Endogenous dopamine can modulate inhibition of substantia nigra pars reticulata neurons elicited by GABA iontophoresis or striatal stimulation

Abstract

Previous reports from this laboratory have described an ability of iontophoretically applied dopamine to attenuate the inhibitory effects of iontophoresed GABA on neurons of the substantia nigra pars reticulata. This finding raised the question of whether endogenous dopamine, released from dendrites of neighboring pars compacta dopamine neurons, might act as a neuromodulator which diminishes the inhibition of pars reticulata neurons evoked by either GABA iontophoresis or electrical stimulation of the striatonigral GABAergic pathway. Extracellular, single-unit activity of pars reticulata neurons was recorded in male rats anesthetized with chloral hydrate. In one set of studies, d-amphetamine, a drug reported to release dopamine from nigral dendrites, was administered intravenously (1.6 mg/kg) during regular, intermittent iontophoretic pulses of GABA. As had been previously observed with iontophoresed dopamine, i.v. amphetamine significantly lessened the inhibition of reticulata neurons produced by GABA application. This change was reflected by a decrease in GABA's inhibitory potency by 22% relative to the control level of inhibition achieved prior to amphetamine administration. Amphetamine caused decreases in GABA' effectiveness, however, in animals that had previously received treatements that depleted or destroyed nigral dopamine stores, i.e., in rats pretreated with reserpine and α-methyl-p-tyrosine, or in rats with 6-hydroxydopamine lesions of the nigrostriatal dopamine pathway. In a second set of experiments, amphetamine or dopamine was delivered iontophoretically while monitoring the GABA-mediated (bicuculline-reversible) inhibition of reticulata neurons that can be elicited by striatal stimulation. Both iontophoretically applied amphetamine and dopamine significantly reduced the ability of striatal stimulation to inhibit reticulata cell firing for 67% (n = 12) and 44% (n = 18) of reticulata cells tested, respectively. For amphetamine, this attenuation was reflected by a 5-fold increase in the number of spikes occurring during the inhibitory interval following delivery of each stimulus. These findings extend those of our previous studies by demonstrating that the dopamine-GABA interaction can occur with physiological release of the two transmitters within the nigra. They further confirm the role of dopamine as a neuromodulator that can act downstream from the striatum, within the substantia nigra, to modify responses of pars reticulata output neurons to their striatonigral GABA ergic innervation.