L-type calcium channel regulation of dopamine activity in the ventral tegmental area to nucleus accumbens pathway: Implications for substance use, mood disorders and co-morbidities

Abstract

L-type calcium channels (LTCCs), including the Ca_v1.2 and Ca_v1.3 LTCC subtypes, are important regulators of calcium entry into neurons, which mediates neurotransmitter release and synaptic plasticity. Ca_v1.2 and Ca_v1.3 are encoded by the CACNA1C and CACNA1D genes, respectively. These genes are implicated in substance use disorders and depression in humans, as demonstrated by genetic-wide association studies (GWAS). Pre-clinical models have also revealed a critical role of LTCCs on drug and mood related behavior, including the co-morbidity of substance use and mood disorders. Moreover, LTCCs have been shown to regulate the neuronal firing of dopamine (DA) neurons as well as drug and stress-induced plasticity within the ventral tegmental area (VTA) to nucleus accumbens (NAc) pathway. Thus, LTCCs are interesting targets for the treatment of neuropsychiatric diseases. In this review, we provide a brief introduction to voltage-gated calcium channels, specifically focusing on the LTCCs. We place particular emphasis on the ability of LTCCs to regulate DA neuronal activity and downstream signaling in the VTA to NAc pathway, and how such processes mediate substance use and mood disorder-related behavioral responses. We also discuss the bi-directional control of VTA LTCCs on drug and mood-related behaviors in pre-clinical models, with implications for co-morbid psychiatric diagnosis. We conclude with a section on the clinical implications of LTCC blockers, many which are already FDA approved as cardiac medications. Thus, pre-clinical and clinical work should examine the potential of LTCC blockers to be repurposed for neuropsychiatric illness. This article is part of the Special Issue on 'L-type calcium channel mechanisms in neuropsychiatric disorders'.