Action potential and calcium dependence of tonic somatodendritic dopamine release in the Substantia Nigra pars compacta

Despite the importance of somatodendritic dopamine (DA) release in the Substantia Nigra pars compacta (SNc), its mechanism remains poorly understood. Using a novel approach combining fast-scan controlled-adsorption voltammetry (FSCAV) and single-unit electrophysiology, we have investigated the mechanism of somatodendritic release by directly correlating basal (non-stimulated) extracellular DA concentration ([DA] ou ), with pharmacologically-induced changes of firing of nigral dopaminergic neurons in rat brain slices. FSCAV measurements indicated that basal [DA] ou in the SNc was 40.7 ± 2.0 nM (at 34 ± 0.5°C), which was enhanced by amphetamine, cocaine, and L-DOPA, and reduced by VMAT2 inhibitor, Ro4-1284. Complete inhibition of firing by TTX decreased basal [DA] ou , but this reduction was smaller than the effect of D 2 receptor agonist, quinpirole. Despite similar effects on neuronal firing, the larger decrease in [DA] ou evoked by quinpirole was attributed to cell membrane hyperpolarization and greater reduction in cytosolic free Ca 2+ ([Ca 2+ ] in ). Decreasing extracellular Ca 2+ also reduced basal [DA] ou , despite increasing firing frequency. Furthermore, inhibiting L-type Ca 2+ channels decreased basal [DA] ou , although specific Ca v 1.3 channel inhibition did not affect firing rate. Inhibition of sarcoplasmic/endoplasmic reticulum Ca 2+ -ATPase (SERCA) also decreased [DA] ou , demonstrating the importance of intracellular Ca 2+ stores for somatodendritic release. Finally, in vivo FSCAV measurements showed that basal [DA] ou in the SNc was 79.8 ± 10.9 nM in urethane-anesthetized rats, which was enhanced by amphetamine. Overall, our findings indicate that although tonic somatodendritic DA release is largely independent of action potentials, basal [DA] ou is strongly regulated by voltage-dependent Ca 2+ influx and release of intracellular Ca 2+ . OPEN SCIENCE BADGES: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.