Effects of long‐term ethanol consumption on cognitive function in group‐housed monkeys

Abstract

In the United States there are approximately 14.4 million adults diagnosed with alcohol use disorder (AUD). Despite this, there is an incomplete understanding of how chronic stress influences the development of AUD. Previous studies have shown that long‐term alcohol drinking negatively impacts cognitive flexibility (the ability to alter behavior in response to changing contingencies) and impulsive choice (the tendency to overvalue smaller, immediate rewards compared to larger, delayed rewards). However, the timing and extent of deficits that result from specific drinking patterns have not been well‐characterized. A better understanding of the progression of cognitive dysfunction is critical because deficits in these processes can perpetuate problematic alcohol use. In the present study, group‐housed adult male cynomolgus monkeys formed social hierarchies, which represent a continuum from environmental enrichment in high‐ranking (dominant; DOM; n=6) monkeys to chronic social stress in low‐ranking (subordinate; SUB; n=6) monkeys. Monkeys were trained to drink an unflavored 4% ethanol (EtOH) solution via schedule induction, then had access to self‐administer EtOH 22 hours/day, 4 days/week in the home cage (“free access”) while concurrently pressing a lever to deliver food pellets. To assess the effects of EtOH consumption on cognitive flexibility, monkeys performed a stimulus discrimination and reversal task (SD/SDR) on non‐drinking days using home cage touchscreen technology. Three stimuli appeared on the screen and the task ended when the monkey chose the correct stimulus on 18 of 20 consecutive trials. The task was administered just after induction and again after 6 months of free access. At this point, two modifications were made to increase task difficulty. First, two stimuli were added as additional distractors. In addition, the session was extended to 90 minutes and the total number of reversals was measured. We also characterized impulsive choice using a mean adjusted delay discounting task just after induction and after 4 months of free access. We hypothesized that subordinate monkeys would have greater EtOH intakes versus dominant monkeys and, as a result, would show greater cognitive dysfunction. As hypothesized, subordinate monkeys maintained greater (1.77 ± 0.95 g/kg) mean daily EtOH intakes compared to dominant monkeys (0.85 ± 0.91 g/kg) during 6 months of free access. However, there were no significant differences between dominant and subordinate monkeys in discrimination or reversal trials to criterion, or number of errors at baseline or after 6 months of free access using the 3‐stimuli SD/SDR task. There were also no rank‐related differences in these dependent variables (or number of reversals completed) when the task was modified to include 5 stimuli. Regarding the delay discounting task, both groups showed decreased impulsive choice from baseline to 4 months of free access, however the effect was lesser in subordinates. Although there are rank‐related differences in mean EtOH intake, monkeys do not appear to have significant EtOH‐induced deficits in these two domains of cognitive function in the present study. This study is ongoing and results following one year of access to EtOH will be assessed.