Dopamine-somatostatin interactions were investigated in the rat striatum using in vivo microdialysis. Somatostatin-14 and somatostatin-28 M) were infused, and the levels of dopamine and its metabolites DOPAC and HVA were assessed using high pressure liquid chromatography with electrochemical detection. Somatostatin-14 was more effective than somatostatin-28 in producing a dose-dependent increase in dopamine levels with no significant alterations in the levels of the metabolites. To assess the effect of dopamine on somatostatinergic neurons, dopaminergic agents were administered and somatostatin levels measured using a radioimmunoassay. The nonselective agonist apomorphine was administered subcutaneously (0.00, 0.05, 0.10, 0.50, 1.00 mgkg) or directly infused M) in the striatum. The selective D1 and D2 dopamine antagonists SCH23390 and sulpiride, respectively, were also infused at concentrations of and M. None of these agents elicited any significant changes in the somatostatin release in the striatum, while altering dopamine release. This study provides for the first time evidence regarding dopamine-somatostatin interactions in the awake and freely moving animal. The results confirm that somatostatin modulates the function of dopaminergic neurons in the striatum and provide new evidence that somatostatin-14 may differentially regulate dopamine release. Furthermore, our findings suggest that dopamine does not play a major role in the regulation of somatostatin neurons.