Synaptic regulation of somatodendritic dopamine release by glutamate and GABA differs between substantia nigra and ventral tegmental area

Midbrain dopamine (DA) cells of the substantia nigra pars compacta (SNc) and the ventral tegmental area (VTA) exhibit somatodendritic release of DA. To address how somatodendritic release is regulated by synaptic glutamatergic and GABAergic input, we examined the effect of ionotropic-receptor antagonists on locally evoked extracellular DA concentration ([DA](o)) in guinea pig midbrain slices. Evoked [DA](o) was monitored with carbon-fiber microelectrodes and fast-scan cyclic voltammetry. In SNc, evoked [DA](o) was 160% of control in the presence of the AMPA-receptor antagonist, GYKI-52466, or the NMDA-receptor antagonist, AP5. Similar increases were seen with the GABA(A)-receptor antagonist, picrotoxin, or the GABA(B)-receptor antagonist, saclofen. The increase seen with GYKI-52466 was prevented when both picrotoxin and saclofen were present, consistent with normal, AMPA-receptor mediated activation of GABAergic inhibition. The increase with AP5 persisted, however, implicating NMDA-receptor mediated activation of another inhibitory circuit in SNc. In the VTA, by contrast, evoked [DA](o) was unaffected by GYKI-52466 and fell slightly with AP5. Neither picrotoxin nor saclofen alone or in combination had a significant effect on evoked [DA](o). When GABA receptors were blocked in the VTA, evoked [DA](o) was decreased by 20% with either GYKI-52466 or AP5. These data suggest that in SNc, glutamatergic input acts predominantly on GABAergic or other inhibitory circuits to inhibit somatodendritic DA release, whereas in VTA, the timing or strength of synaptic input will govern whether the net effect on DA release is excitatory or inhibitory.