Repeated Binge Pattern Ethanol Administration During Adolescence or Adulthood: Long-term Changes in Voluntary Ethanol Intake and Mesolimbic Dopamine Functionality in Male Rats

Binge alcohol consumption is a rising concern in the United States, especially among adolescents as during this developmental period alcohol use is usually initiated and has been shown to cause detrimental effects on brain structure and function. These findings have been established through the use of binge models in animals, where animals are repeatedly administered high doses of ethanol typically over a period of three or four days. While such work has examined the effects of a four-day and repeated three-day binge, there has been almost no work conducted aimed at investigating the long-term behavioral and neurochemical and/or functional consequences of repeated binge pattern administration during adolescence relative to adulthood on later ethanol-induced behavior and neurochemistry in adulthood. The present set of experiments aimed to examine the dose-response and age-related differences induced by repeated binge pattern ethanol administration during adolescence or adulthood on voluntary ethanol consumption (Aim 1), changes in ethanol metabolism following ethanol pretreatment (Aim 2) and mesolimbic dopamine functionality (Aim 3) in adulthood. In both experiments, adolescent and adult male rats were intragastrically administered ethanol (0.5, 1.0 or 2.0 g/kg/ig) or isovolumetric water on postnatal days (PND) 28-31, PND 35-38 and PND 42-45 for adolescent rats and PND 60-64, PND 67-70 and PND 74-77 for adult rats. In both experiments all rats underwent fourteen days of abstinence (PND 46-59 or PND 78-91, respectively). Subsequently, in Experiment 1, all rats underwent voluntary ethanol consumption procedures, in which animals were exposed to 10% ethanol combined with decreasing saccharin concentrations across days from PND 60-82 for adolescent-exposed rats and PND 92-114 for adult-exposed rats. Finally, on PND 83 and PND 115, respectively, all animals were challenged with 2.0 g/kg ethanol and trunk blood samples were collected at 60 and 240 minutes post-injection. Results indicate there was a significant increase in voluntary ethanol intake in adolescent ethanol-exposed rats pretreated with 2.0 g/kg relative to their adult ethanol-pretreated counterparts. Faster ethanol metabolism was observed in adolescent rats pretreated with 2.0 g/kg during adolescence relative to adolescent-exposed rats pretreated with 0.5 g/kg and adults pretreated with 2.0 g/kg. For Experiment 2, all rats underwent surgery (PND 60 for adolescent-exposed and PND 92 for adult-exposed rats). From PND 61-64 for adolescent-exposed and PND 93-96 for adult exposed rats, all animals underwent recovery from surgery. Finally, all rats underwent in vivo microdialysis on PND 65 for adolescent-exposed and PND 97 for adult-exposed rats, with K+ (100 mM) infused into the ventral tegmental area and accumbal dopamine overflow assessed in the nucleus accumbens septi. The results from Experiment 2 indicate lasting changes in mesolimbic dopamine functionality with a trend for decreased potassium-stimulated dopamine overflow in the nucleus accumbens septi in adolescent-ethanol pretreated rats and a trend for increased potassium-stimulated dopamine overflow in adult ethanol-pretreated rats. The results from the present set of experiments show the dose-dependent impact of binge-pattern ethanol exposure during adolescence on subsequent ethanol consumption and ethanol metabolism in adulthood. These findings indeed determine adolescence as a period of vulnerability to the long-term changes in ethanol consumption relative to similarly-exposed adult male rats. Importantly, the results of Experiment 2 indicate an alteration in the functionality of the mesolimbic pathway in adulthood following adolescent binge pattern ethanol exposure, which demonstrates a long-term depression in mesolimbic dopamine functionality following adolescent binge pattern ethanol exposure