Axonal Modulation of Striatal Dopamine Release by Local γ-Aminobutyric Acid (GABA) Signalling

Abstract

Striatal dopamine (DA) release is critical for motivated actions and reinforcement learning, and is locally influenced at the level of DA axons by other striatal neurotransmitters. Here, we review a wealth of historical and more recently refined evidence indicating that DA output is inhibited by striatal γ-aminobutyric acid (GABA) acting via GABA_A and GABA_B receptors. We review evidence supporting the localisation of GABA_A and GABA_B receptors to DA axons, as well as the identity of the striatal sources of GABA that likely contribute to GABAergic modulation of DA release. We discuss emerging data outlining the mechanisms through which GABA_A and GABA_B receptors inhibit the amplitude as well as modulate the short-term plasticity of DA release. Furthermore, we highlight recent data showing that DA release is governed by plasma membrane GABA uptake transporters on striatal astrocytes, which determine ambient striatal GABA tone and, by extension, the tonic inhibition of DA release. Finally, we discuss how the regulation of striatal GABA-DA interactions represents an axis for dysfunction in psychomotor disorders associated with dysregulated DA signalling, including Parkinson's disease, and could be a novel therapeutic target for drugs to modify striatal DA output.

Keywords: GABA; GABA transporters; GABAA receptors; GABAB receptors; Parkinson’s disease; dopamine; striatum; tonic inhibition.

Figure 1

Modulation of striatal DA release in dorsal striatum by GABA_A and GABA_B receptor agonists and antagonists. (A, C, E, G)—Mean [DA]_o transients (left) and mean peak [DA]_o (± SEM) versus time (right) evoked by 1 electrical pulse (1p) in dorsal striatum in the absence (control) and presence of GABA_A agonist muscimol (20 μM) (A), GABA_A antagonist bicuculline (10 μM) (C), GABA_B agonist baclofen (10 μM) (E), or GABA_B antagonist saclofen (100 μM) (G). (B, D, F, H)—Mean [DA]_o transients (left) and mean peak [DA]_o (±SEM) conditions in the absence (control) and presence of GABA_A agonist muscimol (20 μM) (B), GABA_A antagonist bicuculline (10 μM) (D), GABA_B agonist baclofen (10 μM) (F), or GABA_B antagonist saclofen (100 μM) (H). All data were acquired in the presence of nAChR antagonist DHβE (1 μM). * p ≤ 0.05, ** p ≤ 0.01, *** p ≤ 0.001, Mann-Whitney U test (A,C,E,G), Two-way repeated measure ANOVA (B,D,F,H). Figure adapted from [36].