Inhibition of Nigrostriatal Dopamine Release by Striatal GABA_Aand GABA_BReceptors

Abstract

Nigrostriatal dopamine (DA) is critical to action selection and learning. Axonal DA release is locally influenced by striatal neurotransmitters. Striatal neurons are principally GABAergic projection neurons and interneurons, and a small minority of other neurons are cholinergic interneurons (ChIs). ChIs strongly gate striatal DA release via nicotinic receptors (nAChRs) identified on DA axons. Striatal GABA is thought to modulate DA, but GABA receptors have not been documented conclusively on DA axons. However, ChIs express GABA receptors and are therefore candidates for potential mediators of GABA regulation of DA. We addressed whether striatal GABA and its receptors can modulate DA release directly, independently from ChI regulation, by detecting DA in striatal slices from male mice using fast-scan cyclic voltammetry in the absence of nAChR activation. DA release evoked by single electrical pulses in the presence of the nAChR antagonist dihydro-β-erythroidine was reduced by GABA or agonists of GABAA or GABAB receptors, with effects prevented by selective GABA receptor antagonists. GABA agonists slightly modified the frequency sensitivity of DA release during short stimulus trains. GABA agonists also suppressed DA release evoked by optogenetic stimulation of DA axons. Furthermore, antagonists of GABAA and GABAB receptors together, or GABAB receptors alone, significantly enhanced DA release evoked by either optogenetic or electrical stimuli. These results indicate that striatal GABA can inhibit DA release through GABAA and GABAB receptors and that these actions are not mediated by cholinergic circuits. Furthermore, these data reveal that there is a tonic inhibition of DA release by striatal GABA operating through predominantly GABAB receptors.SIGNIFICANCE STATEMENT The principal inhibitory transmitter in the mammalian striatum, GABA, is thought to modulate striatal dopamine (DA) release, but definitive evidence for GABA receptors on DA axons is lacking. Striatal cholinergic interneurons regulate DA release via axonal nicotinic receptors (nAChRs) and also express GABA receptors, but they have not been eliminated as potentially critical mediators of DA regulation by GABA. Here, we found that GABAA and GABAB receptors inhibit DA release without requiring cholinergic interneurons. Furthermore, ambient levels of GABA inhibited DA release predominantly through GABAB receptors. These findings provide further support for direct inhibition of DA release by GABA receptors and reveal that striatal GABA operates a tonic inhibition on DA output that could critically influence striatal output.

Astrocytic striatal GABA transporter activity governs dopamine release and shows maladaptive downregulation in early parkinsonism

“…3b,c). We have previously shown that activation of striatal GABA receptors can slightly promote the activity-dependence of DA release during short stimulus trains (Lopes et al, 2019). Consistent with an increase in GABA receptor activation, GAT inhibitor NPA increased the dependence of [DA]o on pulse number during 50 Hz pulse trains in DLS ( Fig.…”

“…We recently reported that axonal DA release in the dorsal striatum is under tonic inhibition by striatal GABA, as GABAA and GABAB receptor antagonists enhanced DA release evoked by single electrical and targeted optogenetic stimuli (Lopes et al, 2019). Since mechanisms that regulate striatal DA release can diverge between dorsal and ventral striatal territories (Brimblecombe et al, 2015;Britt and McGehee, 2008;Janezic et al, 2013;Shin et al, 2017;Threlfell and Cragg, 2011;Threlfell et al, 2010), we first determined whether DA release in NAcC, within the ventral striatum, is similarly regulated by tonic GABA inhibition.…”

“…This inference was based on detection of mRNA for GAT-1 (and weakly for GAT-3) in the somata of DA neurons in substantia nigra, and on the attenuation of GABA co-release from DA axons after pharmacological inhibition of both GAT-1 and GAT-3 (Tritsch et al, 2014). However, because subsequent work has shown that there is a tonic GABAergic inhibition of DA release mediated by both GABAA and GABAB receptors (Lopes et al, 2019), which we show here is profoundly limited by the GATs, then the observed dependence of GABA co-release on GAT could be explained alternatively by GATs limiting tonic inhibition of GABA co-release, rather than GATs necessarily being required for GABA uptake.…”

“…For experiments involving multiple pulse protocols, each stimulation type was repeated in triplicate, interspersed with 1p stimulations, and then averaged and normalized to 1p stimulations at each recording site, as previously (Lopes et al, 2019;Threlfell et al, 2012).…”

“…Striatal DA release is gated locally by axonal mechanisms and striatal neuromodulators that regulate or even drive DA release (Schmitz et al, 2003;Sulzer et al, 2016). It has recently been revealed that DA release is under tonic inhibition by striatal GABA, operating through GABAA and GABAB receptors (Lopes et al, 2019;Pitman et al, 2014;Schmitz et al, 2002). The striatum contains a high density of GABAergic projection neurons and interneurons and also receives a source of GABA co-released from mesostriatal DA neurons (Kim et al, 2015;Tritsch et al, 2012Tritsch et al, , 2014.…”