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

A. Martínez-Rivera, J. Hao, T. F. Tropea, T. P. Giordano, M. Kosovsky, R. C. Rice, A. Lee, Richard L Huganir, J. Striessnig, N. A. Addy, S. Han, A. M. Rajadhyaksha

Research output: Contribution to journalArticle

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.Molecular Psychiatry advance online publication, 14 February 2017; doi:10.1038/mp.2017.9.

Original languageEnglish (US)
JournalMolecular Psychiatry
DOIs
StateAccepted/In press - Feb 14 2017

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Ventral Tegmental Area
AMPA Receptors
Nucleus Accumbens
Cocaine
Phenotype
Phosphorylation
Calcium
Cocaine-Related Disorders
Acids
Genetic Association Studies
Mood Disorders
Bipolar Disorder
varespladib methyl
Genes
Substance-Related Disorders
Single Nucleotide Polymorphism
Psychiatry
Publications
Rodentia
Depression

ASJC Scopus subject areas

  • Molecular Biology
  • Cellular and Molecular Neuroscience
  • Psychiatry and Mental health

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Enhancing VTA Cav1.3 L-type Ca2+ channel activity promotes cocaine and mood-related behaviors via overlapping AMPA receptor mechanisms in the nucleus accumbens. / Martínez-Rivera, A.; Hao, J.; Tropea, T. F.; Giordano, T. P.; Kosovsky, M.; Rice, R. C.; Lee, A.; Huganir, Richard L; Striessnig, J.; Addy, N. A.; Han, S.; Rajadhyaksha, A. M.

In: Molecular Psychiatry, 14.02.2017.

Research output: Contribution to journalArticle

Martínez-Rivera, A. ; Hao, J. ; Tropea, T. F. ; Giordano, T. P. ; Kosovsky, M. ; Rice, R. C. ; Lee, A. ; Huganir, Richard L ; Striessnig, J. ; Addy, N. A. ; Han, S. ; Rajadhyaksha, A. M. / Enhancing VTA Cav1.3 L-type Ca2+ channel activity promotes cocaine and mood-related behaviors via overlapping AMPA receptor mechanisms in the nucleus accumbens. In: Molecular Psychiatry. 2017.
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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.Molecular Psychiatry advance online publication, 14 February 2017; doi:10.1038/mp.2017.9.",
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AU - Giordano, T. P.

AU - Kosovsky, M.

AU - Rice, R. C.

AU - Lee, A.

AU - Huganir, Richard L

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