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 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.

Dopamine Release in Nucleus Accumbens Is under Tonic Inhibition by Adenosine A1Receptors Regulated by Astrocytic ENT1 and Dysregulated by Ethanol

“…These data indicate that an adenosine tone preferentially limits DA output during the lower frequencies of DA neuron activity that represent tonic activity, while leaving relatively intact the DA release evoked by the higher frequencies associated with phasic activity in DA neurons. The preferential inhibition of DA release by low frequencies of activity parallels the effects of GABA input to DA axons (Lopes et al, 2019;Roberts et al, 2020;Roberts et al, 2021) and could indicate a preferential influence of striatal adenosine on DA functions that are proposed to be mediated by low frequencies of activity e.g. the ongoing monitoring of reward value and its changes (Wang et al, 2021).…”

“…Striatal dopamine (DA) axons are major strategic sites for striatal neuromodulators to influence DA output (Nolan et al, 2020;Rice et al, 2011;Roberts et al, 2021;Sulzer et al, 2016). Adenosine acts at A 1 -and A 2Areceptors on diverse neurons in striatum, and exogenous activation of striatal A 1 -receptors (A 1 Rs) but not A 2receptors inhibits evoked DA release (Okada et al, 1996;O'Neill et al, 2007;O'Connor and O'Neill, 2008;Ross and Venton, 2015).…”

Dopamine release in nucleus accumbens is under tonic inhibition by adenosine A1receptors regulated by astrocytic ENT1 and dysregulated by ethanol

“…These data indicate that an adenosine tone preferentially limits DA output during the lower frequencies of DA neuron activity that represent tonic activity, while leaving relatively intact the DA release evoked by the higher frequencies associated with phasic activity in DA neurons. The preferential inhibition of DA release by low frequencies of activity parallels the effects of GABA input to DA axons (Lopes et al, 2019; Roberts et al, 2020; Roberts et al, 2021) and could indicate a preferential influence of striatal adenosine on DA functions that are proposed to be mediated by low frequencies of activity e.g. the ongoing monitoring of reward value and its changes (Wang et al, 2021).…”

“…Striatal dopamine (DA) axons are major strategic sites for striatal neuromodulators to influence DA output (Nolan et al, 2020; Rice et al, 2011; Roberts et al, 2021; Sulzer et al, 2016). Adenosine acts at A 1 - and A 2A -receptors on diverse neurons in striatum, and exogenous activation of striatal A 1 -receptors (A 1 Rs) but not A 2 -receptors inhibits evoked DA release (Okada et al, 1996; O’Neill et al, 2007; O’Connor and O’Neill, 2008; Ross and Venton, 2015).…”

The Aversion Function of the Limbic Dopaminergic Neurons and Their Roles in Functional Neurological Disorders

“…The VTA and SN in the ventral side of the limbic system have long been considered as the main source of DA transmitters in the cerebral cortex and subcutaneous tissue ( Bjorklund and Dunnett, 2007 ). This area is also involved the processing of reward prediction error calculation ( Schultz et al, 1997 ), with gamma-aminobutyric acid (GABA) in the VTA regulating the amount of reward by inhibiting the activity of DAergic neurons ( Roberts et al, 2021 ), thereby calculating the reward prediction error ( Cohen et al, 2012 ). At the same time, some animal studies have indicated that there are multiple clusters of neurons in this region that are responsible for different motivational functions and may be involved in different neural circuits to process reward and aversive information ( Lammel et al, 2011 ).…”