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

Ditte Dencker Nielsen; Pia Weikop; Gunnar Sørensen; David P D Woldbye; Gitta Wörtwein; Jürgen Wess; Anders Fink-Jensen

doi:10.1007/s00213-012-2751-8

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

Ditte Dencker Nielsen, Pia Weikop, Gunnar Sørensen, David P D Woldbye, Gitta Wörtwein, Jürgen Wess, Anders Fink-Jensen

36 Citations (Scopus)

Abstract

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.

Original language	English
Journal	Psychopharmacology
Volume	224
Issue number	2
Pages (from-to)	277-87
Number of pages	11
ISSN	0033-3158
DOIs	https://doi.org/10.1007/s00213-012-2751-8
Publication status	Published - Nov 2012

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10.1007/s00213-012-2751-8

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@article{81711a0520924d6ea87b725296bfcb77,

title = "An allosteric enhancer of M4 muscarinic acetylcholine receptor function inhibits behavioral and neurochemical effects of cocaine",

abstract = "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.",

author = "Nielsen, {Ditte Dencker} and Pia Weikop and Gunnar S{\o}rensen and Woldbye, {David P D} and Gitta W{\"o}rtwein and J{\"u}rgen Wess and Anders Fink-Jensen",

year = "2012",

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doi = "10.1007/s00213-012-2751-8",

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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.

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DO - 10.1007/s00213-012-2751-8

M3 - Journal article

C2 - 22648127

SN - 0033-3158

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SP - 277

EP - 287

JO - Psychopharmacology

JF - Psychopharmacology

IS - 2

ER -

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

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