|Enhancing VTA Cav1.3 L-type Ca2+ channel activity promotes cocaine and mood-related behaviors via overlapping AMPA receptor mechanisms in the nucleus accumbens.
|Year of Publication
|Martínez-Rivera A, Hao J, Tropea TF, Giordano TP, Kosovsky M, Rice RC, Lee A, Huganir RL, Striessnig J, Addy NA, Han S, Rajadhyaksha AM
Genetic factors significantly influence susceptibility for substance abuse and mood disorders. Rodent studies have begun to elucidate a role of Cav1.3 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 Cav1.3 protein, with bipolar disorder. However, the neurocircuitry and the molecular mechanisms underlying the role of Cav1.3 in neuropsychiatric phenotypes are not well established. In the present study, we directly manipulated Cav1.3 channels in Cav1.2 dihydropyridine insensitive mutant mice and found that ventral tegmental area (VTA) Cav1.3 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 Cav1.3 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 Cav1.3 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 Cav1.3 mediates cocaine-related, depressive-like and social phenotypes, suggesting that Cav1.3 may serve as a target for the treatment of neuropsychiatric symptoms.
|PubMed Central ID
|U01 HG004438 / HG / NHGRI NIH HHS / United States
U01 HG004446 / HG / NHGRI NIH HHS / United States
R01 DA029122 / DA / NIDA NIH HHS / United States
P01 CA089392 / CA / NCI NIH HHS / United States
HHSN268200782096C / HG / NHGRI NIH HHS / United States
U01 HG004422 / HG / NHGRI NIH HHS / United States
R01 DA013423 / DA / NIDA NIH HHS / United States
U10 AA008401 / AA / NIAAA NIH HHS / United States
R01 AA022994 / AA / NIAAA NIH HHS / United States
R21 DA038048 / DA / NIDA NIH HHS / United States