Collections > Electronic Theses and Dissertations > An Examination of D-serine Augmentation on the Behavioral and Cellular Mechanisms of Cocaine Seeking

Withdrawal from chronic cocaine use is characterized by cellular adaptations and structural remodeling within the brain’s reward circuitry, which are believed to drive persistent drug seeking and relapse. In particular, glutamatergic projections onto nucleus accumbens medium spiny neurons (MSNs) exhibit synaptic strengthening but a loss of plasticity in preclinical animal models of cocaine abuse. Recent evidence suggests that levels of D-serine, an astrocyte derived co-agonist of the NDMA receptor, are reduced in the accumbens following withdrawal from chronic non-contingent cocaine exposure, and that administration of D-serine can reverse these synaptic changes. Moreover, we have found that astrocytes in the nucleus accumbens (NAc) core make fewer synaptic connections following cocaine self-administration and extinction, suggesting reduced D-serine tone on NMDA receptors through volume diffusion. Thus, the overarching goal of this dissertation was to investigate the ability of D-serine augmentation to attenuate cocaine seeking following a cocaine plus cue-primed reinstatement event and then to characterize the mechanism by which D-serine augmentation attenuated this cocaine seeking. Using the self-administration and extinction model of cocaine abuse, the present series of experiments found that systemic and intra-accumbal D-serine augmentation attenuated cocaine seeking, and that systemic D-serine augmentation depotentiated the synapse and enhanced NMDA receptor activation in the NAc core. Interestingly, the experiments presented here conclude that there are no changes in surface protein expression of glutamatergic ionotropic subunits from the NMDA and AMPA receptors following D-serine augmentation. Therefore, the experiments were unable to determine the direct mechanism of action by which D-serine augmentation is reducing relapse to cocaine seeking. However, it can be concluded that NMDA receptor induced internalization of AMPA receptors is not likely the mechanism of the D-serine augmentation effect. Together, these data enhance the current understanding of NMDA receptor involvement in cocaine relapse behaviors, such that NMDA receptors oppose reinstatement of cocaine seeking. We also provide a detailed characterization of NMDA and AMPA receptor expression and synaptic function after enhancing the NMDA receptor co-agonist D-serine.