Dopaminergic and neostriatal neurons: dose-dependent changes in sensitivity to amphetamine following long-term treatment.

Rats were pretreated with saline, 1.0 or 5.0 mg/kg of (+)-amphetamine twice daily for 6 consecutive days. Single unit recording in the substantia nigra pars compacta (SNC) and the neostriatum, on the following day, revealed a differential shift in the intravenous dose of the drug required to produce at least a 50% change in neuronal activity (ED50) depending on the pretreatment dose. In the substantia nigra pars compacta, pretreatment with the small dose significantly reduced the ED50, compared to saline controls, whereas in rats pretreated with the large dose, the ED50 was significantly increased. In the neostriatum, control rats responded to increasing incremental doses of (+)-amphetamine with either an inhibition followed by an excitation, or an excitation. Following pretreatment with 1.0 mg/kg, neurons responded with either a depression or an excitation, whereas only amphetamine-induced excitations were recorded in the neostriatum following pretreatment with 5.0 mg/kg. The complex changes in firing rate produced by repeated exposure to amphetamine were dose-dependent in both sites and cannot be simply explained by a decrease in the sensitivity of dopamine neurons to this drug.