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PhD Thesis: Jennifer Buenzle Dwyer

Dissertation Abstract:
Adolescent Maturation of Mesocorticolimbic Dopamine Systems

By Jennifer Buenzle Dwyer
Doctor of Philosophy in Pharmacology and Toxicology
University of California, Irvine, 2010
Professor Frances M. Leslie, Chair

Adolescence is a critical developmental period characterized by heightened vulnerability to initiation of substance abuse and onset of neuropsychiatric disorders. These clinical phenomena likely share common sets of neurobiological substrates, as mesocorticolimbic dopamine systems mature during this period. Consistent with this neurochemical development, adolescents respond uniquely to both therapeutic and illicit drugs that target dopamine systems, with distinct behavioral responses to indirect agonists like amphetamine. Clinical studies show that prenatal exposure to tobacco increases the risk for adolescent-onset disorders, suggesting that this early developmental insult targets late maturing neural circuitry. This dissertation tested the hypothesis that the functional consequences of dopamine receptor activation are immature during adolescence and that gestational exposure to nicotine, the main psychoactive ingredient in tobacco, sex-dependently alters adolescent neurochemical and structural brain development.

Using direct agonists, behavioral studies demonstrated that the functional sensitivity of D1 and D2 receptors changes with age, with a shift from D2 receptor control of locomotor and repetitive behaviors in adolescence, to D1 mechanisms in adulthood. D1/D2 interactions were assessed by combined agonist administration, revealing that D1 and D2 interact synergistically in adulthood, but antagonistically in adolescence, suggesting that fundamental age differences in D1/D2 interactions may underlie the blunted responses to indirect agonists during adolescence. To assess the neural circuitry underlying these responses, dopaminergic regulation of the immediate early genes cfos and arc was examined.

Adults showed greater D1/D2 regulation of cfos, while adolescents showed greater arc regulation, suggesting vulnerabilities to drug-induced plasticity. Novel adaptation of functional network analysis to immediate early gene data demonstrated that D1/D2 stimulation enhances both coordinated activation and plasticity-related gene expression in corticostriatal circuits in adults. In contrast, D1/D2 regulates hippocampal functional connectivity in adolescence, and profoundly disrupts coordinated plasticity-related gene expression across the brain.

Behavioral and neurochemical studies showed that gestational nicotine sex-dependently alters dopamine content and turnover and D2-like receptor function during adolescence. Gestational nicotine also alters the expression of genes related to structural brain development and sex-dependently disrupts adolescent cortical myelination. Together these data suggest that D1/D2 function is immature during adolescence and that late-developing mesocorticolimbic dopamine systems are targeted by gestational nicotine.