title: 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 [(3)H]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.
authors.affiliation: Neuroscience Program, The University of Michigan, Ann Arbor, MI, USA.
authors.forename: Elyse S
authors.initials: ES
authors.lastname: Kemmerer
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Desmond
authors.forename: Roger L
authors.initials: RL
authors.lastname: Albin
authors.forename: Michael R
authors.initials: MR
authors.lastname: Kilbourn
authors.forename: Kirk A
authors.initials: KA
authors.lastname: Frey
mesh_terms: D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D000978:Antiparkinson Agents / Q000627:therapeutic use; D001058:Apomorphine / Q000494:pharmacology; D001345:Autoradiography; D001522:Behavior, Animal / Q000187:drug effects; D052160:Benzothiazoles; D001667:Binding, Competitive / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D007980:Levodopa / Q000627:therapeutic use*; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D026901:Membrane Transport Proteins; D009043:Motor Activity / Q000187:drug effects; D009479:Neuropeptides; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D000077487:Pramipexole; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013844:Thiazoles / Q000627:therapeutic use*; D016896:Treatment Outcome; D014316:Tritium; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins
chemical_list: D000978:Antiparkinson Agents; D052160:Benzothiazoles; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009479:Neuropeptides; C493454:Slc18a2 protein, rat; D013844:Thiazoles; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins; D014316:Tritium; D007980:Levodopa; D000077487:Pramipexole; D016627:Oxidopamine; D000661:Amphetamine; D001058:Apomorphine