M<sub>1</sub> muscarinic receptor activation decreases alcohol consumption via a reduction in consummatory behavior

Campbell, Erin J.; Huckstep, Kate L; Chen, Nicola; Langmead, Christopher J.; Lawrence, Andrew J

doi:10.1002/prp2.907

Cited by 9 publications

(2 citation statements)

References 61 publications

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“…Firstly, clozapine’s selective and relatively low occupancy in striatal dopamine type-2 receptors (Pilowski et al, 1997) may not contribute to further striatal dopaminergic downregulation and results in a low liability to cause EPS. Secondly, clozapine’s propensity to increase γ-aminobutyric acid-B (GABA-B)-mediated inhibitory neurotransmission (Nair et al, 2020), N -desmethylclozapine’s muscarinic acetylcholine receptor M 1 agonist activity (Weiner et al, 2004), and clozapine’s potent blockade of alpha-2 noradrenergic receptors coupled with an increase in norepinephrine levels (Green et al, 2008) are not only hypothesized to be part of the mechanism of treating resistant psychosis but may also have potential roles in treating comorbid SUDs (Cousins et al, 2002; Green et al, 2008; Walker et al, 2022). Lastly, clozapine’s propensity to decrease striatal glutamate levels (McQueen et al, 2021) has potential as an anti-glutamatergic agent to attenuate rewarding effects of substance use (D’Souza, 2015).…”

Section: Discussionmentioning

confidence: 99%

Effects of clozapine treatment on the improvement of substance use disorders other than nicotine in individuals with schizophrenia spectrum disorders: A systematic review and meta-analysis

et al. 2022

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Background: Antipsychotic medications are the mainstay of treatment for schizophrenia and are associated with a reduction in psychiatric hospitalization and overall mortality. Some evidence suggest that antipsychotic medications might have a varying effect on the improvement of comorbid substance use disorders (SUDs), with clozapine showing more favorable outcomes. Aim: We systematically reviewed all available evidence on effects of clozapine on the improvement of SUDs other than nicotine. Methods: Electronic searches of MEDLINE, Embase, PsycINFO, and CINHAL were conducted up to March 1, 2022. Studies of any methodological design involving two concepts: (1) clozapine and (2) SUD terms (excluding nicotine) were included. For SUD outcomes with three or more comparative studies with available raw data meta-analysis was performed. SUD outcomes not meeting criteria for meta-analysis were described qualitatively. Risk of bias was examined using “Downs and Black,” and “Q-Coh” instruments. Results: The majority of individuals in the included 31 studies were male and of European ancestry. Abstinence was the most common outcome. Most of the studies were of low-to-moderate quality, and none of the studies met all the quality criteria. Pooled findings from four observational studies in samples of patients with predominantly comorbid alcohol use disorder showed that clozapine treatment is associated with significantly higher odds of remaining abstinent. In addition clozapine was associated with decreased odds of psychiatric hospitalization in all but one observational study. Conclusions: Our systematic review and meta-analysis builds upon previous reviews, and it suggests the association of clozapine treatment with significantly higher odds of remaining abstinent from substance use and decreased likelihood of psychiatric hospitalization, compared with continuing treatment with other antipsychotic medications. Still, the validity of this association needs greater exploration and providing recommendations for the utility of clozapine in individuals without treatment-resistant psychosis and comorbid SUDs would be premature.

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Section: Discussionmentioning

confidence: 99%

Effects of clozapine treatment on the improvement of substance use disorders other than nicotine in individuals with schizophrenia spectrum disorders: A systematic review and meta-analysis

et al. 2022

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“…Importantly, two of these studies were conducted in histologically normal brains (i.e., no differences attributed to aging, medications, or other morbidities including dementia, head trauma or Alzheimer's disease; Freund & Ballinger, 1988, 1989. More specifically, heavy drinking was associated with downregulation of M4 mAChR mRNA and protein (Walker et al, 2020); the effects of alcohol on M1 mAChR distribution have not been characterized (Walker et al, 2022). It is possible one year of ethanol self-administration decreased M1 and M4 mAChR receptor distribution in subordinate monkeys whereas dominant monkeys experienced little to no change.…”

Section: Discussionmentioning

confidence: 99%

Cognitive-Enhancing Effects of Acetylcholine Receptor Agonists in Group-Housed Cynomolgus Monkeys Who Drink Ethanol

Galbo-Thomma,

Epperly,

Blough

et al. 2023

J Pharmacol Exp Ther

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The cognitive impairments that are often observed in patients with alcohol use disorder (AUD) partially contribute to the extremely low rates of treatment initiation and adherence. Brain acetylcholine receptors (AChR) mediate and modulate cognitive and reward-related behavior and their distribution can be altered by long-term heavy drinking. Therefore, AChRs are promising pharmacotherapeutic targets for treating the cognitive symptoms of AUD. In the present study, the pro-cognitive efficacy of two AChR agonists, xanomeline and varenicline, were evaluated in group-housed monkeys who self-administered ethanol for more than one year. The muscarinic AChR antagonist scopolamine was used to disrupt performance of a serial stimulus discrimination and reversal (SDR) task designed to probe cognitive flexibility, defined as the ability to modify a previously learned behavior in response to a change in reinforcement contingencies. The ability of xanomeline and varenicline to remediate the disruptive effects of scopolamine was compared between dominant and subordinate monkeys, with lighter and heavier drinking histories, respectively. We hypothesized that subordinate monkeys would be more sensitive to all three drugs. Scopolamine dose-dependently impaired performance on the serial SDR task in all monkeys at doses lower than those that produced non-specific impairments (e.g, sedation); its potency did not differ between dominant and subordinate monkeys. However, both AChR agonists were effective in remediating the scopolamine-induced deficit in subordinate monkeys, but not in dominant monkeys. These findings suggest xanomeline and varenicline may be effective for enhancing cognitive flexibility in individuals with a history of heavy drinking.Significance statement: Pro-cognitive effects of two acetylcholine (Ach) receptor agonists were assessed in group-housed monkeys who had several years' experience drinking ethanol. The muscarinic ACh receptor agonist xanomeline and the nicotinic ACh receptor agonist varenicline reversed a cognitive deficit induced by the muscarinic ACh receptor antagonist scopolamine.

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M₁ muscarinic receptor activation decreases alcohol consumption via a reduction in consummatory behavior

Campbell

Huckstep

Chen

et al. 2021

Pharmacology Res & Perspec

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M₁ muscarinic receptor activation decreases alcohol consumption via a reduction in consummatory behavior

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri bution-NonCo mmercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Cited by 9 publications

References 61 publications

Effects of clozapine treatment on the improvement of substance use disorders other than nicotine in individuals with schizophrenia spectrum disorders: A systematic review and meta-analysis

Effects of clozapine treatment on the improvement of substance use disorders other than nicotine in individuals with schizophrenia spectrum disorders: A systematic review and meta-analysis

Cognitive-Enhancing Effects of Acetylcholine Receptor Agonists in Group-Housed Cynomolgus Monkeys Who Drink Ethanol

M₁ muscarinic receptor activation decreases alcohol consumption via a reduction in consummatory behavior

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M1 muscarinic receptor activation decreases alcohol consumption via a reduction in consummatory behavior

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri bution-NonCo mmercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Cited by 9 publications

References 61 publications

Effects of clozapine treatment on the improvement of substance use disorders other than nicotine in individuals with schizophrenia spectrum disorders: A systematic review and meta-analysis

Effects of clozapine treatment on the improvement of substance use disorders other than nicotine in individuals with schizophrenia spectrum disorders: A systematic review and meta-analysis

Cognitive-Enhancing Effects of Acetylcholine Receptor Agonists in Group-Housed Cynomolgus Monkeys Who Drink Ethanol

M1 muscarinic receptor activation decreases alcohol consumption via a reduction in consummatory behavior

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M₁ muscarinic receptor activation decreases alcohol consumption via a reduction in consummatory behavior

M₁ muscarinic receptor activation decreases alcohol consumption via a reduction in consummatory behavior