Behavioral Effects of 5-HT2CReceptor Antagonism in the Substantia Nigra Zona Reticulata of the 6-Hydroxydopamine-Lesioned Rat Model of Parkinson's Disease ☆

Abstract Overactivity of the substantia nigra zona reticulata and the medial segment of the globus pallidus are responsible for the generation of symptoms in Parkinson's disease. Reducing the activity of these regions has been shown to be a viable alternative to dopamine replacement in the symptomatic treatment of Parkinson's disease. 5-HT 2C receptors in the substantia nigra zona reticulata are excitatory. In this study we have shown that intracerebral infusion of the selective 5-HT 2C receptor antagonist SB 206553 (50 nmol) into the substantia nigra zona reticulata has an antiparkinsonian action in the 6-hydroxydopamine-lesioned rat model of Parkinson's disease. SB 206553 did not affect locomotion when injected into the nonparkinsonian substantia nigra. Furthermore, we have demonstrated that systemic administration of selective 5-HT 2C receptor antagonists SB 200646A (20 mg/kg) and SB 206553 (20 mg/kg) can potentiate the antiparkinsonian action of the dopamine D 2 receptor agonist quinpirole in the 6-hydroxydopamine-lesioned rat. Hence, 5-HT 2C receptor antagonists may be useful adjuncts to dopamine agonists in the treatment of Parkinson's disease.