Molecular mechanisms of persistent cocaine-induced alterations in corticostriatal function

The persistent nature of drug addiction has been proposed to result from the fact that drugs of abuse induce long-lasting alterations in the connectivity of the brain reward circuitry. Consistent with this hypothesis, addictive drugs have been shown to induce changes in the density of dendritic spines, thought to be the sites of excitatory synaptic input, in several brain regions associated with addiction, including the nucleus accumbens and prefrontal cortex. These alterations are believed to be mediated by molecular mechanisms similar to those associated with the plasticity underlying learning and memory, but the precise nature of these mechanisms has yet to be determined.; The experiments presented in this dissertation sought to contribute to the understanding of the molecular mechanisms that underlie the changes in corticostriatal function that result from the chronic exposure to cocaine. A neuroproteomics approach was used to screen for long-lasting alterations in the corticostriatal system of Vervet monkeys following prior chronic cocaine administration and three weeks of withdrawal. Approximately 15 proteins were found to be altered significantly, validating the use of this methodology in the identification of novel targets in addiction. In addition, a cell culture-based model system was used to further characterize two of these putative candidate proteins, the PKC substrates GAP-43 and neurogranin. Stimulation of cultures with pharmacological agents that mimic cocaine-induced dopamine D1 receptor signaling resulted in a long-lasting down-regulation of GAP-43 and neurogranin, presumably through a transcriptional mechanism, which resembled the down-regulation of these proteins induced by changes in synaptic activity. These results demonstrate that GAP-43 and neurogranin can potentially be regulated by cocaine-induced signaling pathways, confirming their importance as putative targets in the study of the molecular mechanisms underlying addiction. Finally, chronic cocaine administration in mice was found to enhance nucleus accumbens-dependent reward-related learning while inducing impairments in selective tasks thought to be dependent on prefrontal function. These findings suggest that this mouse model can be used to assess the role of candidate proteins in cocaine-induced alterations in corticostriatal function using transgenic mouse technologies. The results presented here will hopefully contribute both to the current understanding and to future studies of the molecular mechanisms underlying addiction.