The selective positive allosteric M1 muscarinic receptor modulator PQCA attenuates learning and memory deficits in the Tg2576 Alzheimer's disease mouse model

Puri, Vanita; Wang, Xiaohai; Vardigan, Joshua D.; Kuduk, Scott D.; Uslaner, Jason M.

doi:10.1016/j.bbr.2015.03.029

Cited by 40 publications

(24 citation statements)

References 29 publications

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“…Characterization of these compounds in rodent and non-human primate cognition models have further supported the hypothesis that the M 1 receptor activation contributes to the pro-cognitive effects of nonselective muscarinic receptor activators (Uslaner et al, 2013;Ma et al, 2009;Puri et al, 2015;Lange et al, 2015) and is not responsible for the gastrointestinal side-effects (although some recent data suggests that M 1 activation could contribute to gastrointestinal effects (Alt et al, 2016;Davoren et al, 2017)). These findings suggested that a selective M 1 receptor activator could have pro-cognitive effects in humans with a greater therapeutic window than the current standard of care.…”

Section: Introductionmentioning

confidence: 86%

Preclinical to Human Translational Pharmacology of the Novel M₁ Positive Allosteric Modulator MK-7622

Uslaner¹,

Kuduk²,

Wittmann³

et al. 2018

J Pharmacol Exp Ther

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Section: Introductionmentioning

confidence: 86%

Preclinical to Human Translational Pharmacology of the Novel M₁ Positive Allosteric Modulator MK-7622

Uslaner¹,

Kuduk²,

Wittmann³

et al. 2018

J Pharmacol Exp Ther

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“…Although much emphasis has been placed on the role of M 1 in learning deficits such as those observed in models of Alzheimer's disease (Medeiros et al 2011;Puri et al 2015), our finding that M 3 knockdown in DH had a greater impact on learning than M 1 knockdown suggests a more important role for M 3 in context memory. This is supported by work showing that both M 3 knockout mice and mice with M 3 phosphorylation deficiency have deficits in contextual fear conditioning (Poulin et al 2010).…”

Section: Discussionmentioning

confidence: 64%

Muscarinic acetylcholine receptors act in synergy to facilitate learning and memory

et al. 2016

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Understanding how episodic memories are formed and retrieved is necessary if we are to treat disorders in which they malfunction. Muscarinic acetylcholine receptors (mAChR) in the hippocampus and cortex underlie memory formation, but there is conflicting evidence regarding their role in memory retrieval. Additionally, there is no consensus on which mAChR subtypes are critical for memory processing. Using pharmacological and genetic approaches, we found that (1) encoding and retrieval of contextual memory requires mAChR in the dorsal hippocampus (DH) and retrosplenial cortex (RSC), (2) memory formation requires hippocampal M 3 and cooperative activity of RSC M 1 and M 3, and (3) memory retrieval is more impaired by inactivation of multiple M 1 -M 4 mAChR in DH or RSC than inactivation of individual receptor subtypes. Contrary to the view that acetylcholine supports learning but is detrimental to memory retrieval, we found that coactivation of multiple mAChR is required for retrieval of both recently and remotely acquired context memories. Manipulations with higher receptor specificity were generally less potent than manipulations targeting multiple receptor subtypes, suggesting that mAChR act in synergy to regulate memory processes. These findings provide unique insight into the development of therapies for amnestic symptoms, suggesting that broadly acting, rather than receptor-specific, mAchR agonists and positive allosteric modulators may be the most effective therapeutic approach.

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“…Since it was previously reported based upon binding studies that efavirenz does not interact with muscarinic receptors [9], and our data indicated that it inhibits the agonist responses at the human M 3 receptor, we investigated if efavirenz interacts with a different G q -coupled muscarinic receptor. The M 1 receptor was selected because it is the predominant muscarinic receptor in the brain, and because it plays an important role in cognition and learning and memory [38–41]. CHO cells stably expressing the human M 1 receptor were used, to test for possible interactions of efavirenz with the M 1 receptor.…”

Section: Resultsmentioning

confidence: 99%

Molecular mechanisms of serotonergic action of the HIV-1 antiretroviral efavirenz

Dalwadi

Kim

Chen

et al. 2016

Pharmacological Research

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Efavirenz is highly effective at suppressing HIV-1, and the WHO guidelines list it as a component of the first-line antiretroviral (ARV) therapies for treatment-naïve patients. Though the pharmacological basis is unclear, efavirenz is commonly associated with a risk for neuropsychiatric adverse events (NPAEs) when taken at the prescribed dose. In many patients these NPAEs appear to subside after several weeks of treatment, though long-term studies show that in some patients the NPAEs persist. In a recent study focusing on the abuse potential of efavirenz, its receptor psychopharmacology was reported to include interactions with a number of established molecular targets for known drugs of abuse, and it displayed a prevailing behavioral profile in rodents resembling an LSD-like activity. In this report, we discovered interactions with additional serotonergic targets that may be associated with efavirenz-induced NPAEs. The most robust interactions were with 5-HT3A and 5-HT6 receptors, with more modest interactions noted for the 5-HT2B receptor and monoamine oxidase A. From a molecular mechanistic perspective, efavirenz acts as a 5-HT6 receptor inverse agonist of Gs-signaling, 5-HT2A and 5-HT2C antagonist of Gq-signaling, and a blocker of the 5-HT3A receptor currents. Efavirenz also completely or partially blocks agonist stimulation of the M1 and M3 muscarinic receptors, respectively. Schild analysis suggests that efavirenz competes for the same site on the 5-HT2A receptor as two known hallucinogenic partial agonists (±)-DOI and LSD. Prolonged exposure to efavirenz reduces 5-HT2A receptor density and responsiveness to 5-HT. Other ARVs such as zidovudine, nevirapine and emtricitabine did not share the same complex pharmacological profile as efavirenz, though some of them weakly interact with the 5-HT6 receptor or modestly block GABAA currents.

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The selective positive allosteric M1 muscarinic receptor modulator PQCA attenuates learning and memory deficits in the Tg2576 Alzheimer's disease mouse model

Cited by 40 publications

References 29 publications

Preclinical to Human Translational Pharmacology of the Novel M₁ Positive Allosteric Modulator MK-7622

Preclinical to Human Translational Pharmacology of the Novel M₁ Positive Allosteric Modulator MK-7622

Muscarinic acetylcholine receptors act in synergy to facilitate learning and memory

Molecular mechanisms of serotonergic action of the HIV-1 antiretroviral efavirenz

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The selective positive allosteric M1 muscarinic receptor modulator PQCA attenuates learning and memory deficits in the Tg2576 Alzheimer's disease mouse model

Cited by 40 publications

References 29 publications

Preclinical to Human Translational Pharmacology of the Novel M1 Positive Allosteric Modulator MK-7622

Preclinical to Human Translational Pharmacology of the Novel M1 Positive Allosteric Modulator MK-7622

Muscarinic acetylcholine receptors act in synergy to facilitate learning and memory

Molecular mechanisms of serotonergic action of the HIV-1 antiretroviral efavirenz

Contact Info

Product

Resources

About

Preclinical to Human Translational Pharmacology of the Novel M₁ Positive Allosteric Modulator MK-7622

Preclinical to Human Translational Pharmacology of the Novel M₁ Positive Allosteric Modulator MK-7622