Stress-induced alcohol drinking and withdrawal in mice lacking functional natriruetic peptide-A receptors

Aims: Recent results suggest an involvement of the endocrine system in alcohol drinking behavior. For both mice and humans an association between plasma concentration of atrial natriuretic peptide (ANP) with different aspects of severity of alcohol withdrawal, craving and anxiety has been demonstrated. To further examine the involvement of the natriuretic peptide system in neurobehavioral effects of alcohol, we studied free choice alcohol intake, stress induced alcohol intake and withdrawal with mice lacking a functional natriuretic peptide-A (NPR-A) receptor. Methods: NPR-A-knockout and wild-type mice were given a free choice between water and increasing concentrations of alcohol (2–16%). Once a stable baseline of 16% alcohol consumption was established, a forced swim stress was performed on 3 consecutive days to investigate stress-induced alcohol drinking. Additionally, neurobehavioral alcohol withdrawal response was investigated following 14 days of forced-alcohol intake. Results: Whereas both basal alcohol preference and voluntary alcohol intake did not differ between NPR-A mutants and wild-type littermates, stress (three consecutive days of forced swim stress) induced an immediate and prolonged increase in alcohol intake in the NPR-A mutant mice. During alcohol withdrawal, both genotypes differed in the intensity of neurobehavioral withdrawal signs with an increased expression in NPR-A knock outs. Conclusions: Mice lacking a functional NPR-A receptor represent a useful animal model to study the role of the natriuretic peptide receptor system in long-term and stress-induced alcohol self-administration and withdrawal severity. To study the role of the natriuretic NPR-A gene for the modulation of risk of alcohol-related disorders, NPR-A related polymorphisms should be targeted in clinical studies.