Influence of local and circuit-wide modulation of the mesocorticolimbic reward system on the reinstatement of cocaine seeking

Cocaine abuse poses a significant public health concern both in the United States and across the globe. A critical issue with cocaine abuse is the discouragingly high rate of relapse among addicts following detoxification and abstinence. The research presented in this doctoral dissertation examines the influence of local and circuit-wide modulation of the mesocorticolimbic reward system on cocaine reinstatement, an animal model of relapse. The data presented in the second and third chapters of this dissertation demonstrate that DBS may serve as a possible non-pharmacological therapeutic intervention in the treatment of cocaine addiction. In Chapter 2, I show that DBS of the nucleus accumbens shell attenuates the cue-induced reinstatement of cocaine seeking, expanding upon previous work demonstrating the efficacy of accumbal shell DBS in attenuating cocaine priming-induced reinstatement. In Chapter 3, I demonstrate that DBS of the medial prefrontal cortex (mPFC), but not the basolateral amygdala (BLA) or the ventral hippocampus (vHipp) selectively attenuates the reinstatement of cocaine seeking. Moreover, this effect is constrained to the infralimbic subregion of the mPFC as DBS in the prelimbic or anterior cingulate cortices has no effect on cocaine reinstatement. Further, my results also suggest that infralimbic mPFC DBS attenuates cocaine reinstatement by disrupting glutamatergic transmission to the nucleus accumbens. The data presented in Chapter 4 of this dissertation support a substantial body of evidence demonstrating that increased transmission through GluA1-containing AMPA receptors (AMPARs) in the nucleus accumbens shell promotes cocaine reinstatement. These data reveal the novel role of the protein, AKAP150, in the reinstatement of cocaine seeking. My findings indicate that AKAP150 promotes cocaine reinstatement by facilitating D1-like dopamine receptor (D1DR)-induced, PKA-mediated phosphorylation of GluA1-containing AMPARs. Collectively, these findings suggest that AKAP150 may serve as a biochemical bridge linking the dopamine and glutamate systems in the nucleus accumbens during cocaine reinstatement