Regulation of the deleterious effects of binge-like exposure to alcohol during adolescence by α7 nicotinic acetylcholine receptor agents: prevention by pretreatment with a α7 negative allosteric modulator and emulation by a α7 agonist in alcohol-preferring (P) male and female rats

Rationale and objectives Binge-like alcohol consumption during adolescence associates with several deleterious consequences during adulthood including an increased risk for developing alcohol use disorder (AUD) and other addictions. Replicated preclinical data has indicated that adolescent exposure to binge-like levels of alcohol results in a reduction of choline acetyltransferase (ChAT) and an upregulation in the alpha 7 nicotinic receptor (alpha 7). From this information, we hypothesized that the alpha 7 plays a critical role in mediating the effects of adolescent alcohol exposure. Methods Male and female P rats were injected with the alpha 7 agonist AR-R17779 (AR) once during 6 time points between post-natal days (PND) 29-37. Separate groups were injected with the alpha 7 negative allosteric modulator (NAM) dehydronorketamine (DHNK) 2 h before administration of 4 g/kg EtOH (14 total exposures) during PND 28-48. On PND 75, all rats were given access to water and ethanol (15 and 30%) for 6 consecutive weeks (acquisition). All rats were then deprived of EtOH for 2 weeks and then, alcohol was returned (relapse). Results Administration of AR during adolescence significantly increased acquisition of alcohol consumption during adulthood and prolonged relapse drinking in P rats. In contrast, administration of DHNK prior to binge-like EtOH exposure during adolescence prevented the increase in alcohol consumption observed during acquisition of alcohol consumption and the enhancement of relapse drinking observed during adulthood. Discussion The data indicate that alpha 7 mediates the effects of alcohol during adolescence. The data also indicate that alpha 7 NAMs are potential prophylactic agents to reduce the deleterious effects of adolescent alcohol abuse.