Extracellular single unit recording techniques were used to determine whether chronic treatment with D-amphetamine (AMP) causes a subsensitivity of dopamine (DA) autoreceptors on A10 DA neurons in the rat ventral tegmental area. Either once daily or twice daily intraperitoneal (i.p.) administration of 5.0 mg/kg AMP for 1 week significantly reduced the ability of intravenous (i.v.) AMP and apomorphine (APO) to suppress the firing of A10 DA neurons when tested 24-32 h after the final administration of i.p. AMP. For both of these treatment regimens, the dose-response curves for AMP and APO induced suppression were shifted approximately 4-fold to the right of control. Following an 8 day abstinence period, only the rats that received twice daily AMP injections exhibited subsensitivity to i.v. AMP and APO; the degree of subsensitivity was reduced by 50% as compared to that observed 24-32 h post-treatment. These results were not due to acute tolerance phenomena since a single i.p. injection of AMP 24-32 h before testing failed to alter sensitivity to i.v. AMP and APO. Rather, the results indicate that chronic AMP treatment reduces the sensitivity of A10 DA neurons to DA agonists. DA autoreceptor subsensitivity was demonstrated further by the finding that the ability of microiontophoretically applied DA to suppress A10 DA neuronal activity was markedly reduced (5.8-fold shift of the dose-response curve) by chronic AMP treatment (2 X 5 mg/kg/day). In contrast, there was no alteration in the ability of iontophoretic gamma-amino butyric acid (GABA) to suppress A10 DA activity in chronic AMP rats. Chronic AMP-treatment also increased the number of spontaneously active A10 DA neurons as well as their basal firing rate. It is suggested that the ability of chronic AMP treatment to decrease the auto-regulatory ability of A10 DA neurons may be related to the phenomena of behavioral sensitization and AMP psychosis.