title: 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. 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.
authors.affiliation: Division of Pediatric Neurology, Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA.|Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY, USA.
authors.forename: A
authors.initials: A
authors.lastname: Martínez-Rivera
authors.affiliation: Division of Pediatric Neurology, Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA.
authors.forename: J
authors.initials: J
authors.lastname: Hao
authors.affiliation: Division of Pediatric Neurology, Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA.|Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY, USA.
authors.forename: T F
authors.initials: TF
authors.lastname: Tropea
authors.affiliation: Division of Pediatric Neurology, Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA.
authors.forename: T P
authors.initials: TP
authors.lastname: Giordano
authors.affiliation: Division of Pediatric Neurology, Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA.|Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY, USA.
authors.forename: M
authors.initials: M
authors.lastname: Kosovsky
authors.affiliation: Division of Pediatric Neurology, Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA.
authors.forename: R C
authors.initials: RC
authors.lastname: Rice
authors.affiliation: Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Lee
authors.affiliation: Solomon H. Snyder Department of Neuroscience, Kavli Neuroscience Discovery Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: R L
authors.initials: RL
authors.lastname: Huganir
authors.affiliation: Pharmacology and Toxicology, University of Innsbruck, Innsbruck, Austria.|Center for Molecular Biosciences, University of Innsbruck, Innsbruck, Austria.
authors.forename: J
authors.initials: J
authors.lastname: Striessnig
authors.affiliation: Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA.|Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT, USA.|Interdepartmental Neuroscience Program, Yale Graduate School of Arts and Sciences, New Haven, CT, USA.
authors.forename: N A
authors.initials: NA
authors.lastname: Addy
authors.affiliation: Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Han
authors.affiliation: Division of Pediatric Neurology, Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA.|Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY, USA.|Weill Cornell Autism Research Program, Weill Cornell Medicine, New York, NY, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Rajadhyaksha
mesh_terms: D000339:Affect / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism*; D003042:Cocaine / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000378:metabolism; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology; D003863:Depression / Q000378:metabolism; D004195:Disease Models, Animal; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism*; D057907:Post-Synaptic Density / Q000187:drug effects / Q000378:metabolism; D018091:Receptors, AMPA / Q000378:metabolism; D012919:Social Behavior; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000378:metabolism*
chemical_list: C514350:CACNA1C protein, mouse; C472073:CACNA1D protein, human; C485995:Cacna1d protein, mouse; D020746:Calcium Channels, L-Type; D018765:Dopamine Uptake Inhibitors; D018091:Receptors, AMPA; D003042:Cocaine