Negative interaction of dopamine D2 receptor antagonists and GBR 12909 andGBR 12935 dopamine uptake inhibitors in the nucleus accumbens

The objective of this study was to examine the interaction of dopamine D2 r eceptor antagonists and dopamine uptake inhibitors on the regulation of ext racellular dopamine release in the nucleus accumbens of Wistar rats employi ng in vivo microdialysis and in vitro dopamine uptake studies. Application of the D2 receptor antagonists raclopride (100 mum) or sulpiride (100 mum) alone through the microdialysis probe in the nucleus accumbens for 60 min i ncreased the extracellular levels of dopamine in the nucleus accumbens to 1 50% and 200% of basal, respectively. Perfusion of the nucleus accumbens for 60 min with the dopamine uptake inhibitors, 1-[2-[bis(4-Fluorophenyl)metho xy]ethyl]-4-[3-phenylpropyl]piperazine dihydrochloride (GBR 12909; 100 mum) or 1-[2-(Diphenylmethoxy)ethyl]-4-(3-phenylpropyl)-piperazine dihydrochlor ide (GBR 12935; 100 mum) alone, increased the extracellular levels of dopam ine in the nucleus accumbens to 400% and 350% of basal, respectively. Go-pe rfusion of 100 muM GBR 12909 or GBR 12935 with either 100 muM sulpiride or raclopride produced a significant reduction in the GBR 12909 or GBR 12935 i nduced increase in the extracellular levels of dopamine to basal levels. In vitro, GBR 12909 (1-9 nM) dose-dependently inhibited active uptake of [H-3 ]dopamine in homogenates of the nucleus accumbens. Addition of 100 mum sulp iride had little effect on GBR 12909 inhibition of [H-3] dopamine uptake, s uggesting that dopamine D2 receptor antagonists are not blocking the action s of the GBR-type dopamine uptake inhibitors at the dopamine transporter. O verall, the data suggest that complex interactions occur in vivo between D2 antagonists and GBR-type dopamine uptake inhibitors, which negate their ef fects on elevating the extracellular levels of dopamine in the nucleus accu mbens. (C) 2001 Published by Elsevier Science B.V.