine receptor function inhibits behavioral and neurochemical effects of cocaine
AU - Nielsen, Ditte Dencker
AU - Weikop, Pia
AU - Sørensen, Gunnar
AU - Woldbye, David P D
AU - Wörtwein, Gitta
AU - Wess, Jürgen
AU - Fink-Jensen, Anders
PY - 2012/11
Y1 - 2012/11
N2 - Rationale 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 M 4 receptors could be a novel target for modulating psychostimulant effects of cocaine. Objectives 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 cocaineinduced 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.
AB - Rationale 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 M 4 receptors could be a novel target for modulating psychostimulant effects of cocaine. Objectives 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 cocaineinduced 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.
U2 - 10.1007/s00213-012-2751-8
DO - 10.1007/s00213-012-2751-8
M3 - Journal article
C2 - 22648127
SN - 0033-3158
VL - 224
SP - 277
EP - 287
JO - Psychopharmacology
JF - Psychopharmacology
IS - 2
ER -