Increased amphetamine-induced locomotor activity, sensitization, and accumbal dopamine release in M5 muscarinic receptor knockout mice

Lene S Schmidt; Anthony D Miller; Deranda B Lester; Cecilie Bay-Richter; Christina Schülein; Henriette Frikke-Schmidt; Jürgen Wess; Charles D Blaha; David P D Woldbye; Anders Fink-Jensen; Gitta Wörtwein

doi:10.1007/s00213-009-1685-2

Increased amphetamine-induced locomotor activity, sensitization, and accumbal dopamine release in M5 muscarinic receptor knockout mice

Lene S Schmidt, Anthony D Miller, Deranda B Lester, Cecilie Bay-Richter, Christina Schülein, Henriette Frikke-Schmidt, Jürgen Wess, Charles D Blaha, David P D Woldbye, Anders Fink-Jensen, Gitta Wörtwein

27 Citations (Scopus)

Abstract

Introduction: Muscarinic M₅ receptors are the only muscarinic receptor subtype expressed by dopamine-containing neurons of the ventral tegmental area. These cells play an important role for the reinforcing properties of psychostimulants and M₅ receptors modulate their activity. Previous studies showed that M₅ receptor knockout (M ₅ ^-/- ) mice are less sensitive to the reinforcing properties of addictive drugs. Materials and methods: Here, we investigate the role of M₅ receptors in the effects of amphetamine and cocaine on locomotor activity, locomotor sensitization, and dopamine release using M ₅ ^-/- mice backcrossed to the C57BL/6NTac strain. Statistical analyses: Sensitization of the locomotor response is considered a model for chronic adaptations to repeated substance exposure, which might be related to drug craving and relapse. The effects of amphetamine on locomotor activity and locomotor sensitization were enhanced in M ₅ ^-/- mice, while the effects of cocaine were similar in M ₅ ^-/- and wild-type mice. Results: Consistent with the behavioral results, amphetamine-, but not cocaine, -elicited dopamine release in nucleus accumbens was enhanced in M ₅ ^-/- mice. Discussion: The different effects of amphetamine and cocaine in M ₅ ^-/- mice may be due to the divergent pharmacological profile of the two drugs, where amphetamine, but not cocaine, is able to release intracellular stores of dopamine. In conclusion, we show here for the first time that amphetamine-induced hyperactivity and dopamine release as well as amphetamine sensitization are enhanced in mice lacking the M₅ receptor. These results support the concept that the M₅ receptor modulates effects of addictive drugs.

Original language	English
Journal	Psychopharmacology
Volume	207
Issue number	4
Pages (from-to)	547-58
Number of pages	11
ISSN	0033-3158
DOIs	https://doi.org/10.1007/s00213-009-1685-2
Publication status	Published - Jan 2010

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Schmidt, L. S., Miller, A. D., Lester, D. B., Bay-Richter, C., Schülein, C., Frikke-Schmidt, H., Wess, J., Blaha, C. D., Woldbye, D. P. D., Fink-Jensen, A., & Wörtwein, G. (2010). Increased amphetamine-induced locomotor activity, sensitization, and accumbal dopamine release in M5 muscarinic receptor knockout mice. Psychopharmacology, 207(4), 547-58. https://doi.org/10.1007/s00213-009-1685-2

Schmidt, LS, Miller, AD, Lester, DB, Bay-Richter, C, Schülein, C, Frikke-Schmidt, H, Wess, J, Blaha, CD, Woldbye, DPD , Fink-Jensen, A & Wörtwein, G 2010, 'Increased amphetamine-induced locomotor activity, sensitization, and accumbal dopamine release in M5 muscarinic receptor knockout mice', Psychopharmacology, vol. 207, no. 4, pp. 547-58. https://doi.org/10.1007/s00213-009-1685-2

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title = "Increased amphetamine-induced locomotor activity, sensitization, and accumbal dopamine release in M5 muscarinic receptor knockout mice",

abstract = "Introduction: Muscarinic M5 receptors are the only muscarinic receptor subtype expressed by dopamine-containing neurons of the ventral tegmental area. These cells play an important role for the reinforcing properties of psychostimulants and M5 receptors modulate their activity. Previous studies showed that M5 receptor knockout (M 5 -/- ) mice are less sensitive to the reinforcing properties of addictive drugs. Materials and methods: Here, we investigate the role of M5 receptors in the effects of amphetamine and cocaine on locomotor activity, locomotor sensitization, and dopamine release using M 5 -/- mice backcrossed to the C57BL/6NTac strain. Statistical analyses: Sensitization of the locomotor response is considered a model for chronic adaptations to repeated substance exposure, which might be related to drug craving and relapse. The effects of amphetamine on locomotor activity and locomotor sensitization were enhanced in M 5 -/- mice, while the effects of cocaine were similar in M 5 -/- and wild-type mice. Results: Consistent with the behavioral results, amphetamine-, but not cocaine, -elicited dopamine release in nucleus accumbens was enhanced in M 5 -/- mice. Discussion: The different effects of amphetamine and cocaine in M 5 -/- mice may be due to the divergent pharmacological profile of the two drugs, where amphetamine, but not cocaine, is able to release intracellular stores of dopamine. In conclusion, we show here for the first time that amphetamine-induced hyperactivity and dopamine release as well as amphetamine sensitization are enhanced in mice lacking the M5 receptor. These results support the concept that the M5 receptor modulates effects of addictive drugs.",

author = "Schmidt, {Lene S} and Miller, {Anthony D} and Lester, {Deranda B} and Cecilie Bay-Richter and Christina Sch{\"u}lein and Henriette Frikke-Schmidt and J{\"u}rgen Wess and Blaha, {Charles D} and Woldbye, {David P D} and Anders Fink-Jensen and Gitta W{\"o}rtwein",

note = "Keywords: Amphetamine; Animals; Cocaine; Dopamine; Dopamine Uptake Inhibitors; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Motor Activity; Nucleus Accumbens; Receptor, Muscarinic M5",

year = "2010",

month = jan,

doi = "10.1007/s00213-009-1685-2",

language = "English",

volume = "207",

pages = "547--58",

journal = "Psychopharmacology",

issn = "0033-3158",

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T1 - Increased amphetamine-induced locomotor activity, sensitization, and accumbal dopamine release in M5 muscarinic receptor knockout mice

AU - Schmidt, Lene S

AU - Miller, Anthony D

AU - Lester, Deranda B

AU - Bay-Richter, Cecilie

AU - Schülein, Christina

AU - Frikke-Schmidt, Henriette

AU - Wess, Jürgen

AU - Blaha, Charles D

AU - Woldbye, David P D

AU - Fink-Jensen, Anders

AU - Wörtwein, Gitta

N1 - Keywords: Amphetamine; Animals; Cocaine; Dopamine; Dopamine Uptake Inhibitors; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Motor Activity; Nucleus Accumbens; Receptor, Muscarinic M5

PY - 2010/1

Y1 - 2010/1

N2 - Introduction: Muscarinic M5 receptors are the only muscarinic receptor subtype expressed by dopamine-containing neurons of the ventral tegmental area. These cells play an important role for the reinforcing properties of psychostimulants and M5 receptors modulate their activity. Previous studies showed that M5 receptor knockout (M 5 -/- ) mice are less sensitive to the reinforcing properties of addictive drugs. Materials and methods: Here, we investigate the role of M5 receptors in the effects of amphetamine and cocaine on locomotor activity, locomotor sensitization, and dopamine release using M 5 -/- mice backcrossed to the C57BL/6NTac strain. Statistical analyses: Sensitization of the locomotor response is considered a model for chronic adaptations to repeated substance exposure, which might be related to drug craving and relapse. The effects of amphetamine on locomotor activity and locomotor sensitization were enhanced in M 5 -/- mice, while the effects of cocaine were similar in M 5 -/- and wild-type mice. Results: Consistent with the behavioral results, amphetamine-, but not cocaine, -elicited dopamine release in nucleus accumbens was enhanced in M 5 -/- mice. Discussion: The different effects of amphetamine and cocaine in M 5 -/- mice may be due to the divergent pharmacological profile of the two drugs, where amphetamine, but not cocaine, is able to release intracellular stores of dopamine. In conclusion, we show here for the first time that amphetamine-induced hyperactivity and dopamine release as well as amphetamine sensitization are enhanced in mice lacking the M5 receptor. These results support the concept that the M5 receptor modulates effects of addictive drugs.

AB - Introduction: Muscarinic M5 receptors are the only muscarinic receptor subtype expressed by dopamine-containing neurons of the ventral tegmental area. These cells play an important role for the reinforcing properties of psychostimulants and M5 receptors modulate their activity. Previous studies showed that M5 receptor knockout (M 5 -/- ) mice are less sensitive to the reinforcing properties of addictive drugs. Materials and methods: Here, we investigate the role of M5 receptors in the effects of amphetamine and cocaine on locomotor activity, locomotor sensitization, and dopamine release using M 5 -/- mice backcrossed to the C57BL/6NTac strain. Statistical analyses: Sensitization of the locomotor response is considered a model for chronic adaptations to repeated substance exposure, which might be related to drug craving and relapse. The effects of amphetamine on locomotor activity and locomotor sensitization were enhanced in M 5 -/- mice, while the effects of cocaine were similar in M 5 -/- and wild-type mice. Results: Consistent with the behavioral results, amphetamine-, but not cocaine, -elicited dopamine release in nucleus accumbens was enhanced in M 5 -/- mice. Discussion: The different effects of amphetamine and cocaine in M 5 -/- mice may be due to the divergent pharmacological profile of the two drugs, where amphetamine, but not cocaine, is able to release intracellular stores of dopamine. In conclusion, we show here for the first time that amphetamine-induced hyperactivity and dopamine release as well as amphetamine sensitization are enhanced in mice lacking the M5 receptor. These results support the concept that the M5 receptor modulates effects of addictive drugs.

U2 - 10.1007/s00213-009-1685-2

DO - 10.1007/s00213-009-1685-2

M3 - Journal article

C2 - 19820917

SN - 0033-3158

VL - 207

SP - 547

EP - 558

JO - Psychopharmacology

JF - Psychopharmacology

IS - 4

ER -

Increased amphetamine-induced locomotor activity, sensitization, and accumbal dopamine release in M5 muscarinic receptor knockout mice

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