The selective D(3) receptor antagonist, S33084, improves parkinsonian-like motor dysfunction but does not affect L-DOPA-induced dyskinesia in 6-hydroxydopamine hemi-lesioned rats.
Despite evidence linking dopamine D(3) receptors to the etiology of Parkinson's disease and L-DOPA-induced dyskinesia, the potential therapeutic utility of D(3) receptor ligands remains unclear. In the present study, we investigated whether the selective D(3) receptor antagonist, S33084, affects development and expression of abnormal involuntary movements (AIMs), a behavioural correlate of dyskinesia, in rats hemi-lesioned with 6-hydroxydopamine and chronically treated with L-DOPA. The ability of S33084, alone or in combination with L-DOPA, to attenuate 6-hydroxydopamine induced motor deficits was also investigated employing a battery of behavioural tests. Acute administration of S33084 (0.64 mg/kg, s.c.) did not attenuate the induction of AIMs in dyskinetic rats upon challenge with L-DOPA (6 mg/kg, s.c.). Moreover, S33084 (0.64 mg/kg) did not prevent the development of AIMs affecting axial, limb and orolingual muscles when chronically administered together with L-DOPA (6 mg/kg for 21 days). However, both acute and chronic administration of S33084 enhanced L-DOPA-induced contralateral turning, suggesting potential antiparkinsonian properties. Furthermore, S33084 (0.01-0.64 mg/kg) dose-dependently attenuated parkinsonian disabilities, including bradykinesia, in drag and rotarod tests, although, in these procedures, the combination of S33084 with L-DOPA did not produce synergistic effect. It is concluded that sustained D(3) receptor blockade does not blunt L-DOPA-induced dyskinesia in hemiparkinsonian rats. However, D(3) receptor antagonism may be associated with antiparkinsonian properties. The clinical relevance of these observations will be of interest to explore further.
Mela
Flora
F
Department of Experimental and Clinical Medicine, Section of Pharmacology, University of Ferrara, via Fossato di Mortara 17-19, 44100 Ferrara, Italy.
Millan
Mark J
MJ
Brocco
Mauricette
M
Morari
Michele
M
D000818:Animals; D000978:Antiparkinson Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D001578:Benzopyrans / Q000008:administration & dosage / Q000627:therapeutic use*; D004185:Disability Evaluation; D018492:Dopamine Antagonists / Q000008:administration & dosage / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy*; D018476:Hypokinesia / Q000188:drug therapy; D007980:Levodopa / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D008297:Male; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy*; D011758:Pyrroles / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D050637:Receptors, Dopamine D3 / Q000037:antagonists & inhibitors*; D013997:Time Factors; D016896:Treatment Outcome
D000978:Antiparkinson Agents; D001578:Benzopyrans; D018492:Dopamine Antagonists; D011758:Pyrroles; D050637:Receptors, Dopamine D3; C408389:S 33084; D007980:Levodopa; D016627:Oxidopamine