Paul W. Czoty

Drugs that interact with brain nociceptin/orphanin FQ (NOP) receptors can decrease ethanol consumption in preclinical models of alcohol use disorder (AUD). Studies using positron emission tomography (PET imaging) in humans with AUD reported lower levels of NOP receptors compared to controls. Here, uptake of the NOP receptor–selective PET radiotracer [ ¹¹ C]NOP‐1A was measured in monkeys (six males, five females) when ethanol‐naïve and again after a 4‐month induction procedure plus 6 months of ethanol drinking (22 h/day, 5 days/week). Although there were no sex differences in brain uptake of [ ¹¹ C]NOP‐1A before ethanol self‐administration, sex differences were observed in relationships between [ ¹¹ C]NOP‐1A uptake and ethanol‐related measures. Baseline [ ¹¹ C]NOP‐1A uptake in the orbitofrontal cortex in males and caudate nucleus in females predicted future ethanol intakes. Moreover, chronic ethanol self‐administration produced changes in [ ¹¹ C]NOP‐1A uptake in AUD‐related brain areas. Increases in uptake were observed in the putamen of both sexes and in the nucleus accumbens and amygdala of males; females showed a decrease in the insula. Changes in [ ¹¹ C]NOP‐1A uptake in the orbitofrontal cortex, putamen and hypothalamus of males and caudate nucleus of females were related to ethanol intake. These results demonstrate bidirectional relationships between brain NOP receptors and ethanol self‐administration and provide evidence of subtle sex differences in these interactions.

Background: Clinical and preclinical alcohol use disorder (AUD) research demonstrates that males and females differ in motivations behind drinking, patterns of drinking behaviors, and alcohol‐related physiological responses and health consequences. Nonhuman primate (NHP) models of AUD have the potential to enhance our understanding of such sex differences. In NHP models, schedule‐induced polydipsia is a common method to initiate ethanol drinking. In males, characteristics of drinking during the final stage of induction, when monkeys consume 1.5 g/kg/day, predict subsequent drinking patterns when monkeys have unlimited access to ethanol. The present study assessed sex differences in those predictive behaviors during induction and characterized patterns and intakes during 6 months of ethanol drinking. Methods: Eleven singly housed adult cynomolgus monkeys (six male, five female) were induced to consume water, then increasing doses of ethanol for 4 weeks per dose (0.5, 1.0, and 1.5 g/kg) using a 300‐s fixed‐time schedule of food pellet delivery. Following induction, monkeys switched to an “open‐access” regimen wherein water and ethanol were available 22 h/day, 5 days/week. Results: Predictive relationships between drinking characteristics during the final phase of induction and subsequent open‐access drinking were replicated, with no evidence of sex differences. Although weekly and total ethanol intakes were higher in males over 6 months of open access, the difference did not reach statistical significance. However, there were sex differences in the distribution of ethanol intake across the day. Males drank significantly more when meals were available, whereas females spread their drinking throughout the first half of the session; these differences were exacerbated in Month 2 and remained for the duration of the study. Conclusions: These results replicate previous findings of a predictive relationship between drinking variables during induction and later open‐access drinking and reveal sex differences in daily patterns of ethanol intake that may inform treatment approaches.

Microtubules (MTs), as structural components of the cytoskeleton, are vital for axonal transport, information processing, and signaling within the brain. Disruption of MT integrity has been associated with neurological disorders, including alcohol use disorder (AUD). This study used positron emission tomography (PET) imaging with the radiotracer [¹¹C]MPC-6827 to investigate alcohol-induced changes in MT dynamics in a nonhuman primate model of AUD. Dynamic PET scans (0–120 min) were conducted in male cynomolgus monkeys (n = 4) before and after ∼7 months of ethanol self-administration (EtOH SA). Quantitative analysis of standardized uptake values and time-activity curves demonstrated a consistent decrease in [¹¹C]MPC-6827 uptake across multiple brain regions, particularly in the amygdala, globus pallidus, and substantia innominata. Statistically significant reductions in tracer uptake were observed in early scan windows (15 and 30 min), suggesting compromised MT integrity due to chronic EtOH SA. These findings provide compelling evidence that chronic alcohol consumption induces significant changes in microtubule dynamics, potentially contributing to pathological processes underlying AUD.

Awareness of one’s position in the social hierarchy is essential for survival. Conversely, poor social cognition is associated with several neuropsychiatric diseases. Although brain regions that mediate understanding of the social hierarchy are poorly understood, recent evidence implicates the insula. Magnetic resonance imaging (MRI) scans were acquired in twelve individually housed male cynomolgus monkeys to determine whether structural and functional characteristics of the insular cortex predicted the social rank that monkeys would attain once they formed stable social hierarchies. Structural MRI revealed that left insular volume was significantly larger in monkeys that would become dominant vs. subordinate. No differences were observed in other areas including amygdala, caudate nucleus, or prefrontal cortex. Volumetric differences were localized to dorsal anterior regions of both left and right insulae. Functional MRI revealed that global correlation, a measure of connectedness to the rest of the brain, was significantly lower in the left insula of monkeys who would become dominant vs. subordinate. Moreover, the fractional amplitude of low-frequency fluctuations, a reflection of spontaneous brain activity, trended lower in bilateral insula in the future dominant monkeys. This prospective study provides evidence for a role of the insula in the establishment and maintenance of social dominance relationships.

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. 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.

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.