RESUMO
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 procognitive efficacy of two AChR agonists, xanomeline and varenicline, were evaluated in group-housed monkeys who self-administered ethanol for more than 1 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 socially 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 nonspecific 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: Procognitive 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. However, this effect was observed only in lower-ranking (subordinate) monkeys and not higher-ranking (dominant monkeys). Results suggest that ACh agonists may effectively remediate alcohol-induced cognitive deficits in a subpopulation of those with alcohol use disorder.
Assuntos
Etanol , Macaca fascicularis , Escopolamina , Animais , Masculino , Etanol/farmacologia , Escopolamina/farmacologia , Cognição/efeitos dos fármacos , Consumo de Bebidas Alcoólicas/tratamento farmacológico , Consumo de Bebidas Alcoólicas/psicologia , Vareniclina/farmacologia , Agonistas Colinérgicos/farmacologia , Nootrópicos/farmacologiaRESUMO
BACKGROUND: Chronic stress contribute to the development of alcohol use disorder (AUD). However, characterizing the role of chronic social stressors in the development of problematic drinking trajectories in humans is complicated by practical and ethical constraints. Group-housed nonhuman primates develop social dominance hierarchies that represent a continuum of social experiences from enrichment in higher-ranked (dominant) monkeys to chronic social stress in lower-ranked (subordinate) individuals. This framework provides a translationally relevant model of chronic social stress that can be used to characterize its effects on vulnerability to AUD. METHODS: Twelve male cynomolgus monkeys living in three social groups with established social dominance hierarchies were provided access to ethanol and water for 22 h/day, 4-5 days/week, for 1 year. Ethanol-free periods (2- or 3-day "weekends" or longer periods up to 10 days) were spent in social groups to maintain the stability of the social hierarchies. Observational studies conducted 6 months into the year of drinking assessed signs of ethanol withdrawal. After 1 year, monkeys were individually housed 24 h/day, 7 days/week for four consecutive weeks to examine the effect of eliminating the "weekends" spent socially housed. RESULTS: Subordinate monkeys had significantly higher mean daily ethanol intakes than dominant monkeys across 1 year of open access. Subordinates also had higher intakes on the first day back drinking following ethanol-free periods of 9-10 days. Moreover, during the last 4 weeks of open access, intakes on the first drinking day after an ethanol-free weekend increased significantly in subordinate monkeys. This effect diminished when all monkeys were individually housed for 4 weeks, indicating that the increased intake in subordinates was driven by the social environment. CONCLUSIONS: These data demonstrate that social subordination, which is associated with chronic social stress, results in increased vulnerability to the development and maintenance of heavy drinking trajectories.