s-33084 and Parkinsonian-Disorders

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.

Topics: Animals; Antiparkinson Agents; Benzopyrans; Disability Evaluation; Dopamine Antagonists; Dose-Response Relationship, Drug; Drug Interactions; Dyskinesia, Drug-Induced; Hypokinesia; Levodopa; Male; Oxidopamine; Parkinsonian Disorders; Pyrroles; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D3; Time Factors; Treatment Outcome

Development of L-DOPA-induced dyskinesia (LID) remains a major problem in the long-term treatment of Parkinson's disease (PD). Sensitization to L-DOPA correlates with ectopic expression of D3 dopamine receptors in the striatum, implicating D3 receptors in development of LID. We demonstrate that the selective D3 antagonist S33084 abolishes development of LID over 30 days in MPTP-lesioned marmosets without effecting the anti-parkinsonian actions of L-DOPA. Furthermore, following a 14 day washout, when challenged with L-DOPA in the absence of S33084, these animals continued to exhibit reduced LID. In the 6-OHDA-lesioned rat, S33084 similarly attenuated development of behavioural sensitization to L-DOPA. Additionally, L-DOPA-induced elevations in striatal pre-proenkephalin-A (PPE-A) (but not PPE-B, phospho[Thr(34)]DARPP-32, D1, and D2 receptor mRNA or D3 receptor levels) were reduced in S33084 treated animals. Our data suggest a role for D3 receptors in the development of LID and suggest that initiating L-DOPA treatment with a D3 antagonist may reduce the development of LID in PD.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Antiparkinson Agents; Benzopyrans; Callithrix; Corpus Striatum; Disease Models, Animal; Dopamine and cAMP-Regulated Phosphoprotein 32; Dopamine Antagonists; Dyskinesia, Drug-Induced; Enkephalins; Female; Levodopa; Male; Oxidopamine; Parkinsonian Disorders; Protein Precursors; Pyrroles; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D1; Receptors, Dopamine D2; Receptors, Dopamine D3; RNA, Messenger

To date, the lack of highly selective antagonists at the dopamine D(3) receptor has hampered clarification of their involvement in the actions of currently used therapies in Parkinson's disease. However, the novel benzopyranopyrrole, S33084, displays greater than 100-fold selectivity as an antagonist for D(3) versus D(2) receptors and all other sites tested. S33084 was administered to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmosets previously primed with levodopa to elicit dyskinesia. Administered alone, S33084 exerted a modest, but significant, anti-parkinsonian effect without provoking dyskinesia. At low D(3)-selective doses (0.16 and 0.64 mg/kg), S33084 potentiated, though to different extents and in qualitatively different ways, the anti-parkinsonian actions of both ropinirole and levodopa. At these doses, S33084 did not significantly modify levodopa-induced or ropinirole-induced dyskinesia. These data suggest that ropinirole and levodopa do not exert their anti-parkinsonian or pro-dyskinetic actions via D(3) receptor stimulation. Indeed, stimulation of D(3) receptors may be detrimental to the anti-parkinsonian properties of D(2)/D(3) agonists. Selectivity for stimulation of D(2), over D(3), receptors may therefore be a beneficial property of dopamine receptor agonists in management of motor symptoms of Parkinson's disease patients with established dyskinesia.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Benzopyrans; Brain; Callithrix; Disease Models, Animal; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Indoles; Levodopa; Parkinsonian Disorders; Pyrroles; Receptors, Dopamine D2; Receptors, Dopamine D3