Glucose modulates substantia nigra (SN) dopamine (DA) neuronal activity and GABA axon terminal transmitter release by actions on an ATP-sensitive potassium channel (K(ATP)). Here, the effect of altering SN glucose levels on striatal DA release was assessed by placing microdialysis probes into both the SN and striatum of male Sprague-Dawley rats. Reverse dialysis of 20 mM glucose through the SN probes transiently decreased striatal DA efflux by 32% with a return to baseline after 45 min despite constant glucose levels. During 50 mM glucose infusion, striatal DA efflux increased transiently by 50% and returned to baseline after 60 min. Infusion of 100 mM glucose produced a transient 25% decrease in striatal DA efflux followed by a sustained 50% increase above baseline. Efflux increased by a further 30% when the GABA(A) antagonist bicuculline (50 microM) was added to the 100 mM glucose infusate. At basal glucose levels, nigral bicuculline alone raised striatal DA efflux by 31% suggesting a tonic GABA inhibitory input to the DA neurons. The sulfonylurea glipizide (50 microM) produced a transient 25% increase in striatal DA release that became sustained when bicuculline was added. Thus, striatal DA release is affected by changing SN glucose levels. This response may well reflect the known effect of glucose on K(ATP) channel activity on both SN DA neurons and GABA axon terminals in the substantia nigra. These interactions could provide a mechanism whereby glucose modulates motor activity involved in food intake.