THE EFFECTS OF COCAINE SELF-ADMINISTRATION AND NICOTINAMIDE ON ASTROGLIAL MITOCHONDRIA

Effective treatment interventions for psychostimulant use disorders are a considerable need in the United States. A deep understanding of cellular responses to chronic drug abuse is required in order to develop pharmacological treatment strategies. Evidence accumulated across the last 15 years indicates that rat cocaine self-administration leads to both structural and functional impairments in astrocytes in the nucleus accumbens (NAc), a region key to the brain’s reward circuitry. In particular, cocaine impairs the ability of NAc astrocytes to maintain glutamate homeostasis, the balance between extra-synaptic and synaptic levels of glutamate. Disruptions in NAc glutamate homeostasis are believed to contribute to cellular mechanisms which mediate relapse vulnerability. Maintenance of glutamate homeostasis carries a high energetic cost, which is met by mitochondria. Nicotinamdie (NAM) is a form of vitamin B3 which can protect and improve mitochondrial function through its function as a precursor of nicotinamide adenine dinucleotide (NAD+). Accordingly, the goals of this dissertation were to investigate the effects of systemic NAM on reinstatement to cocaine seeking, and to examine the effects of cocaine self-administration on astrocyte mitochondria in the NAc. NAM reduced reinstatement behavior in male, but not female rats. Twenty-four hours following the end of cocaine self-administration, mitochondria in NAc astrocytes exhibited a transient, significant increase in volume, surface area, and diameter as compared to those within saline self-administering animals. Morphological measurements were no longer significant following extinction training. Accordingly, NAM demonstrates efficacy against reinstatement in male, but not female rats, and cocaine self-administration results in temporary adaptations in astrocyte mitochondria. However, given the transient nature of mitochondria responses to cocaine, it is unclear to what extent NAM effects on astrocyte mitochondria contribute to its behavioral effects. Future studies will be necessary to determine the functional consequences of the observed morphological changes and to determine if NAM administration is most effective in early abstinence and the effects it may have on neuronal mitochondria.Doctor of Philosoph