Increased amphetamine-induced locomotor activity, sensitization, and accumbal dopamine release in M5 muscarinic receptor knockout mice.
BACKGROUND
Muscarinic M(5) 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 M(5) receptors modulate their activity. Previous studies showed that M(5) receptor knockout (M (5) (-/-) ) mice are less sensitive to the reinforcing properties of addictive drugs.


METHODS
Here, we investigate the role of M(5) 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.


METHODS
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.


CONCLUSIONS
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 M(5) receptor. These results support the concept that the M(5) receptor modulates effects of addictive drugs.
Schmidt
Lene S
LS
Laboratory of Neuropsychiatry, Psychiatric Center, Rigshospitalet, O-6102, Blegdamsvej 3, 2100 Copenhagen, Denmark.
Miller
Anthony D
AD
Lester
Deranda B
DB
Bay-Richter
Cecilie
C
Schülein
Christina
C
Frikke-Schmidt
Henriette
H
Wess
Jürgen
J
Blaha
Charles D
CD
Woldbye
David P D
DP
Fink-Jensen
Anders
A
Wortwein
Gitta
G
D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D003042:Cocaine / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D043642:Receptor, Muscarinic M5 / Q000235:genetics / Q000378:metabolism*
D018765:Dopamine Uptake Inhibitors; D043642:Receptor, Muscarinic M5; D000661:Amphetamine; D003042:Cocaine; D004298:Dopamine