title: Reduced levels of Cacna1c attenuate mesolimbic dopamine system function.
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.
authors.affiliation: Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA.|Program in Neuroscience, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: C E
authors.initials: CE
authors.lastname: Terrillion
authors.affiliation: Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: D T
authors.initials: DT
authors.lastname: Dao
authors.affiliation: Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: R
authors.initials: R
authors.lastname: Cachope
authors.affiliation: Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA.|Program in Neuroscience, University of Maryland School of Medicine, Baltimore, MD, USA.|Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: M K
authors.initials: MK
authors.lastname: Lobo
authors.affiliation: Program in Neuroscience, University of Maryland School of Medicine, Baltimore, MD, USA.|Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: A C
authors.initials: AC
authors.lastname: Puche
authors.affiliation: Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA.|Program in Neuroscience, University of Maryland School of Medicine, Baltimore, MD, USA.|Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: J F
authors.initials: JF
authors.lastname: Cheer
authors.affiliation: Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA.|Program in Neuroscience, University of Maryland School of Medicine, Baltimore, MD, USA.|Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA.|Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: T D
authors.initials: TD
authors.lastname: Gould
mesh_terms: D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism*; D059333:Central Nervous System Sensitization; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D005260:Female; D008124:Locomotion; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009553:Nimodipine / Q000494:pharmacology; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D010879:Piperazines / Q000494:pharmacology; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology
chemical_list: C514350:CACNA1C protein, mouse; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D010879:Piperazines; D009553:Nimodipine; C043425:vanoxerine; D004298:Dopamine
keywords: Behavior; CACNA1C; bipolar disorder; depression; dopamine; fast-scan cyclic voltammetry; nucleus accumbens; schizophrenia; sensitization; ventral tegmental area