Enhancing VTA Ca v 1.3 L-type Ca²⁺ channel activity promotes cocaine and mood-related behaviors via overlapping AMPA receptor mechanisms in the nucleus accumbens

Genetic factors significantly influence susceptibility for substance abuse and mood disorders. Rodent studies have begun to elucidate a role of Ca v 1.3 L-type Ca²⁺ channels in neuropsychiatric-related behaviors, such as addictive and depressive-like behaviors. Human studies have also linked the CACNA1D gene, which codes for the Ca v 1.3 protein, with bipolar disorder. However, the neurocircuitry and the molecular mechanisms underlying the role of Ca v 1.3 in neuropsychiatric phenotypes are not well established. In the present study, we directly manipulated Ca v 1.3 channels in Ca v 1.2 dihydropyridine insensitive mutant mice and found that ventral tegmental area (VTA) Ca v 1.3 channels mediate cocaine-related and depressive-like behavior through a common nucleus accumbens (NAc) shell calcium-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (CP-AMPAR) mechanism that requires GluA1 phosphorylation at S831. Selective activation of VTA Ca v 1.3 with (±)-BayK-8644 (BayK) enhanced cocaine conditioned place preference and cocaine psychomotor activity while inducing depressive-like behavior, an effect not observed in S831A phospho-mutant mice. Infusion of the CP-AMPAR-specific blocker Naspm into the NAc shell reversed the cocaine and depressive-like phenotypes. In addition, activation of VTA Ca v 1.3 channels resulted in social behavioral deficits. In contrast to the cocaine- and depression-related phenotypes, GluA1/A2 AMPARs in the NAc core mediated social deficits, independent of S831-GluA1 phosphorylation. Using a candidate gene analysis approach, we also identified single-nucleotide polymorphisms in the CACNA1D gene associated with cocaine dependence in human subjects. Together, our findings reveal novel, overlapping mechanisms through which VTA Ca v 1.3 mediates cocaine-related, depressive-like and social phenotypes, suggesting that Ca v 1.3 may serve as a target for the treatment of neuropsychiatric symptoms.