Positive Allosteric Modulation of the Muscarinic M₁Receptor 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 M 1 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. This study investigated the effect of the M 1 mAChR 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)-(1)-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 M 1 2/2 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 M 1 mAChR positive allosteric modulator can extend antipsychotic efficacy in glutamatergic deficit models of behavior.

M1-positive allosteric modulators lacking agonist activity provide the optimal profile for enhancing cognition

“…Future studies are necessary to develop a better understanding of the mechanisms by which M 1 PAMs enhance cognitive function and whether allosteric modulators that display stimulus bias can be used to selectively modulate specific aspects of M 1 signaling and in vivo activity. Lastly, while these studies shed light on the different properties of structurally distinct M 1 PAMs, recent literature has shown that sub-efficacious doses of M 1 PAMs co-administered with sub-efficacious concentrations of cholinesterase inhibitors [44,45] or antipsychotics [46] can yield efficacy in animal models. However, future studies are necessary to fully evaluate the clinical implications M 1 PAMs used in conjunction with currently approved neuropsychiatric medications.…”

Biased M1positive allosteric modulators reveal novel role of phospholipase D in M1-dependent rodent cortical plasticity

“…To date, we and others have identified highly subtype-selective positive allosteric modulators (PAMs) of the M1 receptor that avoid activation of other mAChR subtypes (see reviews (10)(11)(12)). Importantly, M1 PAMs have shown robust efficacy in enhancing cognition and rescuing cognitive deficits in preclinical animal models relevant for AD and schizophrenia (13)(14)(15)(16)(17)(18).…”

Allosteric Modulation of GPCRs: New Insights and Potential Utility for Treatment of Schizophrenia and Other CNS Disorders

“…Taken together with multiple studies demonstrating robust effects of M 1 PAMs on other aspects of cognitive function, these studies support the exciting possibility that highly selective M 1 PAMs may provide a novel approach for reducing cognitive deficits and negative symptoms associated with changes in cortical plasticity in schizophrenia patients. Furthermore, while M 4 PAMs are likely to have more robust antipsychotic-like effects, M 1 PAMs can augment the antipsychotic-like effects of atypical antipsychotics in wild type, but not M 1 knock-out mice (Choy et al, 2016). Accordingly, M 1 PAMs either alone or in combination with current antipsychotics, have the potential to provide comprehensive relief across symptom clusters.…”