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

Abstract

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.

A Little “Re-Cognition” Goes a Long Way for Pro-Cognitive Therapeutics in Alcohol Studies

“…Likewise in the SDR task in monkeys here, the ratio of correct trials to omissions may indicate attentional engagement, and the dose-dependent deficits in task performance varied across monkeys, leading to variability in the maximally-impairing dose. Of note, varenicline improved this ratio in subordinate monkeys only (Galbo-Thomma et al, 2024). This is particularly interesting given that attentional systems are implicated in social hierarchy rank and impacted by chronic alcohol (Shnitko et al, 2020;Dwortz et al, 2022).…”

“…Varenicline is clinically used for nicotine cessation, and one study shows that it can reduce the number of heavy drinking days in men, but not women, with co-occurring nicotine and alcohol use disorders (O'Malley et al, 2018). The findings in Galbo-Thomma et al (2024) further support varenicline as a potential treatment of disrupted neurocognitive processes in AUD, such as cognitive flexibility and attention, which might play an important role in reducing heavy drinking and preventing relapse.…”

“…The lack of an effect on SDR task performance between dominant and subordinate monkeys and the lack of correlation between SDR performance and lifetime alcohol intake was surprising given previous literature showing that chronic alcohol drinking impairs behavioral flexibility on the ASST task (Wright and Taffe, 2014; Shnitko et al, 2020;Galbo-Thomma et al, 2024). To induce an observable cognitive deficit, the authors administered scopolamine to impair reversal performance.…”

“…Thus, naturalistic-minded NHP alcohol drinking models serve as the gold standard for modeling the complexity of human alcohol drinking and related behavior, giving them high translational value for testing novel therapeutic strategies under valid conditions. In this issue of Journal of Pharmacology and Experimental Therapeutics, Galbo-Thomma et al (2024) use such an alcohol model to evaluate the effectiveness of drugs targeting the acetylcholine signaling system to rescue cognitive flexibility deficits in male alcohol drinking cynomolgus monkeys, evaluating how social stress and status impact these outcomes.…”

“…Thus, it is possible that effects of varenicline here on reversal performance in subordinate monkeys are driven by attentional processing rather than cognitive flexibility per se. Intriguingly, reduced attentional control is a common neurocognitive deficit related to AUD, and some clinical subpopulations may especially benefit from the pharmacological approach used in Galbo-Thomma et al (2024). For instance, individuals with attention deficit hyperactivity disorder experience greater social stress, have higher rates of AUD comorbidity, and display poorer adherence to AUD treatment; in addition, pharmacological treatment of attention deficit hyperactivity disorder early in life reduces lifetime substance abuse liability (Wilens et al, 2003;Luderer et al, 2021).…”