The emerging role of the L-type calcium channels in cocaine-induced AMPA receptor plasticity

From animal studies it is evident that repeated cocaine exposure induces persistent adaptations in glutamatergic signaling mechanisms in both the mesocorticolimbic and mesostriatal circuits of the brain, that support long-term alterations in behavior. However, the region-specific molecular mechanisms that support these alterations in cell signaling and behavior are unknown. Consequently, my thesis focused on identifying the role of the L-type calcium channels in persistent cocaine-induced AMPAR plasticity and in cocaine-induced brain-derived neurotrophic factor regulation that underlies the behavioral maladaptations that are characteristic of addiction. To examine these molecular alterations in the context of the long-term behavioral changes that are associated with addiction, I used the psychomotor sensitization paradigm, which heavily recruits the ventral tegmental area (VTA), the nucleus accumbens (NAc) and the dorsal striatum (dStr). To further characterize these alterations in the context of a paradigm that examines cocaine-induced relapse, I used the conditioned place preference assay to examine acquisition and extinction of cocaine contextual learning. Specifically, I demonstrated that a cocaine- and dopamine Dl receptor-induced, Cav1.2-dependent increase in cell surface levels of the GluAl subunit of AMPARs in the NAc underlies long-term expression of cocaine-induced sensitization. This change in GIuA1 localization is accompanied by a Ca v1.2-dependent increase in phosphorylation of this subunit at its S831 residue and requires both CaMK II and extracellular signal-regulated kinase 2 (ERK2). I additionally show that Cav1.3 channels in the VTA are required for both the long-term behavioral expression of sensitization and for the G1uA1 receptor adaptations observed in the NAc. Moreover, I demonstrate that repeated cocaine results in a basal reduction of S845 GluAl and cell surface G1uA1 levels in the dStr following a protracted withdrawal period, an adaptation that is dependent on Cavl.3 channels but not those expressed in the VTA. I demonstrate that loss of the Cav1.2 LTCC isoform mediates potentiated cocaine-induced acquisition of contextual learning via a chromatin remodeling-regulated mechanism that affects expression of the bdnf gene in the hippocampus, a brain region that is important in the contextual aspects of addictive behavior. In conclusion these findings extend our knowledge of the neurobiological consequences of repeated cocaine exposure, which could lead to the development of improved pharmacotherapeutic strategies to combat addiction.