Methamphetamine-Induced Dopamine Overflow and Injury to Striatal Dopamine Terminals: Attenuation by Dopamine D1 or D2 Antagonists

Abstract: Pharmacological blockade of either D₁ or D₂ dopamine (DA) receptors prevents damage of striatal DA terminals by repeated doses of methamphetamine (m-AMPH). Because the substantial DA overflow produced by multiple m-AMPH treatments appears to contribute to the subsequent injury, we have investigated the effects of blockade of D₁ or D₂ receptors on m-AMPH-induced DA efflux using in vivo microdialysis. Four treatments with 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 themselves, four injections of the D₁ antagonist SCH 23390 or the D₂ antagonist eticlopride (0.5 mg/kg, i.p., 2-h intervals) significantly increased striatal DA overflow. However, treatment with either SCH 23390 or eticlopride 15 min before each of four m-AMPH injections attenuated the marked DA peak otherwise seen after the fourth m-AMPH injection. These effects on DA overflow were related to subsequent DA depletions. Although our m-AMPH regimen produced a 54% reduction in striatal DA tissue content 1 week later, pretreatments with either the D₁ or the D₂ antagonist completely prevented subsequent DA content depletions. Furthermore, the DA content of striatal tissue remaining 1 week after m-AMPH treatment was significantly correlated with the magnitude of the cumulative DA overflow during the m-AMPH treatment ( r = -0.69). Thus, the extensive DA overflow seen during neurotoxic regimens of m-AMPH appears critical to the subsequent neurotoxicity, and the neuroprotective action of DA receptor antagonists seems to result from their attenuation of stimulant-induced DA overflow.