Partial D2 receptor deletion causes a sex-dependent reduction of striatal dopamine signals

Authors

• ES Swanson
• VA Alvarez

Abstract

Dopamine signaling in the striatum is a crucial component of drug reinforcement that, when dysregulated, is thought to increase the risk for substance use disorders. In particular, low availability of the dopamine D2 receptor (D2R) has traditionally been linked to the development of substance use disorders in humans. Yet the mechanisms by which low levels of striatal D2Rs generate vulnerability are not fully understood. Here, we directly manipulate the levels of striatal D2Rs in transgenic mice to explore the impact on dopamine signals in the striatum. These mice have a ~25-30% reduction in D2-like agonist binding throughout the striatum, compared to littermate controls that are bred alongside these animals from the cross between Adora2a-cre x Drd2loxP/wt mice. Using fast-scan cyclic voltammetry, we recorded ex vivo electrically-evoked dopamine signals in the dorsomedial striatum (DMS) of male and female mice of both genotypes. Relative to controls, we find that the magnitude of dopamine transmission in mice expressing partial D2R deletion is significantly reduced at baseline, and the extent of this reduction differs between sexes. Later, we block nicotinic acetylcholine receptors, GABAA and GABAB receptors, and kappa opioid receptors with a variety of drug antagonists while recording dopamine signals. In so doing, we aim next to identify systems that regulate the mechanism of D2R modulation of dopamine signaling in the striatum. This work will facilitate our understanding of the role of D2Rs in drug reinforcement and may shed light on the mechanism by which only certain individuals develop substance use disorders.

Scientific Focus Area: Neuroscience

This page was last updated on Monday, September 25, 2023