HETEROGENEITY OF ELECTRICALLY-EVOKED DOPAMINE RELEASE AND REUPTAKE INSUBSTANTIA-NIGRA, VENTRAL TEGMENTAL AREA, AND STRIATUM

Somatodendritic dopamine (DA) released in substantia nigra pars compac ta (SNc) and the ventral tegmental area (VTA) may mediate extrasynapti c neuronal signaling. The concentration of extracellular DA ([DA](o)) attained during somatodendritic activation will be governed by the den sity of release sites and properties of DA uptake. We evaluated these factors in SNc, VTA, and dorsal striatum with carbon-fiber microelectr odes and fast-scan cyclic voltammetry to monitor [DA](o) during local electrical stimulation (10 Hz, 5 s) in guinea pig brain slices. Stimul ated DA efflux was site specific, with significantly higher [DA](o) in caudal (0.48 +/- 0.03 mu M, mean +/- SE) than rostral SNc (0.16 +/- 0 .01 mu M), averaged over their mediolateral extents, and higher [DA](o ) in VTA (0.74 +/- 0.07 mu M) than in medial (0.43 +/- 0.04 mu M) or l ateral SNc (0.29 +/- 0.05 mu M), averaged rostrocaudally. Throughout S Nc, evoked [DA](o) correlated positively (r = 0.91) with the density o f tyrosine-hydroxylase-immunoreactive cells. Modulation of evoked [DA] (o) by uptake was also site specific. The selective DA uptake inhibito r GBR 12909 significantly increased evoked [DA](o) in caudal SNc (to 1 85 +/- 27%) and striatum (408 +/- 24%), but had no effect in rostral S Nc or VTA. Conversely, the norepinephrine (NE) uptake inhibitor desipr amine did not alter stimulated [DA](o) in caudal SNc or striatum, but caused significant enhancement in rostral SNc (196 +/- 17%) and VTA (1 26 +/- 12%). Paroxetine, a selective 5-hydroxytryptamine uptake inhibi tor, had little effect in any region tested. Site-specific sensitivity to desipramine mandated evaluation of dopamine-beta-hydroxylase immun oreactivity (D beta H-ir) in midbrain. The density of filaments positi ve for D beta H-ir was greater in rostral SNc and VTA than in caudal S Nc, suggesting DA clearance via the NE transporter in these regions. I mportantly, D beta H-ir was most dense in sections rostral to SNc wher e no catecholamine signal was detected and no enhancement was observed with desipramine, indicating a lack of NE contribution to evoked rele ase in any region examined. Taken together, these data confirmed that evoked somatodendritic [DA](o) depends on DA cell density and on local uptake properties. Uptake was less efficient in SNc and VTA than in s triatum. Moreover, enhancement of stimulated [DA](o) by GBR 12909 demo nstrated that evoked release from dendrites is not via reversal of the DA transporter. Lastly, the heterogeneous patterns of DA uptake withi n SNc and VTA were consistent with the pattern of degeneration in Park inson's disease: less vulnerable DA cells, e.g., those in VTA, have le ss DA uptake than the more vulnerable cells of caudal SNc.