title: Positive Allosteric Modulation of the Muscarinic M1 Receptor Improves Efficacy of Antipsychotics in Mouse Glutamatergic Deficit Models of Behavior.
abstract: Current antipsychotics are effective in treating the positive symptoms associated with schizophrenia, but they remain suboptimal in targeting cognitive dysfunction. Recent studies have suggested that positive allosteric modulation of the M1muscarinic 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. This study investigated the effect of the M1mAChR positive allosteric modulator BQCA [1-(4-methoxybenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid], 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 receptor antagonist, MK-801 [(5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine]. Sensorimotor gating and spatial memory induction are two models that represent aspects of schizophrenia modeled in rodents. In prepulse inhibition (an operational measure of sensorimotor gating), BQCA alone had minimal effects but exhibited different levels of efficacy in reversing MK-801-induced prepulse inhibition disruptions when combined with a subeffective 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 M1mAChR positive allosteric modulator can extend antipsychotic efficacy in glutamatergic deficit models of behavior.
authors.affiliation: Drug Discovery Biology (K.H.C.C., D.T.M, C.J.L, P.M.S, J.R.L, A.C.), Centre for Drug Candidate Optimization (D.M.S., R.T.P.), and Medicinal Chemistry (S.N.M, P.J.S.), Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia; and Melbourne Neuropsychiatry Centre, Department of Psychiatry and Centre for Neural Engineering, University of Melbourne, Melbourne, Australia (C.P.).
authors.forename: Kwok H C
authors.identifier: http://orcid.org/0000-0002-4650-2220
authors.initials: KH
authors.lastname: Choy
authors.affiliation: Drug Discovery Biology (K.H.C.C., D.T.M, C.J.L, P.M.S, J.R.L, A.C.), Centre for Drug Candidate Optimization (D.M.S., R.T.P.), and Medicinal Chemistry (S.N.M, P.J.S.), Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia; and Melbourne Neuropsychiatry Centre, Department of Psychiatry and Centre for Neural Engineering, University of Melbourne, Melbourne, Australia (C.P.).
authors.forename: David M
authors.initials: DM
authors.lastname: Shackleford
authors.affiliation: Drug Discovery Biology (K.H.C.C., D.T.M, C.J.L, P.M.S, J.R.L, A.C.), Centre for Drug Candidate Optimization (D.M.S., R.T.P.), and Medicinal Chemistry (S.N.M, P.J.S.), Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia; and Melbourne Neuropsychiatry Centre, Department of Psychiatry and Centre for Neural Engineering, University of Melbourne, Melbourne, Australia (C.P.).
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Malone
authors.affiliation: Drug Discovery Biology (K.H.C.C., D.T.M, C.J.L, P.M.S, J.R.L, A.C.), Centre for Drug Candidate Optimization (D.M.S., R.T.P.), and Medicinal Chemistry (S.N.M, P.J.S.), Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia; and Melbourne Neuropsychiatry Centre, Department of Psychiatry and Centre for Neural Engineering, University of Melbourne, Melbourne, Australia (C.P.).
authors.forename: Shailesh N
authors.initials: SN
authors.lastname: Mistry
authors.affiliation: Drug Discovery Biology (K.H.C.C., D.T.M, C.J.L, P.M.S, J.R.L, A.C.), Centre for Drug Candidate Optimization (D.M.S., R.T.P.), and Medicinal Chemistry (S.N.M, P.J.S.), Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia; and Melbourne Neuropsychiatry Centre, Department of Psychiatry and Centre for Neural Engineering, University of Melbourne, Melbourne, Australia (C.P.).
authors.forename: Rahul T
authors.initials: RT
authors.lastname: Patil
authors.affiliation: Drug Discovery Biology (K.H.C.C., D.T.M, C.J.L, P.M.S, J.R.L, A.C.), Centre for Drug Candidate Optimization (D.M.S., R.T.P.), and Medicinal Chemistry (S.N.M, P.J.S.), Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia; and Melbourne Neuropsychiatry Centre, Department of Psychiatry and Centre for Neural Engineering, University of Melbourne, Melbourne, Australia (C.P.).
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Scammells
authors.affiliation: Drug Discovery Biology (K.H.C.C., D.T.M, C.J.L, P.M.S, J.R.L, A.C.), Centre for Drug Candidate Optimization (D.M.S., R.T.P.), and Medicinal Chemistry (S.N.M, P.J.S.), Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia; and Melbourne Neuropsychiatry Centre, Department of Psychiatry and Centre for Neural Engineering, University of Melbourne, Melbourne, Australia (C.P.).
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Langmead
authors.affiliation: Drug Discovery Biology (K.H.C.C., D.T.M, C.J.L, P.M.S, J.R.L, A.C.), Centre for Drug Candidate Optimization (D.M.S., R.T.P.), and Medicinal Chemistry (S.N.M, P.J.S.), Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia; and Melbourne Neuropsychiatry Centre, Department of Psychiatry and Centre for Neural Engineering, University of Melbourne, Melbourne, Australia (C.P.).
authors.forename: Christos
authors.initials: C
authors.lastname: Pantelis
authors.affiliation: Drug Discovery Biology (K.H.C.C., D.T.M, C.J.L, P.M.S, J.R.L, A.C.), Centre for Drug Candidate Optimization (D.M.S., R.T.P.), and Medicinal Chemistry (S.N.M, P.J.S.), Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia; and Melbourne Neuropsychiatry Centre, Department of Psychiatry and Centre for Neural Engineering, University of Melbourne, Melbourne, Australia (C.P.).
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Sexton
authors.affiliation: Drug Discovery Biology (K.H.C.C., D.T.M, C.J.L, P.M.S, J.R.L, A.C.), Centre for Drug Candidate Optimization (D.M.S., R.T.P.), and Medicinal Chemistry (S.N.M, P.J.S.), Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia; and Melbourne Neuropsychiatry Centre, Department of Psychiatry and Centre for Neural Engineering, University of Melbourne, Melbourne, Australia (C.P.).
authors.forename: Johnathan R
authors.initials: JR
authors.lastname: Lane
authors.affiliation: Drug Discovery Biology (K.H.C.C., D.T.M, C.J.L, P.M.S, J.R.L, A.C.), Centre for Drug Candidate Optimization (D.M.S., R.T.P.), and Medicinal Chemistry (S.N.M, P.J.S.), Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia; and Melbourne Neuropsychiatry Centre, Department of Psychiatry and Centre for Neural Engineering, University of Melbourne, Melbourne, Australia (C.P.) arthur.christopoulos@monash.edu rob.lane@monash.edu.
authors.forename: Arthur
authors.initials: A
authors.lastname: Christopoulos
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005971:Glutamates / Q000378:metabolism*; D006801:Humans; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D051379:Mice; D065808:Prepulse Inhibition / Q000187:drug effects; D011804:Quinolines / Q000494:pharmacology*; D043643:Receptor, Muscarinic M1 / Q000737:chemistry / Q000378:metabolism*
chemical_list: C583161:1-(4-methoxybenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; D014150:Antipsychotic Agents; D005971:Glutamates; D011804:Quinolines; D043643:Receptor, Muscarinic M1; D016291:Dizocilpine Maleate; D000109:Acetylcholine