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]out), with pharmacologically‐induced changes of firing of nigral dopaminergic neurons in rat brain slices. FSCAV measurements indicated that basal [DA]out 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]out, but this reduction was smaller than the effect of D2 receptor agonist, quinpirole. Despite similar effects on neuronal firing, the larger decrease in [DA]out evoked by quinpirole was attributed to cell membrane hyperpolarization and greater reduction in cytosolic free Ca2+ ([Ca2+]in). Decreasing extracellular Ca2+ also reduced basal [DA]out, despite increasing firing frequency. Furthermore, inhibiting L‐type Ca2+ channels decreased basal [DA]out, although specific Cav1.3 channel inhibition did not affect firing rate. Inhibition of sarcoplasmic/endoplasmic reticulum Ca2+‐ATPase (SERCA) also decreased [DA]out, demonstrating the importance of intracellular Ca2+ stores for somatodendritic release. Finally, in vivo FSCAV measurements showed that basal [DA]out 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]out is strongly regulated by voltage‐dependent Ca2+ influx and release of intracellular Ca2+.