Alpha1 adrenergic receptors integrate across multiple separable heart rate variability metrics during alcohol drinking

Alcohol Use Disorder remains a major challenge and is now a leading cause of death in adults. Biomarkers like heart rate variability (HRV) could give important and novel insights into how pharmacotherapies counteract excessive drive for alcohol, including those promoted by adrenergic receptors (AR). Indeed, α1AR inhibition helps heavy drinkers with greater withdrawal-related mood disruption and arousal, while α1ARs more generally are implicated in cognitive flexibility. To uncover how α1ARs might regulate drinking-related arousal, we used cardiovascular telemetry in adult male and female rats. In particular, we examined how HRV patterns were altered by lower doses of α1AR or βAR antagonists, which reveal arousal regulation with less behavioral disruption. Interestingly, HRV entropy has also been linked to cognitive flexibility, and we newly show that α1ARs supported HRV entropy in both sexes. However, in males but not females, α1ARs promoted pNN50, a parasympathetic metric indexing high variability in heartbeat timing. On the other hand, α1ARs with βARs in both sexes promoted a pro-sympathetic influence centered on a Power-law/fractal HRV metric previously linked to attentional effort, while α1ARs inhibited HF-HRV, a related parasympathetic metric, in females. Thus, α1ARs regulated multiple differing HRV arousal metrics, with both sympathetic and parasympathetic influences and sex similarities and differences. This was strongly different from the sex-similar pro-sympathetic βARs effects. Thus, our findings suggest that α1ARs are critical for multiple, differing aspects of physiological flexibility, which likely facilitates α1AR-mediated cognitive flexibility and the many other α1AR-regulated behaviors.