Pharmacological Antagonism of T-Type Calcium Channels Constrains Rebound Burst Firing in Two Distinct Subpopulations of GABA Neurons in the Rat Ventral Tegmental Area: Implications for α-Lipoic Acid.

Taylor Joel Woodward,Vesna Jevtovic-Todorovic,Slobodan M Todorovic,Vesna Tesic,Tamara Timic Stamenic

doi:10.3389/fphar.2019.01402

Abstract

The ventral tegmental area (VTA) is a midbrain region highly involved in motivation and reward. A large body of work has investigated synaptic plasticity and ion channel excitability in this area, which has strong implication in drug abuse. We recently provided electrophysiological and pharmacological evidence that the CaV3.1 isoform of T-type voltage-gated calcium channels contributes to the excitability of VTA dopamine (DA) neurons. However, the role of T-channels in excitability of VTA gamma-amino-butyric acid (GABA) neurons remained unaddressed. Here, with a population study of rat VTA GABA neurons, we provide evidence that T-channels contribute to rebound spiking activity in two phenotypically distinct subpopulations of GABAergic neurons, each with differing electrophysiological characteristics. Additionally, we provide the first study to investigate the effect of α-lipoic acid (ALA) on ion channels in mesolimbic reward circuitry. Taken together, our population study and pharmacology experiments implicate T-channels as a target for therapies aimed at tempering VTA and mesolimbic circuit excitability.

Highlights

The ventral tegmental area (VTA), which provides strong dopaminergic projections to the ventral striatum, prefrontal cortex, amygdala, and hippocampus, plays a vital role in motivation and reward processes
Our recent patch-clamp recordings in acute VTA brain slices from WT rats clearly demonstrated expression of classic T-type currents that underlie post-inhibitory rebound burst firing in a subset of VTA neurons (Tracy et al, 2018)
As direct application of TTA-P2 abolished rebound spiking in all GABAergic neurons tested, we provide evidence that manipulations of T-channels can affect VTA DA excitability, but could be used to manipulate other aspects of VTA circuitry as well

Summary

Introduction

The ventral tegmental area (VTA), which provides strong dopaminergic projections to the ventral striatum, prefrontal cortex, amygdala, and hippocampus, plays a vital role in motivation and reward processes. The VTA, consisting of dopamine (DA) neurons (~65%), gamma-amino-butyric acid (GABA) neurons (~30%) and glutamatergic neurons (~5%) (Yamaguchi et al, 2007; Nair-Roberts et al, 2008), has been implicated in many neurobiological and neuropathological functions including substance abuse, arousal (Yu et al, 2019), pain modulation (Jarcho et al, 2012; Navratilova et al, 2015), and affective states (Nestler and Carlezon, 2006) These phenomena have sparked interest into the mechanisms of neural plasticity in the VTA and the respective roles of various ionotropic and. Others have demonstrated alterations in GABAergic transmission and increased GABA-release in the VTA and nucleus accumbens (NAc) in animals during withdrawal from opioids and ethanol (Bonci and Williams, 1997; Chieng and Williams, 1998; Ibrahim et al, 2000; Kaufling and Aston-Jones, 2015; Nelson et al, 2018)

Objectives

Methods

Results

Discussion

Conclusion