Decreased prepulse inhibition and increased sensitivity to muscarinic, but not dopaminergic drugs in M5 muscarinic acetylcholine receptor knockout mice.
BACKGROUND
Schizophrenic patients show decreased measures of sensorimotor gating, such as prepulse inhibition of startle (PPI). In preclinical models, these measures may be used to predict antipsychotic activity. While current antipsychotic drugs act largely at dopamine receptors, the muscarinic acetylcholine receptors offer promising novel pharmacotherapy targets. Of these, the M(5) receptor gene was recently implicated in susceptibility to schizophrenia. Due to the lack of selective ligands, muscarinic receptor knockout mice have been generated to elucidate the roles of the five receptor subtypes (M(1)-M(5)).


OBJECTIVE
Here, we used M(5) receptor knockout (M(5)-/-) mice to investigate the involvement of M(5) receptors in behavioral measures pertinent to schizophrenia. We tested the hypothesis that disruption of M(5) receptors affected PPI or the effects of muscarinic or dopaminergic agents in PPI or psychomotor stimulation.


METHODS
We measured PPI in M(5)-/-, heterozygous and wild-type mice without drugs, and with clozapine (0.56-3.2 mg/kg) or haloperidol (0.32-3.2 mg/kg) alone, and as pretreatment to D: -amphetamine. In addition, we evaluated locomotor stimulation by the muscarinic antagonist trihexyphenidyl (0.56-56 mg/kg) and by cocaine (3.2-56 mg/kg).


RESULTS
The M(5)-/- mice showed decreased PPI relative to wild-type mice, and clozapine appeared to reduce this difference, while haloperidol increased PPI regardless of genotype. The M(5)-/- mice also showed more locomotor stimulation by trihexyphenidyl than wild-type mice, while cocaine had similar effects between genotypes.


CONCLUSIONS
These data suggest that disruption of the M(5) receptor gene affected sensorimotor gating mechanisms, increased sensitivity to clozapine and to the psychostimulant effects of muscarinic antagonists without modifying the effect of dopaminergic drugs.
Thomsen
Morgane
M
Alcohol and Drug Abuse Research Center, McLean Hospital/Harvard Medical School, 115 Mill Street, Belmont, MA 02478, USA. mthomsen@mclean.harvard.edu
Wörtwein
Gitta
G
Fink-Jensen
Anders
A
Woldbye
David P D
DP
Wess
Jürgen
J
Caine
S Barak
SB
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001522:Behavior, Animal; D003024:Clozapine / Q000494:pharmacology*; D003042:Cocaine / Q000494:pharmacology; D003913:Dextroamphetamine / Q000494:pharmacology; D018491:Dopamine Agonists / Q000494:pharmacology*; D005260:Female; D005838:Genotype; D006220:Haloperidol / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D018721:Muscarinic Agonists / Q000494:pharmacology*; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000235:genetics; D012018:Reflex; D013216:Reflex, Startle; D012559:Schizophrenia / Q000188:drug therapy / Q000503:physiopathology; D014282:Trihexyphenidyl
D014150:Antipsychotic Agents; D018491:Dopamine Agonists; D018721:Muscarinic Agonists; D011976:Receptors, Muscarinic; D014282:Trihexyphenidyl; D003042:Cocaine; D003024:Clozapine; D006220:Haloperidol; D003913:Dextroamphetamine