Nigrostriatal dopaminergic denervation enhances dopamine D 4 receptor binding in rat caudate–putamen

Abstract

Radioligand binding to dopamine (DA) D 4 receptors was examined in adult rat forebrain 5 weeks after unilateral 6-hydroxydopamine (6-OHDA) lesioning of substantia nigra to remove ascending nigrostriatal dopaminergic projections. D 4 receptor binding was increased by up to 47% in denervated caudate–putamen (CPu) in rats that rotated away from the lesioned side with apomorphine challenge, with lesser changes in rats that failed to rotate with apomorphine. Functional significance of D 4 receptor upregulation induced by the lesions was investigated by examining behavioral effects of the highly selective D 4 agonist CP-226,269 and antagonist CP-293,019. Neither agent induced rotation at doses as high as 30 mg/kg ip. Pretreatment with the D 4 antagonist CP-293,019 did not affect rotation induced by either a D 1-like (SKF-38393) or D 2-like receptor (quinpirole) agonist. These findings provide the first evidence that D 4 receptors can be upregulated by nigrostriatal dopaminergic denervation. They also suggest that, unlike D 1 and D 2 receptors, D 4 receptors do not play a pivotal role in rotational behavior in rats with unilateral dopaminergic lesions.