Muscarinic Excitation of Dopamine Neurons in the Ventral Tegmental Area via Activation of a TRPC-like Cation Conductance

Author

Yu Tzu Chen, Virginia Commonwealth UniversityFollow

DOI

https://doi.org/10.25772/2W81-BT03

Author ORCID Identifier

https://orcid.org/0000-0002-9031-8105

Defense Date

2021

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Physiology and Biophysics

First Advisor

Jose M. Eltit, Ph.D.

Second Advisor

A. Rory McQuiston, Ph.D.

Abstract

Dopaminergic (DA) neurons in the ventral tegmental area (VTA) play a crucial role in reward and motivational behaviors, including the development of drug addictions. VTA DA neurons receive excitatory cholinergic inputs from the mesopontine tegmentum. Blockage of the M5 muscarinic receptor in DA neurons has been shown to attenuate drug-induced DA release and abuse-related behaviors, but the molecular mechanism is unknown. In this study, experiments were designed to identify the electrophysiological effects of muscarinic agonism in the modulation of action potential kinetics and firing patterns in VTA DA neurons of mice. Pharmacology of the muscarinic receptor-evoked current was also characterized. In the presence of tetrodotoxin (TTX), the cholinergic receptor agonist carbachol (Carb) depolarized membrane potential and decreased input resistance, effects that were completely inhibited by the muscarinic receptor antagonist atropine (Atro). This carbachol-induced depolarization caused an increase in spontaneous firing frequency without affecting firing regularity, frequency-current relationship, HCN sag ratio, or the kinetics of action potential shape. In addition, carbachol had no effects on spontaneous inhibitory postsynaptic currents (sIPSCs) in VTA DA neurons. In the voltage-clamp configuration, carbachol induced a non-desensitizing inward current and an increase in current fluctuations that were insensitive to TTX and Cs⁺ but sensitive to tetraethylammonium (TEA), Cd²⁺, and the TRPC channel blocker BTP2. Collectively, the current evidence suggests that activation of HCN channels, inhibition of potassium channels, and changes in inhibitory synaptic inputs do not participate in the muscarinic slow depolarization in VTA DA neurons, but points toward activation of a non-selective cation conductance mediated by TRPC channels.

Rights

© Rita Yu-Tzu Chen

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

12-17-2021