Modulation of prepulse inhibition through both M(1) and M (4) muscarinic receptors in mice.
BACKGROUND
Muscarinic cholinergic M(1) and M(4) receptors may participate in schizophrenia's etiology and have been proposed as targets for antipsychotic medications.


OBJECTIVE
Here, we investigated the involvement of these receptors in behavioral measures pertinent to schizophrenia using knockout mice lacking M(1) receptors (M(1)-/-), M(4) receptors (M(4)-/-), or both (M(1)-/-M(4)-/-).


METHODS
We measured prepulse inhibition (PPI) of startle without drugs and after treatment with scopolamine (0.32-1.8 mg/kg), xanomeline (3.2 mg/kg), oxotremorine (0.032-0.1 mg/kg), clozapine (1.0-5.6 mg/kg), or haloperidol (0.32-3.2 mg/kg).


RESULTS
In female (but not male) mice, combined deletion of both M(1) and M(4) receptors decreased PPI relative to wild-type mice, while knockout of either receptor alone had no significant effect. Scopolamine disrupted PPI in wild-type and M(4)-/- mice, but not in female M(1)-/-M(4)-/- or female M(1)-/- mice. When administered before scopolamine, xanomeline restored PPI in wild-type mice and M(1)-/- mice, but not in M(4)-/- mice. In contrast, pretreatment with oxotremorine increased PPI regardless of genotype. Effects of clozapine and haloperidol on PPI were not hindered by either mutation.


CONCLUSIONS
Deletion of both M(1) and M(4) receptors can disrupt PPI, suggesting that (at least partially redundant) M(1) and M(4) receptor-dependent functions are involved in sensorimotor gating mechanisms. PPI-disrupting effects of muscarinic antagonists appeared dependent upon M(1) receptor blockade. Our data also suggest that xanomeline exerts antipsychotic-like effects mainly through M(4) receptor stimulation, while stimulation of non-M(1)/M(4) subtypes may also have antipsychotic potential. Finally, our results do not support a role of M(1)/M(4) receptors in mediating antipsychotic-like effects of clozapine.
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
Wess
Jürgen
J
Fulton
Brian S
BS
Fink-Jensen
Anders
A
Caine
S Barak
SB
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D003024:Clozapine / Q000494:pharmacology; D005260:Female; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018721:Muscarinic Agonists / Q000494:pharmacology*; D018727:Muscarinic Antagonists / Q000494:pharmacology; D010095:Oxotremorine / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D043643:Receptor, Muscarinic M1 / Q000502:physiology*; D043588:Receptor, Muscarinic M4 / Q000502:physiology*; D013216:Reflex, Startle / Q000187:drug effects* / Q000502:physiology; D012601:Scopolamine / Q000494:pharmacology; D013830:Thiadiazoles / Q000494:pharmacology
D014150:Antipsychotic Agents; D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D011725:Pyridines; D043643:Receptor, Muscarinic M1; D043588:Receptor, Muscarinic M4; D013830:Thiadiazoles; D010095:Oxotremorine; C075257:xanomeline; D012601:Scopolamine; D003024:Clozapine; D006220:Haloperidol