Orphanin FQ nociceptin modulation of mesolimbic dopamine transmission determined by microdialysis

Orphanin FQ has been reported to suppress extracellular dopamine levels in the nucleus accumbens after intracerebroventricular administration. This st udy sought to provide evidence for an intra-ventral tegmental site of actio n for this effect using a dual-probe microdialysis experimental design. Orp hanin FQ was applied to the ventral tegmental area of anesthetized rats by reverse dialysis while extracellular dopamine was sampled with a second dia lysis probe in the nucleus accumbens. Orphanin FQ at a probe concentration of 1 mM (but not at 0.1 mM) significantly reduced nucleus accumbens dialysa te dopamine levels. The receptor-inactive analogue, des-Phe(1)-orphanin FQ (1 mM), produced a small but significant increase in nucleus accumbens dial ysate dopamine levels. Simultaneous measurement of ventral tegmental area d ialysate amino acid content revealed significant increases in both GABA and glutamate during infusion of orphanin FQ (1 mM). To determine if increased GABA overflow mediates the action of orphanin FQ on mesolimbic neurons, or phanin FQ (10 nmol) was microinjected directly into the ventral tegmental a rea in the presence or absence of the GABA(A) receptor antagonist, bicucull ine (1 nmol). Bicuculline transiently blocked the suppressive action of orp hanin FQ on accumbens dialysate dopamine levels. These data indicate that o rphanin FQ decreases dopamine transmission in the nucleus accumbens by inhi biting dopamine neuronal activity in the Ventral tegmental area through a m echanism that may involve an increased overflow of GABA.