Using cholinergic M1 receptor positive allosteric modulators to improve memory via enhancement of brain cholinergic communication

Chambon, Caroline; Jatzke, Claudia; Wegener, Nico; Gravius, Andreas; Danysz, Wojciech

doi:10.1016/j.ejphar.2012.10.011

Cited by 29 publications

(36 citation statements)

References 23 publications

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“…By binding to the allosteric site, muscarinic PAMs increase the affinity of the receptor for ACh at the orthosteric binding site and consequentially potentiate the receptors response to ACh (see Conn et al, 2009;Melancon et al, 2012;Nickols and Conn, 2014). BQCA, is a potent, highly selective M1 receptor PAM that has been reported to express antipsychotic drug-like qualities and produce pro-cognitive responses, including enhancing memory function and increasing spontaneous prefrontal brain activity in transgenic mice/rat models (Chambon et al, 2012;Chambon et al, 2011;Ma et al, 2009;Shirey et al, 2008). Likewise, PQCA is another highly selective M1 receptor PAM that has been reported to enhance cognitive function in both rat and non-human primates and without any of the gastrointestinal issues elicited by xanomeline (Uslaner et al, 2013;Vardigan et al, 2014).…”

Section: Referencementioning

confidence: 99%

The muscarinic system, cognition and schizophrenia

Carruthers

Gurvich

Rossell

2015

Neuroscience & Biobehavioral Reviews

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Section: Referencementioning

confidence: 99%

The muscarinic system, cognition and schizophrenia

Carruthers

Gurvich

Rossell

2015

Neuroscience & Biobehavioral Reviews

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“…The hippocampus has a high expression of M 1 mAChRs, which are important for memory formation in rodents (Talts et al, 1998;Anagnostaras et al, 2003;Lee and Kesner, 2003;Newell et al, 2007;Mauck et al, 2010;Peng et al, 2012). Indeed, BQCA enhances baseline spatial and object recognition memory in rodents (Chambon et al, 2011(Chambon et al, , 2012, reverses scopolamine-disrupted fear and working memory, and restores memory function in Tg2576 mice (Ma et al, 2009;Shirey et al, 2009;Chambon et al, 2012). To our knowledge, however, ours is the first study to extend these effects to rescue of MK-801-induced memory impairments, albeit in the presence of a coadministered antipsychotic.…”

Section: Discussionmentioning

confidence: 59%

“…Encouragingly, mAChRs possess spatially distinct allosteric sites that offer alternative strategies for greater selectivity (Christopoulos, 2002;Bridges et al, 2010;Bolbecker and Shekhar, 2012;Conn et al, 2014;Kruse et al, 2014;Thal et al, 2016). BQCA [1-(4-methoxybenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid], a highly selective M 1 mAChR positive allosteric modulator (PAM) with no reported off-target activities, reversed scopolamine-disrupted memory, rescued memory deficits in a mouse model of Alzheimer disease, and also had procognitive effects on baseline memory performance (Ma et al, 2009;Shirey et al, 2009;Chambon et al, 2011Chambon et al, , 2012Galloway et al, 2014). The effects may be due to activation of neurons in the prefrontal cortex and hippocampus, as these regions express high levels of M 1 mAChRs (Porter et al, 2002;Ma et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Positive Allosteric Modulation of the Muscarinic M₁Receptor Improves Efficacy of Antipsychotics in Mouse Glutamatergic Deficit Models of Behavior

Choy

Shackleford

Malone

et al. 2016

J Pharmacol Exp Ther

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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.

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“…In the presence of muscarinic antagonists, both M1 and M2 selective agonists can improve memory deficits, with the M1 agonists potentially reversing some of the postsynaptic effects of scopolamine and the M2 potentially reducing the amount of acetylcholine release (Chambon et al 2012; Nakahara et al 1990; Stone et al 1991; Wanibuchi et al 1994). …”

Section: Discussionmentioning

confidence: 99%

Attenuation in rats of impairments of memory by scopolamine, a muscarinic receptor antagonist, by mecamylamine, a nicotinic receptor antagonist

Newman

Gold

2015

Psychopharmacology

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Rationale Scopolamine, a muscarinic antagonist, impairs learning and memory for many tasks, supporting an important role for the cholinergic system in these cognitive functions. The findings are most often interpreted to indicate that a decrease in postsynaptic muscarinic receptor activation mediates the memory impairments. However, scopolamine also results in increased release of acetylcholine in the brain as a result of blocking presynaptic muscarinic receptors. Objectives The present experiments assess whether scopolamine-induced increases in acetylcholine release may impair memory by overstimulating postsynaptic cholinergic nicotinic receptors, i.e., by reaching the high end of a nicotinic receptor activation inverted-U dose-response function. Results Rats tested in a spontaneous alternation task showed dose-dependent working memory deficits with systemic injections of mecamylamine and scopolamine. When an amnestic dose of scopolamine (0.15 mg/kg) was co-administered with a subamnestic dose of mecamylamine (0.25 mg/kg), this dose of mecamylamine significantly attenuated the scopolamine-induced memory impairments. We next assessed the levels of acetylcholine release in the hippocampus in the presence of scopolamine and mecamylamine. Mecamylamine injections resulted in decreased release of acetylcholine, while scopolamine administration caused a large increase in acetylcholine release. Conclusions These findings indicate that a nicotinic antagonist can attenuate impairments in memory produced by a muscarinic antagonist. The nicotinic antagonist may block excessive activation of nicotinic receptors postsynaptically or attenuate increases in acetylcholine release presynaptically. Either effect of a nicotinic antagonist—to decrease scopolamine-induced increases in acetylcholine output or to decrease post-synaptic acetylcholine receptor activation—may mediate the negative effects on memory of muscarinic antagonists.

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Using cholinergic M1 receptor positive allosteric modulators to improve memory via enhancement of brain cholinergic communication

Cited by 29 publications

References 23 publications

The muscarinic system, cognition and schizophrenia

The muscarinic system, cognition and schizophrenia

Positive Allosteric Modulation of the Muscarinic M₁Receptor Improves Efficacy of Antipsychotics in Mouse Glutamatergic Deficit Models of Behavior

Attenuation in rats of impairments of memory by scopolamine, a muscarinic receptor antagonist, by mecamylamine, a nicotinic receptor antagonist

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Using cholinergic M1 receptor positive allosteric modulators to improve memory via enhancement of brain cholinergic communication

Cited by 29 publications

References 23 publications

The muscarinic system, cognition and schizophrenia

The muscarinic system, cognition and schizophrenia

Positive Allosteric Modulation of the Muscarinic M1Receptor Improves Efficacy of Antipsychotics in Mouse Glutamatergic Deficit Models of Behavior

Attenuation in rats of impairments of memory by scopolamine, a muscarinic receptor antagonist, by mecamylamine, a nicotinic receptor antagonist

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Positive Allosteric Modulation of the Muscarinic M₁Receptor Improves Efficacy of Antipsychotics in Mouse Glutamatergic Deficit Models of Behavior