Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Anatomy and Cell Biology

Supervisor

Lique M. Coolen

Abstract

Drugs of abuse are hypothesized to usurp brain reward circuits by causing neuroplasticity that contributes to the development and expression of addiction. However, little is known about how these brain circuits are altered in response to natural reward experience. Using male rodent sexual behavior, the goal of my thesis was to determine whether natural reward experience produces neural alterations in the mesolimbic dopamine system, that in turn, regulate incentive motivation for natural as well as drug reward. First, it was determined that male rat sexual experience causes facilitation of sexual behavior, sensitized amphetamine reward, and increased dendritic spines in the nucleus accumbens (NAc). Second, it was found that levels of the transcription factor deltaFosB were increased by sexual experience in several reward-related brain regions, notably the NAc. Blocking deltaFosB activity in the NAc using viral vector-mediated gene transfer attenuated long-term effects of sexual experience on sexual behavior, drug reward, and dendritic spines on NAc neurons. Then, we determined that NAc deltaFosB accumulation and sensitized drug reward caused by sexual experience were dependent on D1, but not D2, dopamine receptor activation during mating. Next, we demonstrated sex experience-induced neuroplasticity in the ventral tegmental area, consisting of an immediate but transient decrease in soma size of dopamine neurons, and reduced tonic dopamine input to NAc. This reduction in soma size was shown to be dependent on endogenous opioids, and critical for morphine reward tolerance, facilitation of sexual behavior, deltaFosB accumulation in the NAc, and mating cue-induced neuronal activity. Finally, sexual experience was found to cause short and long-term increases in NNMDA and AMPA receptor subunit expression/trafficking respectively. Moreover, sexual experience caused an immediate and long-lasting reduction in AMPA/NMDA ratio of synaptic currents in PFC-responding NAc shell neurons. Together, these studies begin to fill an important gap in our knowledge concerning the molecular/cellular basis for natural reward and extend our understanding of the underlying mechanisms of substance abuse.


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