Adolescent cocaine abuse increases the risk and severity of lifelong addiction and decreases the likelihood that cocaine-abusing individuals will seek treatment. Developing and understanding therapeutic approaches that mitigate maladaptive decision-making and cocaine-seeking behaviors in organisms with a history of cocaine exposure during adolescence could reduce the high societal cost of cocaine addiction. During adolescence, dendritic spines in the prefrontal cortex (PFC), a brain region critical for complex decision-making, proliferate markedly and then prune, refine, and mature. This process is believed to optimize cellular connectivity and set the neural stage for adult functioning, but such dramatic cellular reorganization within a narrow developmental period may also open a window of vulnerability to insults. We have shown that in adolescent mice, experimenter-administered cocaine derails neural development in the orbital PFC (oPFC), eliminating dendrites and dendritic spines. It also impairs complex decision-making, accelerating the development of stimulus-response habits in adulthood. We have also shown that adolescent mice develop marked individual differences in their cocaine self-administration patterns, and that mice self- administering escalating amounts of cocaine most readily develop stimulus-response habits in adulthood.
In Aim I, we will test the hypothesis that individual differences in cocaine self-administration in adolescence determine effects on oPFC dendritic spines, such that mice that escalate are more susceptible to spine deficiencies in adulthood. We will then assess whether ifenprodil, an NR2B-selective NMDA receptor antagonist that blocks the reinstatement of heroin-, nicotine-, and alcohol-seeking behaviors in rodent models will also have therapeutic-like effects after adolescent cocaine exposure, occluding cocaine-induced habits. In humans, adolescent cocaine exposure increases the risk of substance use, dependence, and relapse in adulthood.
In Aim II, we will examine whether individual differences in cocaine self-administration in adolescence are associated with individual differences in cocaine self-administration and the reinstatement of cocaine seeking in adulthood. We expect that mice with a history of escalating cocaine exposure will respond more for cocaine as adults and be more likely to reinstate responding after extinction conditioning. In these experiments, ifenprodil will be paired with extinction training in an attempt to mitigate the reinstatement of cocaine seeking. This approach models the use of ifenprodil as a therapeutic adjunct to behavioral therapy in humans and is strongly supported by our preliminary findings. Finally, we will test the utility of ifenprodil as an adolescent-targeted intervention strategy. Cortical development is characterized by a reduction in NMDA NR2B:NR2A subunit ratios, which facilitates spine and synapse stabilization. We hypothesize that application of the NR2B-selective antagonist ifenprodil during critical adolescent developmental periods will have corrective behavioral benefits that persist into adulthood.
Adolescent substance abuse dramatically increases the likelihood of developing substance dependence that persists across the lifespan. In mice, adolescent cocaine exposure derails normative decision-making strategies and the development of the orbitofrontal cortex, a brain region critical for impulse control and complex decision-making in humans. We will test whether cocaine self-administration during adolescence predisposes mice to habitual reward seeking and vulnerability to cocaine self-administration across the lifespan, specifically by acting on cortical development systems.
