Enhancing VTA Cav1.3 L-type Ca2+ channel activity promotes cocaine and mood-related behaviors via overlapping AMPA receptor mechanisms in the nucleus accumbens

Abstract

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 (BD). 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 (DHP) insensitive mutant mice and found that VTA Cav1.3 channels mediate cocaine-related and depressive-like behavior through a common nucleus accumbens (NAc) shell calcium permeable AMPA 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 (CPP) 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 (CD) 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.

Cocaine Self-Administration and Abstinence Modulate NMDA Receptor Subunits and Active Zone Proteins in the Rat Nucleus Accumbens

“…Since RIM1, Munc13 and Rab3A exist in all synaptic terminals, further research is needed to explain these phenomena. Increased RIM1 levels were consistent with the known annotation of these proteins to calcium availability, transport processes and calcium channel activity [32,33]. RIM1 is involved in the facilitation of neurotransmitter release through the regulation of voltage-gated calcium channels, L type, alpha 1D subunit (Cav1.3) by G-proteins [33].…”

“…RIM1 is involved in the facilitation of neurotransmitter release through the regulation of voltage-gated calcium channels, L type, alpha 1D subunit (Cav1.3) by G-proteins [33]. Enhanced Cav1.3 channel activity was reported in the mouse nucleus accumbens after cocaine conditioned place preference test, and it was emphasized that this up-regulation seems to be one potential mechanism underlying drug abuse and mood disorders [32]. On the other hand, the level of D2 receptors and Cav1.3 channels in the dorsomedial striatum was reduced in the well-established habitual-seeking behavior in animals [34].…”

Interplay Between Amphetamine and Activity Level in Gene Networks of the Mouse Striatum

“…The direction of the differential expression within contrast is consistent with the known annotation of these genes to calcium availability and transport processes and calcium channel activity that have been associated with substance abuse and emotional behaviors. 73 In agreement with the profiles in Figures 1 and 2 , Nrgn was positively associated with neural plasticity and negatively associated with cognition deficit. These associations are related to the binding of Nrgn to calmodulin and lowering calcium availability.…”

De novo CACAN1D Ca2+ channelopathies: clinical phenotypes and molecular mechanism

“…Loss of Cav1.3 resulted in an antidepressant-like phenotype in mice [11], while the opposite was observed upon selective Cav1.3 activation [78]. Also, stimulation of Cav1.3 within the ventral tegmental area (VTA; dopamine midbrain system) was sufficient to elicit the depressive-like behavior together with a social deficit and enhanced cocaine-associated behaviors [49]. This was in line with previous reports linking Cav1.3 activity to the development of psychostimulant-induced sensitized behaviors [20,33,71].…”