Alcohol's Effects on the Adolescent: Correlation Between the Dopaminergic System

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DESCRIPTION (provided by applicant): The objective of this research is to determine if the developing dopaminergic system in the adolescent is a significant factor in the adolescent's vulnerability to alcohol abuse and, ultimately, to developing alcohol addiction and dependence. The high risk period for abuse of various substances, including alcohol, is from 12 to 22 years of age, with a peak time from about 15 to 19 years old. From late childhood and into young adulthood, while unique developmental changes in behavioral characteristics are occurring, changes in neurotransmitter systems, including the dopaminergic system, are also taking place. These changes in the dopaminergic system during adolescence can influence behavior and could be one of the underlying causes of the differential response to alcohol seen in juveniles compared to adults. Using immunocytochemical staining of FOS protein, we previously identified individual brain nuclei activated by exposure to ethanol (EtOH), all of which either contain dopaminergic neurons or innervate dopaminergic neurons in other nuclei. EtOH activation of these brain nuclei cause a wide spectrum of behavioral effects, including rewarding and dependence. Animal studies have shown that repetitive exposure to EtOH causes the development of EtOH- induced behavioral sensitization (BS), which is characterized by increased locomotor activity and self- administration of EtOH, both of which have been shown to correlate with dopamine transmission in various areas of the brain, including the prefrontal cortex and striatum. Drug-induced BS in humans has been proposed as one of the possible mechanisms underlying addiction and dependence. Taken together, these findings have led us to hypothesize that the differential behavioral effects of EtOH that occur in adolescents are the result of age-dependent developmental changes in the dopaminergic system in the brain. To test this hypothesis, we propose to use the rat model to achieve the following aims: 1) To investigate the age-dependent effects of EtOH on dopamine release from pre-synaptic dopaminergic neurons in the brain; 2) To investigate the age-dependent effects of EtOH on dopamine uptake and re-uptake in the brain; and 3) To determine if the age-dependent effects of EtOH on the dopaminergic system result in differential behavioral effects. This project will define the age-dependent EtOH-induced dopaminergic responses at the molecular, cellular, and behavioral levels simultaneously. The proposed studies will provide important information on the possible mechanisms underlying the increased vulnerability to alcohol abuse in the adolescent. PUBLIC HEALTH RELEVANCE: The goal of this proposed research is to investigate, at both the molecular and behavioral levels, the increased vulnerability of adolescents to alcohol abuse that appears to result from age-dependent developmental changes in the dopaminergic system in the brain. We propose to use a rat model for these studies and to correlate alcohol-induced behavioral sensitization with alcohol's effects on various components of the dopaminergic system. Thus, the studies as proposed have high clinical relevance and will contribute significantly to the understanding and treatment of alcohol abuse and alcohol related behavior disorders in the adolescent.