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NEUROPHARMACOLOGY

Negative Feedback Regulation of Nigrostriatal Dopamine Release: Mediation by Striatal D1 Receptors

Departments of Biochemistry (S.S.S.), Psychiatry (O.S.M., E.A.P.), and Neurosciences (E.A.P.), Case Western Reserve University, Cleveland, Ohio; and Louis Stokes Cleveland DVA Medical Center (S.S.S., O.S.M., E.A.P.), Cleveland, Ohio

The nigrostriatal dopamine system of the mammalian brain is necessary for normal voluntary motor activity. Dopamine exerts its effects by acting on two primary receptor subtypes: D1-like (D1 and D5) and D2-like (D2, D3, and D4) receptors. Previous research has indicated that both subtypes are involved in the negative feedback regulation of dopamine release in the brain. However, the role of D1-like receptors localized within the striatum remains controversial. Using in vivo microdialysis, we report that infusions of the D1/D5 antagonist SCH 23390 [R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine] (5–200 µM) directly into the striatum increased dopamine release in a concentration-dependent manner. Systemic administration of the novel, full D1/D5 agonist A-77636 [(-)-(1R,3S)-3-adamantyl-1-(aminomethyl)-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyran] produced the opposite effect, a dose-dependent (0.75–3.0 mg/kg s.c.) decrease in striatal dopamine efflux. Infusions of SCH 23390 (5.0 µM) attenuated this decrease. These findings suggest that endogenous dopamine acts on D1-like receptors localized within the striatum to decrease nigrostriatal dopamine release. This negative feedback may be due to the activation of an inhibitory long-loop pathway. Knowledge of the circuitry underlying D1-mediated regulation of nigrostriatal neurons may have significance in current research on treatments for Parkinson's disease.

Address correspondence to: Dr. Elizabeth A. Pehek, Louis Stokes Cleveland VA Medical Center 151(W), 10701 East Blvd., Cleveland, OH 44106. E-mail: eap6{at}cwru.edu