GABA_B modulation of dopamine release in the nucleus accumbens core

Abstract

Modulation of the concentration of dopamine (DA) released from dopaminergic terminals in the nucleus accumbens (NAc) influences behaviours such as the motivation to obtain drugs of abuse. γ-Aminobutyric acid type B (GABAB ) receptors are expressed throughout the mesolimbic circuit, including in the NAc, and baclofen, an agonist of GABAB receptors, can decrease drug-seeking behaviours. However, the mechanism by which GABAB receptors modulate terminal DA release has not been well studied. We explored how baclofen modulates the concentration of DA released from terminals in the NAc core using fast-scan cyclic voltammetry in brain slices from adult male C57BL/6J mice. We found that baclofen concentration-dependently decreased single pulse-evoked DA release. This effect was blocked by the GABAB antagonist, CGP 52432, but not by a nicotinic acetylcholine receptor antagonist. Suppression of DA release by a saturating concentration of baclofen was sustained for up to 1 h. The effect of baclofen was reduced with electrical stimulations mimicking burst firing of DA neurons. Similar to the D2 receptor agonist, quinpirole, baclofen reduced the probability of DA release, supporting a mechanistic overlap with D2 receptors. Baclofen-mediated suppression of DA release persisted after a locomotor-sensitizing cocaine treatment, indicating that GABAB receptors on DA terminals were not altered by cocaine exposure. These data suggest that baclofen-mediated suppression of terminal DA release is due to GABAB activation on DA terminals to reduce the probability of DA release. This effect does not readily desensitize, and persists regardless of chronic cocaine treatment.

Chronic ethanol exposure increases inhibition of optically targeted phasic dopamine release in the nucleus accumbens core and medial shell ex vivo

“…Prior ethanol exposure has been suggested to augment GABA interneuron inhibition of DA neurons in the ventral tegmental area (Melis et al 2002). A similar mechanism may be occurring in the NAc where populations of GABAergic interneurons (Tepper et al 2010) may modulate DA release via terminal GABA B receptors when using electrical stimulation (Pitman et al 2014). Similarly, concurrent stimulation of local acetylcholine interneurons significantly augments stimulated DA release (Threlfell et al 2012; Cachope et al 2012), providing a means through with ethanol-induced inhibition of cholinergic transmission would be detected in the DA signal (Dohrman and Reiter 2003; Boutros et al 2016).…”

Striatal dopamine neurotransmission: Regulation of release and uptake

“…In FCV recordings in mouse striatal slices, GABA B receptor agonists inhibit single-pulse evoked release in CPu and NAc with kinetic parameters similar to those of D2 autoreceptors [226] [268]. In guinea-pig or mouse striatal slices, however, GABA B receptor antagonism has no effect on single-pulse or pulse-train evoked DA release [255,269].…”

Nicotine‐induced molecular alterations are modulated by GABAB receptor activity

“…Based on our results, we can assume that GABA B receptors are involved in the control of α 4 β 2 nAChRs synthesis in VTA during the rewarding effects induced by NIC. In fact, it has been well established that the expression, activity and function of α 4 β 2 nAChRs in the VTA is regulated by GABA B receptors (McClure‐Begley et al ; Pitman, Puil & Borgland ; Ngolab et al ). Therefore, we confirm that an increase of α 4 β 2 nAChRs density in the VTA would be responsible, at least in part, of NIC‐induced rewarding effects, and GABA B receptors would modulate these alterations.…”