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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

Molecular Psychiatry volume 22, pages 1735–1745 (2017)Cite this article

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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.

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Acknowledgements

This work was supported by the National Institute of Health Grants R01DA029122 (to AMR), R01AA022994 (to SH), R21DA038048 (to NAA and AMR), NINDS R01NS036715 (to RLH), DC009433 and NS084190 (to AL), the NIDA Diversity Supplement 3R01DA029122-04S2 (to AM-R), The Weill Cornell Autism Research Program (to AMR), and the Austrian Science Fund FWF P-27809 (to JS). The Study of Addiction: Genetics and Environment (SAGE) GWAS data set used for the analyses described in this manuscript were obtained from http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gap through dbGaP accession number phs000092.v1.p. Funding support for the SAGE was provided through the NIH Genes, Environment and Health Initiative (GEI) (U01 HG004422). SAGE is one of the genome-wide association studies funded as part of the Gene Environment Association Studies (GENEVA) under GEI. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the GENEVA Coordinating Center (U01 HG004446). Assistance with data cleaning was provided by the National Center for Biotechnology Information. Support for the collection of data sets and samples was provided by the Collaborative Study on the Genetics of Alcoholism (COGA; U10 AA008401), the Collaborative Genetic Study of Nicotine Dependence (COGEND; P01 CA089392) and the Family Study of Cocaine Dependence (FSCD; R01 DA013423). Funding support for genotyping, which was performed at the Johns Hopkins University Center for Inherited Disease Research, was provided by the NIH GEI (U01HG004438), the National Institute on Alcohol Abuse and Alcoholism, the National Institute on Drug Abuse and the NIH contract ‘High throughput genotyping for studying the genetic contributions to human disease’ (HHSN268200782096C).

Author contributions

AM-R, JH, TFT, TPG, NAA and AMR contributed to the overall experimental design and data interpretation. AM-R, NAA and AMR wrote the manuscript. AL, RLH and JS provided reagents and edited the manuscript. AM-R, JH, TFT, TPG, MK and RCR performed research and analyzed data. MK and RCR edited the manuscript. SH contributed to the design and performed the GWAS and wrote the manuscript.

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Authors and Affiliations

  1. Division of Pediatric Neurology, Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA

    A Martínez-Rivera, J Hao, T F Tropea, T P Giordano, M Kosovsky, R C Rice & A M Rajadhyaksha

  2. Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY, USA

    A Martínez-Rivera, T F Tropea, M Kosovsky & A M Rajadhyaksha

  3. Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA, USA

    A Lee

  4. Solomon H. Snyder Department of Neuroscience, Kavli Neuroscience Discovery Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    R L Huganir

  5. Pharmacology and Toxicology, University of Innsbruck, Innsbruck, Austria

    J Striessnig

  6. Center for Molecular Biosciences, University of Innsbruck, Innsbruck, Austria

    J Striessnig

  7. Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA

    N A Addy

  8. Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT, USA

    N A Addy

  9. Interdepartmental Neuroscience Program, Yale Graduate School of Arts and Sciences, New Haven, CT, USA

    N A Addy

  10. Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, USA

    S Han

  11. Weill Cornell Autism Research Program, Weill Cornell Medicine, New York, NY, USA

    A M Rajadhyaksha

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Martínez-Rivera, A., Hao, J., Tropea, T. et al. Enhancing VTA Cav1.3 L-type Ca2+ channel activity promotes cocaine and mood-related behaviors via overlapping AMPA receptor mechanisms in the nucleus accumbens. Mol Psychiatry 22, 1735–1745 (2017). https://doi.org/10.1038/mp.2017.9

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