Unpredictable intermittent access exacerbates loss of control over ethanol drinking

Background Loss of control over drinking is a hallmark feature of alcohol use disorder (AUD) that is modeled preclinically through escalation of ethanol consumption and aversion-resistant drinking. Prior work with other reinforcers suggests that within-session unpredictable, intermittent access (uIntA) promotes these phenotypes. However, the effect of uIntA on voluntary ethanol consumption is unknown. Methods Male and female Long-Evans rats ( n =9-10/group) underwent seven weeks of daily voluntary ethanol (20% v/v) drinking sessions under either a continuous access (ContA) or uIntA schedule. Following four weeks of baseline, rats were rendered dependent using a two-week chronic intermittent ethanol vapor exposure procedure. Daily testing was maintained through one week into withdrawal from vapor exposure. On the final day of testing, ethanol was adulterated with quinine (30 mg/L) to assess aversion-resistant drinking. Results Rats drinking under ContA and uIntA exhibited similar levels of average daily ethanol consumption at baseline. However, uIntA elicited a more robust dependence-induced escalation of ethanol consumption compared to ContA, with uIntA sustaining escalation through early withdrawal. Additionally, while rats with ContA to ethanol remained sensitive to quinine even after chronic ethanol vapor exposure, uIntA promoted aversion-resistant drinking in ethanol dependent rats. Conclusions These results demonstrate that, compared to ContA, uIntA maintains ethanol drinking and exacerbates dependence-induced escalation and aversion-resistant ethanol consumption. This work positions uIntA as a powerful tool to assess psychological and neurobiological factors that underlie loss of control over drinking.