Single unit electrophysiology was used to explore the role of cannabinoid receptors in the substantia nigra pars reticulata. Intravenous and intraperitoneal injections of the potent and selective synthetic cannabinoid (R)-(+)-[2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrrolo[1,2,3- de]-1,4-benzoxazin-6-yl](1-naphthalenyl) methanone (WIN 55,212-2) produced modest but significant increases in the spontaneous firing rate of neurons in the substantia nigra pars reticulata. In a second set of experiments, WIN 55,212-2 (up to 1.0 mg/kg i.v.) antagonized the inhibition of firing produced in the substantia nigra pars reticulata by electrical stimulation of the striatum. The pharmacological specificity of this effect was demonstrated using the inactive enantiomer WIN 55,212-3. The possibility that WIN 55,212-2 exerts its effects by regulating gamma-aminobutyric acid (GABA) release from striatonigral fibers was suggested by the observation that bicuculline (up to 0.5 mg/kg i.v.) reversed the effect of striatal stimulation. It thus appears that cannabinoid receptors on striatonigral neuron terminals may regulate movement by disinhibiting the activity of substantia nigra pars reticulata neurons, perhaps by inhibiting the release of GABA into the substantia nigra pars reticulata.