Sex differences in PFC-related behavior after amphetamine exposure and across adolescent development

Adolescence is a time of experimentation and risk taking. Experimentation with drug use during this period can have especially harmful consequences, however, as adolescent-onset substance use is more likely to lead to dependence. Brain regions within the mesocorticolimbic circuit are involved in the control of reward behavior and undergo dramatic and sex-specific remodeling during adolescence. In particular, changes within the prefrontal cortex (PFC) are thought to mediate the lack of control over reward behavior that is thought to be characteristic of adolescents. A lack of control may lead to more drug use, which may then alter the function of the PFC, leading to further deficits in control in a positive feedback loop. It is also possible that the developing PFC is especially sensitive to perturbations caused by drug exposure, so that adolescents may be more sensitive to this positive feedback loop and thus more likely to go on to develop drug dependence following experimentation. I hypothesized that top-down control of reward-related behavior is reduced during adolescent development, which in turn results in poorer performance on PFC-sensitive tasks. Moreover, I hypothesized that adolescents and females would be especially susceptible to the effects of amphetamine (AMPH) exposure on PFC function, given sex differences in the development of the PFC. Using a rodent model, this hypothesis was tested with two specific aims: (1) by determining whether there were age and sex differences in reward processing and impulsivity (Chapters 3 and 5) and (2) by investigating the long term effects of adolescent AMPH exposure on behavior and PFC function (Chapters 4 and 6). In chapter 3, rats performed a set of PFC-dependent tests following acquisition of Pavlovian approach: outcome devaluation, extinction, reinstatement. In chapter 4 rats were exposed to AMPH during adolescence or adulthood and then impulsive action was assessed alongside the response to NMDA antagonism. In chapter 5 rats were tested on a novel action-choice task, where each behavior was assessed during adolescence or adulthood. In chapter 6 I examined the long term effects of adolescent AMPH exposure on habit formation and orbitofrontal cortex activity. The results reveal a complex relationship between age, sex, drug exposure, and even motivational state. In general, female adults exhibit more perseverative or habitual-like behavior, relative to male adults, while adolescents tend to behave more habitually. Adolescent males, but not females, may be especially sensitive to the effects of AMPH exposure on PFC-sensitive tasks. Taken together, the results of these studies suggest that age and sex interact to mediate vulnerability to both the loss of control over drug use as well as the long-term effects of drugs on brain and behavior