Nigrostriatal dopaminergic denervation enhances dopamine D(4) receptor binding in rat caudate-putamen

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.