ELECTROPHYSIOLOGICAL EFFECTS OF SKF-38393 IN RATS WITH RESERPINE TREATMENT AND 6-HYDROXYDOPAMINE-INDUCED NIGROSTRIATAL LESIONS REVEAL 2 TYPES OF PLASTICITY IN D1 DOPAMINE-RECEPTOR MODULATION OF BASAL GANGLIA OUTPUT

To examine the role of D1 dopamine receptors in modulating basal gangl ia output and how this role may be altered by changes in dopaminergic transmission, the effects of a D1 dopamine agonist on firing rates of substantia nigra pars reticulata (SNpr) neurons were determined in res erpine-treated rats and compared with effects observed in nigrostriata l-lesioned and normal rats. It was confirmed that systemic administrat ion of the D1 dopamine agonist SKF 38393 (10 mg/kg i.v.) induces a sma ll (averaging 20% above base line) increase in firing rates of SNpr ne urons in normal rats and significantly inhibits SNpr single unit activ ity in rats studied 6 to 26 weeks after 6-hydroxydopamine (6-OHDA)indu ced substantia nigra dopamine cell lesion. In contrast to results obta ined after 6-OHDA lesions, SKF 38393 administration consistently and s ignificantly increased the firing rates of SNpr neurons in rats treate d for 6 days with reserpine (1 mg/kg/day s.c.); increases averaged 88% above base line. Five days after the 6-day reserpine treatment was di scontinued, administration of SKF 38393 still induced a pronounced inc rease in SNpr activity These increases were reversed by the administra tion of the D1 dopamine antagonist SCH 23390. SKF 38393 also significa ntly increased the firing rates of a subpopulation of SNpr neurons in rats treated with only a single dose of reserpine (10 mg/kg s.c, 4-7 h r). The difference between responses in reserpine and 6-OHDA-treated r ats was not due to the shorter time course of the reserpine treatments , as SKF 38393 did not consistently affect the activity of SNpr neuron s 7 days after 6-OHDA nigral dopamine cell lesion. When the subchronic reserpine treatment was administered to rats lesioned previously with 6-OHDA, D1 dopamine agonist-mediated inhibition of SNpr neuronal acti vity was obtained. The results show that SNpr responses to D1 dopamine agonist administration after reserpine treatment are enhanced (''supe rsensitive'') relative to normal, whereas SNpr responses to D1 dopamin e agonists in animals with 6-OHDA-induced dopamine cell degeneration a re opposite to those observed in normal and in reserpinized animals. C urrent models of basal ganglia function predict that D1 dopamine agoni sts should reduce activity in the SNpr, because D1 dopamine receptors on striatonigral neurons are thought to stimulate striatonigral firing rates and to enhance the release of tau-aminobutyric acid in the SNpr . The present results call for modification of these concepts.