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 GABAA and GABAB receptors. We review evidence supporting the localisation of GABAA and GABAB 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 GABAA and GABAB 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.
Highlights
Release of the neurotransmitter dopamine (DA) in the brain is critical for action selection, motivation and cognition and is dysregulated across a diversity of disorders including Parkinson’s disease (PD) and addictions
While GABAB receptors on striatal DA axons function to inhibit the overall amplitude of DA release, which could be consistent with modified voltage-gated calcium channels (VGCCs) activity, they might simultaneously gate short-term plasticity of DA release by modifying axonal excitability via potassium-dependent conductances through activation of Kir3-type potassium channels
Two isoforms of GAT, namely GAT-1 (Slc6a1) and GAT-3 (Slc6a11), determine striatal ambient GABA tone. They limit tonic GABA inhibition of striatal neurons e.g., GABAA receptormediated inhibitory conductances detected in spiny projection neurons (SPNs) [87,89,100,101,102], and we recently revealed that striatal GATs support DA release in the dorsal striatum by limiting tonic GABA inhibition of DA release [39]
Summary
Release of the neurotransmitter dopamine (DA) in the brain is critical for action selection, motivation and cognition and is dysregulated across a diversity of disorders including Parkinson’s disease (PD) and addictions. No GABAergic axoaxonic synapses have been identified on DA axons [23], but a wealth of historical and more recently refined evidence has revealed that local GABA signalling in striatum can powerfully modulate DA release through action at GABAA and GABAB receptors. We review these actions, sources and substrates, in detail here
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