GABA co-released from striatal dopamine axons dampens phasic dopamine release through autoregulatory GABAA receptors

Striatal dopamine axons co-release dopamine and gamma-aminobutyric acid (GABA), using GABA provided by uptake via GABA transporter-1 (GAT1). Functions of GABA co-release are poorly understood. We asked whether co-released GABA autoinhibits dopamine release via axonal GABA type A receptors (GABAARs), complementing established inhibition by dopamine acting at axonal D2 autoreceptors. We show that dopamine axons express α3-GABAAR subunits in mouse striatum. Enhanced dopamine release evoked by single-pulse optical stimulation in striatal slices with GABAAR antagonism confirms that an endogenous GABA tone limits dopamine release. Strikingly, an additional inhibitory component is seen when multiple pulses are used to mimic phasic axonal activity, revealing the role of GABAAR-mediated autoinhibition of dopamine release. This autoregulation is lost in conditional GAT1-knockout mice lacking GABA co-release. Given the faster kinetics of ionotropic GABAARs than G-protein-coupled D2 autoreceptors, our data reveal a mechanism whereby co-released GABA acts as a first responder to dampen phasic-to-tonic dopamine signaling. [Display omitted] •Dopamine axons express GABAARs that inhibit optically evoked dopamine (DA) release•GABA inhibition of DA release is greater with phasic burst vs. tonic single-pulse stimulation•Enhanced inhibition of phasic DA release is absent in mice lacking GABA co-release•GABA co-released from DA axons acts as a physiological autoregulator of DA release Striatal dopamine (DA) axons co-release GABA as well as DA. The actions and consequences of GABA co-release are not fully understood. Patel et al. show co-released GABA is an autoregulatory messenger that curtails burst-evoked DA release via GABAARs on DA axons thereby rapidly suppressing the contrast in phasic-to-tonic DA signaling.