Quetiapine attenuates levodopa-induced motor complications in rodent and primate parkinsonian models.
The contribution of serotoninergic mechanisms to motor dysfunction in Parkinson's disease (PD) has yet to be fully elucidated. Recent clinical observations increasingly suggest that drugs able to block serotonin 5HT2A/C receptors can benefit patients with certain extrapyramidal movement disorders. To further explore the roles of these and other neurotransmitter receptors in the pathogenesis of parkinsonian signs and levodopa-induced dyskinesias; we evaluated the effects of quetiapine, an atypical antipsychotic with 5HT2A/C and D2/3 antagonistic activity, on motor behavior in 6-hydroxydopamine-lesioned rats and MPTP-lesioned nonhuman primates. In hemiparkinsonian rats, quetiapine (5 mg/kg, po) reversed the shortened motor response to levodopa challenge produced by 3 weeks of twice-daily levodopa treatment (P < 0.01). Quetiapine (5 mg/kg po) also normalized the shortened response to the acute injection of either a dopamine D1 receptor agonist (SKF 38392) or a D2 agonist (quinpirole) in rats that had received chronic levodopa treatment. Quetiapine had no effect on parkinsonian dysfunction when given alone or with levodopa to parkinsonian rats and monkeys. Quetiapine (4 mg/kg, po) did, however, substantially reduce levodopa-induced dyskinesias when coadministered with levodopa (P < 0.05). These results suggest that quetiapine could confer therapeutic benefits to patients with levodopa-induced motor complications. Moreover, our findings may indicate that 5HT2A/C receptor-mediated mechanisms, alone or in combination with other mechanisms, contribute to the pathogenesis of the altered motor responses associated with the treatment of PD.
Oh
Justin D
JD
Department of Psychology, Central Michigan University, Sloan 224, Mount Pleasant, Michigan 48859, USA.
Bibbiani
Francesco
F
Chase
Thomas N
TN
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D003987:Dibenzothiazepines / Q000494:pharmacology*; D004195:Disease Models, Animal; D018491:Dopamine Agonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004359:Drug Therapy, Combination; D004409:Dyskinesia, Drug-Induced / Q000517:prevention & control*; D005260:Female; D007980:Levodopa / Q000009:adverse effects / Q000627:therapeutic use*; D008252:Macaca fascicularis; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D000069348:Quetiapine Fumarate; D051381:Rats; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D017447:Receptors, Dopamine D1 / Q000819:agonists; D017448:Receptors, Dopamine D2 / Q000819:agonists; D011985:Receptors, Serotonin / Q000187:drug effects; D012702:Serotonin Antagonists / Q000494:pharmacology
D014150:Antipsychotic Agents; D003987:Dibenzothiazepines; D018491:Dopamine Agonists; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D000069348:Quetiapine Fumarate; D007980:Levodopa; D016627:Oxidopamine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine