METHAMPHETAMINE-INDUCED DOPAMINE OVERFLOW AND INJURY TO STRIATAL DOPAMINE TERMINALS - ATTENUATION BY DOPAMINE D(1) OR D(2) ANTAGONISTS

Pharmacological blockade of either D1 or D2 dopamine (DA) receptors pr events damage of striatal DA terminals by repeated doses of methamphet amine (m-AMPH). Because the substantial DA overflow produced by multip le m-AMPH treatments appears to contribute to the subsequent injury, w e have investigated the effects of blockade of D1 or D2 receptors on m -AMPH-induced DA efflux using in vivo microdialysis. Four treatments w ith m-AMPH (4 mg/kg, s.c., 2-h intervals) produced large increases in striatal DA overflow, with particularly marked overflow (10 times the basal values) following the fourth injection. Administered by themselv es, four injections of the D1 antagonist SCH 23390 or the D2 antagonis t eticlopride (0.5 mg/kg, i.p., 2-h intervals) significantly increased striatal DA overflow. However, treatment with either SCH 23390 or eti clopride 15 min before each of four m-AMPH injections attenuated the m arked DA peak otherwise seen after the fourth m-AMPH injection. These effects on DA overflow were related to subsequent DA depletions. Altho ugh our m-AMPH regimen produced a 54% reduction in striatal DA tissue content 1 week later, pretreatments with either the D1 or the D2 antag onist completely prevented subsequent DA content depletions. Furthermo re, the DA content of striatal tissue remaining 1 week after m-AMPH tr eatment was significantly correlated with the magnitude of the cumulat ive DA overflow during the m-AMPH treatment (r = -0.69). Thus, the ext ensive DA overflow seen during neurotoxic regimens of m-AMPH appears c ritical to the subsequent neurotoxicity, and the neuroprotective actio n of DA receptor antagonists seems to result from their attenuation of stimulant-induced DA overflow.