Role of dopamine D3 and serotonin 5-HT 1A receptors in L: -DOPA-induced dyskinesias and effects of sarizotan in the 6-hydroxydopamine-lesioned rat model of Parkinson's disease.
Sarizotan, a 5-HT(1A) agonist with additional affinity for D(3) and D(4) receptors, has been demonstrated to have anti-dyskinetic effects. The mechanism by which these effects occur is not clear. Using unilateral 6-hydroxydopamine-lesioned rats that received chronic intraperitoneal (ip) administration of L: -3,4-dihydroxyphenylalanine (L: -DOPA) we investigated the involvement of D(3) and 5-HT(1A) receptors in the effects of sarizotan on contraversive circling and abnormal involuntary movements (AIMs). Before sensitization by chronic L: -DOPA treatment (12.5 with 3.25 mg/kg benserazide ip, twice daily for 21 days), no effect of the selective D(3) agonist, PD128907 (1 or 3 mg/kg ip), or the selective D(3) antagonist, GR103691 (0.5 or 1.5 mg/kg ip), was observed. Treatment with sarizotan (1 or 5 mg/kg ip) dose-dependently inhibited the L: -DOPA-induced contraversive turning and AIMs. In co-treatment with the 5-HT(1A) antagonist, WAY100635 (1 mg/kg ip), sarizotan failed to affect this behaviour, confirming the prominent 5-HT(1A) receptor-mediated mechanism of action. In the presence of PD128907 (3 mg/kg ip), the effects of sarizotan on contraversive turning, locomotive dyskinesia and axial dystonia, but not on orolingual and forelimb dyskinesia, were blocked. On its own, PD128907 had no effect on the behavioural effects of L: -DOPA except that it tended to reduce orolingual and forelimb dyskinesia. GR103691 had no effect on its own or in combination with sarizotan. These data identify an involvement of D(3) receptors in the action of sarizotan on some, but not all L: -DOPA-induced motor side effects. This selective involvement is in contrast to the more general involvement of 5-HT(1A) receptors in the anti-dyskinetic effects of sarizotan.
Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Laboratory for Clinical Neurobiology, University of Würzburg, Füchsleinstrasse 15, 97080, Würzburg, Germany. manfred.gerlach@uni-wuerzburg.de
Manfred
M
Gerlach
Gerd D
GD
Bartoszyk
Peter
P
Riederer
Olivia
O
Dean
Maarten
M
van den Buuse
D000704:Analysis of Variance; D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects; D004195:Disease Models, Animal; D015259:Dopamine Agents / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy* / Q000378:metabolism*; D007980:Levodopa / Q000009:adverse effects; D008297:Male; D009930:Organic Chemicals / Q000627:therapeutic use; D016627:Oxidopamine / Q000633:toxicity; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D050637:Receptors, Dopamine D3 / Q000378:metabolism*; D058825:Serotonin 5-HT1 Receptor Agonists / Q000627:therapeutic use*; D013997:Time Factors
D000978:Antiparkinson Agents; D015259:Dopamine Agents; D009930:Organic Chemicals; D050637:Receptors, Dopamine D3; D058825:Serotonin 5-HT1 Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A; D007980:Levodopa; C443959:sarizotan; D016627:Oxidopamine
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