TY - JOUR
T1 - Modulation of prepulse inhibition through both M(1) and M (4) muscarinic receptors in mice
AU - Thomsen, Morgane
AU - Wess, Jürgen
AU - Fulton, Brian S
AU - Fink-Jensen, Anders
AU - Caine, S Barak
PY - 2010/2/1
Y1 - 2010/2/1
N2 - Rationale: Muscarinic cholinergic M1 and M4 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 M1 receptors (M1-/-), M4 receptors (M4-/-), or both (M1-/-M4-/-). 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 M1 and M4 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 M4-/- mice, but not in female M1-/-M4-/- or female M1-/- mice. When administered before scopolamine, xanomeline restored PPI in wild-type mice and M1-/- mice, but not in M4-/- 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 M1 and M4 receptors can disrupt PPI, suggesting that (at least partially redundant) M1 and M4 receptor-dependent functions are involved in sensorimotor gating mechanisms. PPI-disrupting effects of muscarinic antagonists appeared dependent upon M1 receptor blockade. Our data also suggest that xanomeline exerts antipsychotic-like effects mainly through M4 receptor stimulation, while stimulation of non-M1/M4 subtypes may also have antipsychotic potential. Finally, our results do not support a role of M1/M4 receptors in mediating antipsychotic-like effects of clozapine.
AB - Rationale: Muscarinic cholinergic M1 and M4 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 M1 receptors (M1-/-), M4 receptors (M4-/-), or both (M1-/-M4-/-). 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 M1 and M4 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 M4-/- mice, but not in female M1-/-M4-/- or female M1-/- mice. When administered before scopolamine, xanomeline restored PPI in wild-type mice and M1-/- mice, but not in M4-/- 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 M1 and M4 receptors can disrupt PPI, suggesting that (at least partially redundant) M1 and M4 receptor-dependent functions are involved in sensorimotor gating mechanisms. PPI-disrupting effects of muscarinic antagonists appeared dependent upon M1 receptor blockade. Our data also suggest that xanomeline exerts antipsychotic-like effects mainly through M4 receptor stimulation, while stimulation of non-M1/M4 subtypes may also have antipsychotic potential. Finally, our results do not support a role of M1/M4 receptors in mediating antipsychotic-like effects of clozapine.
U2 - http://dx.doi.org/10.1007/s00213-009-1740-z
DO - http://dx.doi.org/10.1007/s00213-009-1740-z
M3 - Journal article
SN - 0033-3158
VL - 208
SP - 401
EP - 416
JO - Psychopharmacology
JF - Psychopharmacology
IS - 3
ER -