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Suppression of L-dopa-induced circling in rats with nigral lesions by blockade of central dopa-decarboxylase

Implications for mechanism of action of L-dopa in parkinsonism

From the Department of Neurology (Drs. Melamed, Bitton, and Globus), Hadassah University Hospital, Jerusalem, Israel, and the Department of Preclinical Sciences (Dr. Hefti), Sandoz A.G., Basel, Switzerland.

Dopamine (DA) elevations in rat striatum produced by combined administration of L-dopa and carbidopa were abolished when L-dopa was injected with NSD-1015, an inhibitor of central dopa-decarboxylase. In all rats with unilateral 6-OH-DA nigral lesions, L-dopa-induced contraversive circling occurred after carbidopa, but was totally abolished (in 60%) or markedly suppressed after pretreatment with NSD-1015. Administration of the DA metabolites DOPAC and HVA systemically and of 3-methoxytyramine intrastriatally evoked nocircling in animals with 6-OH-DA lesions. In rats with unilateral nigrotomies, the direction of L-dopa-induced circling was reversed and became ipsiversive after DA receptors were reduced by the addition of kainic acid lesions in ipsilateral striata. Findings provide evidence that circling in rats—and by analogy, efficacy in parkinsonians—requires the decarboxylation of exogenous L-dopa and interaction of the formed DA with DA receptors in striatum.

Address correspondence and reprint requests to Dr. Melamed, Department of Neurology, Hadassah University Hospital, Jerusalem, Israel.

Supported by the Israeli Center for Psychobiology, Charles A. Smith Family Foundation; by the US-Israel Binational Science Foundation (grant no. 2348); by the Chief Scientist, Israel Ministry of Health; and by a grant from the Warschaw family in honor of L.A. Harvey.

Presented in Part at the 35th annual meeting of the American Academy of Neurology, San Diego, CA, April 1983.

Accepted for publication April 3, 1984.