Decreased prepulse inhibition and increased sensitivity to muscarinic, but not dopaminergic drugs in M5 muscarinic acetylcholine receptor knockout mice

• Published in: Psychopharmacologia Vol. 192; no. 1; pp. 97 - 110
• Main Authors: THOMSEN, Morgane, WÖRTWEIN, Gitta, FINK-JENSEN, Anders, WOLDBYE, David P. D, WESS, Jurgen, CAINE, S. Barak
• Format: Journal Article
• Language: English
• Published: Berlin Springer 01.05.2007; Springer Nature B.V
• Subjects: Acetylcholine receptors (muscarinic); Amphetamines; Animals; Antagonists; Antipsychotic Agents - pharmacology; Antipsychotics; Behavior, Animal; Biological and medical sciences; Channel gating; Clozapine; Clozapine - pharmacology; Cocaine; Cocaine - pharmacology; Dextroamphetamine - pharmacology; Dopamine Agonists - pharmacology; Dopamine receptors; Drug therapy; Drugs; Female; Genotype; Genotypes; Haloperidol; Haloperidol - pharmacology; Inhibitor drugs; Male; Medical sciences; Mental disorders; Mice; Mice, Inbred C57BL; Mice, Knockout; Motor Activity - drug effects; Muscarinic Agonists - pharmacology; Neuropharmacology; Pharmacology; Pharmacology. Drug treatments; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psycholeptics: tranquillizer, neuroleptic; Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Psychotropic drugs; Receptors, Muscarinic - drug effects; Receptors, Muscarinic - genetics; Reflex; Reflex, Startle; Rodents; Schizophrenia; Schizophrenia - drug therapy; Schizophrenia - physiopathology; Sensorimotor gating; Trihexyphenidyl; Drug; Dopamine; CNS stimulant; Neuroleptic; Psychotropic; M5 muscarinic receptor; M5; Catecholamine; Chemotherapy; Cholinergic receptor; Sensitivity; Treatment; Knockout mouse; Neurotransmitter; Antipsychotic; Acetylcholine; Muscarinic receptor; Muscarinic· Acetylcholine receptor; Prepulse inhibition; Psychostimulant·Antipsychotic· Knockout mice
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-006-0682-y

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)). 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. 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). 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. 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.