Profiling the effects of alcohol history on cognitive performance during abstinence: an examination of proenkephalin-A-derived peptides in the medial prefrontal cortex

ABSTRACT: AUD is characterized, in part, by cognitive impairments that emerge during early abstinence and may compound the effects of stress and other challenges to maintaining abstinence. Yet whether these impairments persist through prolonged abstinence or become more apparent as cognitive demands increase remains unclear. Here, we examined whether chronic EtOH exposure in rats produces enduring effects on cognitive function across abstinence. Using a longitudinal, operant-based approach, we assessed cognitive flexibility during early abstinence and delay-dependent working memory during protracted abstinence. A secondary goal was to characterize the long-term effects of EtOH history on mPFC enkephalins and the broader PENK-derived peptide profile. Overall, EtOH-related differences emerged as task demands increased. During the more demanding reversal, EtOH rats used reinforcement feedback less effectively to disengage from the previously reinforced response. At the longest working memory delays, EtOH rats also began showing lower accuracy. Performance across these tasks correlated in EtOH rats, suggesting that individual differences were maintained over time. At the molecular level, targeted analyses revealed no change in canonical mPFC enkephalins, whereas broader peptide profiling suggested differences in the relative composition of PENK-derived fragments, particularly in the C-terminal region. Together, these findings suggest that chronic EtOH exposure leaves lasting cognitive vulnerabilities that emerge under greater task demands, with some rats remaining more susceptible than others. Noncanonical PENK-derived peptides in the mPFC may further contribute to this enduring cognitive vulnerability.

INSTRUMENT(S):

ORGANISM(S): Rattus Norvegicus (rat)

TISSUE(S): Brain

SUBMITTER: Meera Asokan  

LAB HEAD: Luis A Natividad

PROVIDER: PXD081634 | Pride | 2026-10-08

REPOSITORIES: Pride