TY - JOUR T1 - Positive allosteric modulation of the muscarinic M<sub>1</sub> receptor improves efficacy of antipsychotics in mouse glutamatergic deficit models of behavior JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.116.235788 SP - jpet.116.235788 AU - Kwok HC Choy AU - David M Shackleford AU - Daniel T Malone AU - Shailesh N Mistry AU - Rahul T Patil AU - Peter J Scammells AU - Christopher J Langmead AU - Christos Pantelis AU - Patrick M Sexton AU - Johnathan R Lane AU - Arthur Christopoulos Y1 - 2016/01/01 UR - http://jpet.aspetjournals.org/content/early/2016/09/14/jpet.116.235788.abstract N2 - Current antipsychotics are effective in treating the positive symptoms, but remain suboptimal in targeting cognitive dysfunction, associated with schizophrenia. Recent studies have suggested that positive allosteric modulation of the M1 muscarinic acetylcholine receptor (mAChR) may provide a novel means of improving cognition. However, very little is known about the potential of combination therapies in extending coverage across schizophrenic symptom domains. The current study investigated the effect of the M1 mAChR positive allosteric modulator (PAM), 1-(4-methoxybenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (BQCA), alone or in combination with haloperidol (a first generation antipsychotic), clozapine (a second generation atypical antipsychotic), or aripiprazole (a third generation atypical antipsychotic), in reversing deficits in sensorimotor gating and spatial memory induced by the N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801; two models that represent aspects of schizophrenia modeled in rodents. In prepulse inhibition (PPI), an operational measure of sensorimotor gating, BQCA alone had minimal effects, but exhibited different levels of efficacy in reversing MK-801-induced PPI disruptions when combined with a sub-effective dose of each of the three (currently-prescribed) antipsychotics. Furthermore, the combined effect of BQCA and clozapine was absent in M1-/- mice. Interestingly, although BQCA alone had no effect in reversing MK-801-induced memory impairments in a Y-maze spatial test, we observed a reversal upon the combination of BQCA with atypical antipsychotics, but not with haloperidol. These findings provide proof-of-concept that a judicious combination of existing antipsychotics with a selective M1 mAChR PAM can extend antipsychotic efficacy in glutamatergic deficit models of behavior. ER -