Alcohol exposure leads to differential neuroadaptations in the ERK/MAPK signaling pathway in adolescents as compared to adults.

摘要

Evidence suggests that behavioral and neurobiological changes may leave adolescents vulnerable to experimenting with drugs of abuse and to drug-induced neuroadaptations. Neuroadaptations in cell signaling pathways mediate behavioral pathologies in drug addiction including alcohol addiction. The ERK/MAPK signaling pathway has received attention in addiction due to its fundamental role in neuroplasticity and other cellular processes. However, the influence of this signaling pathway as a potential mediator of adolescent vulnerability to alcohol has not been studied. Results of this dissertation show that adolescent C57BL/6J mice are more sensitive to acute alcohol-induced changes in ERK1/2 activity than their adult counterparts. Increased alcohol-induced p-ERK1/2 in the BLA during adolescence may mediate associative learning processes that could lead to a potential addiction during adulthood. Decreased alcohol-induced p-ERK1/2 in the hippocampus was associated with age-related differences in novel object recognition task (NOR). Increased sensitivity in the ERK/MAPK pathway during adolescence may allow for immediate consequences including those observed in the NOR test or more long-term changes that are brought about by the first exposure to alcohol. Chronic alcohol exposure shows that inhibition of p-ERK1/2 caused an age-dependent effect on alcohol intake (g/kg) in C57BL/6J mice. Systemic administration of the MEK/ERK inhibitor, increased alcohol intake in adolescent mice. Since chronic alcohol self-administration increased p-ERK1/2 in a brain region known to regulate self-administration (CeA) these data are consistent with the hypothesis that p-ERK1/2 in the CeA is an important pharmacological effect of alcohol that maintains self-administration in adolescents. Adolescents exposed to chronic alcohol prior to an acute stressor had unaffected CORT responses however, adult CORT responses were blunted by alcohol self-administration. Stress-induced, circulating levels of glucocorticoids may increase the pleasurable effects of drinking and HPA axis activation is thought to contribute to initiation, maintenance and relapse to alcohol abuse. An inability of the HPA axis to adapt, to stress may make the adolescent brain more vulnerable to a future addiction. Overall, a lack of sensitivity to the negative effects of alcohol and an increase in the pleasurable effects of alcohol during adolescence may increase their vulnerability to future alcohol dependence.