Reduced levels of Cacna1c attenuate mesolimbic dopamine system function

Chantelle Terrillion, D. T. Dao, R. Cachope, M. K. Lobo, A. C. Puche, J. F. Cheer, T. D. Gould

Research output: Contribution to journalArticle

Abstract

Genetic variation in CACNA1C, which codes for the L-type calcium channel (LTCC) Cav1.2, is associated with clinical diagnoses of bipolar disorder, depression and schizophrenia. Dysregulation of the mesolimbic-dopamine (ML-DA) system is linked to these syndromes and LTCCs are required for normal DAergic neurotransmission between the ventral tegmental area (VTA) and nucleus accumbens (NAc). It is unclear, however, how variations in CACNA1C genotype, and potential subsequent changes in expression levels in these regions, modify risk. Using constitutive and conditional knockout mice, and treatment with the LTCC antagonist nimodipine, we examined the role of Cacna1c in DA-mediated behaviors elicited by psychomotor stimulants. Using fast-scan cyclic voltammetry, DA release and reuptake in the NAc were measured. We find that subsecond DA release in Cacna1c haploinsufficient mice lacks normal sensitivity to inhibition of the DA transporter (DAT). Constitutive haploinsufficiency of Cacna1c led to attenuation of hyperlocomotion following acute administration of stimulants specific to DAT, and locomotor sensitization of these mice to the DAT antagonist GBR12909 did not reach the same level as wild-type mice. The maintenance of sensitization to GBR12909 was attenuated by administration of nimodipine. Sensitization to GBR12909 was attenuated in mice with reduced Cacna1c selectively in the VTA but not in the NAc. Our findings show that Cacna1c is crucial for normal behavioral responses to DA stimulants and that its activity in the VTA is required for behavioral sensitization. Cacna1c likely exerts these effects through modifications to presynaptic ML-DA system function.

Original languageEnglish (US)
Pages (from-to)495-505
Number of pages11
JournalGenes, Brain and Behavior
Volume16
Issue number5
DOIs
StatePublished - Jun 1 2017
Externally publishedYes

Fingerprint

Ventral Tegmental Area
Dopamine
Nucleus Accumbens
L-Type Calcium Channels
Nimodipine
Bipolar Disorder
Tegmentum Mesencephali
Haploinsufficiency
Calcium Channel Blockers
Knockout Mice
Synaptic Transmission
Schizophrenia
Genotype
Maintenance
Therapeutics

Keywords

  • Behavior
  • bipolar disorder
  • CACNA1C
  • depression
  • dopamine
  • fast-scan cyclic voltammetry
  • nucleus accumbens
  • schizophrenia
  • sensitization
  • ventral tegmental area

ASJC Scopus subject areas

  • Genetics
  • Neurology
  • Behavioral Neuroscience

Cite this

Terrillion, C., Dao, D. T., Cachope, R., Lobo, M. K., Puche, A. C., Cheer, J. F., & Gould, T. D. (2017). Reduced levels of Cacna1c attenuate mesolimbic dopamine system function. Genes, Brain and Behavior, 16(5), 495-505. https://doi.org/10.1111/gbb.12371

Reduced levels of Cacna1c attenuate mesolimbic dopamine system function. / Terrillion, Chantelle; Dao, D. T.; Cachope, R.; Lobo, M. K.; Puche, A. C.; Cheer, J. F.; Gould, T. D.

In: Genes, Brain and Behavior, Vol. 16, No. 5, 01.06.2017, p. 495-505.

Research output: Contribution to journalArticle

Terrillion, C, Dao, DT, Cachope, R, Lobo, MK, Puche, AC, Cheer, JF & Gould, TD 2017, 'Reduced levels of Cacna1c attenuate mesolimbic dopamine system function', Genes, Brain and Behavior, vol. 16, no. 5, pp. 495-505. https://doi.org/10.1111/gbb.12371
Terrillion, Chantelle ; Dao, D. T. ; Cachope, R. ; Lobo, M. K. ; Puche, A. C. ; Cheer, J. F. ; Gould, T. D. / Reduced levels of Cacna1c attenuate mesolimbic dopamine system function. In: Genes, Brain and Behavior. 2017 ; Vol. 16, No. 5. pp. 495-505.
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