Treatment effects on nigrostriatal projection integrity in partial 6-OHDA lesions: comparison of l-DOPA and pramipexole

Abstract

There is controversy over potential effects of dopaminergic replacement therapies on the partially lesioned nigrostriatal dopaminergic projection. We evaluated indirect (levodopa, l-DOPA) versus direct (pramipexole, PRA) dopaminergic treatment effects on nigrostriatal lesion severity as measured with vesicular monoamine transporter type-2 (VMAT2) binding. Prior studies have shown that striatal VMAT2 density provides an objective estimate of dopaminergic neuronal integrity, without confounding effects of compensatory regulation. Partial unilateral median forebrain bundle lesions were made by injection of 6-hydroxydopamine in adult male Sprague–Dawley rats. Lesion severity was estimated using rotational behavior after injections of apomorphine and amphetamine. Rats were ranked and matched in pairs by rotation and assigned to receive either PRA (1 mg/kg/day) or l-DOPA/benserazide (100/25 mg/kg/day) ip via osmotic pump. After 4 weeks of drug treatment, in vitro autoradiography was performed with [3H]methoxytetrabenazine to measure striatal VMAT2 binding density. Lesion-to-intact VMAT2 density correlated with rotation in both treatment groups. There was no treatment effect on VMAT2 expression in the partially lesioned striatum and thus no differential effect of indirect versus direct dopamimetic treatment on nigrostriatal integrity.