Reduction of 3H-spiroperidol binding in rat striatum and frontal cortex by chronic amphetamine: dose response, time course and role of sustained dopamine release.

After 5 days of continuous treatment with d-amphetamine base in doses greater than 0.5 mg/kg/h maintained by subcutaneously implanted osmotic minipumps, specific binding of 3H-spiroperidol was reduced in rat striatum and frontal cortex as previously reported. These effects were dose-dependent at lower doses of amphetamine, whereas with higher doses an apparent ceiling for the reduction in binding was reached at approximately 70% of control values. Similarly, increasing the exposure time to amphetamine for up to 14 days only slightly augmented the reduction in 3H-spiroperidol binding already present after 5 days of treatment. In rats treated for 5 days with amphetamine, concomitant treatment with the dopamine (DA) synthesis inhibitor alpha-methyl-p-tyrosine prevented the decrease in 3H-binding in corpus striatum, and attenuated the decrease in frontal cortex. Furthermore, in rats with unilateral 6-hydroxydopamine lesions of the nigro-striatal DA tract, 5 days of chronic amphetamine had no significant effect on 3H-spiroperidol binding in the denervated striatal tissue. Since a major effect of amphetamine is to release DA from nerve terminals, these results indicate that the reduction of DA receptors by chronic amphetamine in the striatum is mediated by sustained release of DA.