Local administration of sarizotan into the subthalamic nucleus attenuates levodopa-induced dyskinesias in 6-OHDA-lesioned rats.
BACKGROUND
Dyskinesia affects the majority of levodopa-treated parkinsonian patients within 5-10 years of treatment with levodopa. Clinical and preclinical observations suggest that an increase in serotoninergic transmission can contribute to the appearance of dyskinesias. It is thus conceivable that a modulation of synaptic dopamine (DA) levels induced by the inhibition of serotonin (5-HT) release, as a consequence of 5-HT(1A) agonists administration, might alleviate dyskinesias.


OBJECTIVE
Since 5-HT(1A) receptors are expressed in the subthalamic nucleus (STN), the aim of the present study was to assess the effect of the intrasubthalamic administration of sarizotan, a compound with full 5-HT(1A) agonist properties, on levodopa-induced dyskinesias in the 6-hydroxydopamine (6-OHDA) model of parkinsonism.


METHODS
Male Sprague-Dawley rats received a unilateral 6-OHDA administration in the nigrostriatal pathway. A test of apomorphine was performed to evaluate dopamine depletion. One week later, a cannula was implanted in the STN. Animals were treated with levodopa (6 mg/kg, i.p., twice at day) for 22 consecutive days. On day 23, several doses (1 ng, 10 ng, or 1 microg) of sarizotan were administered through the cannula to the STN. The higher doses of sarizotan effectively attenuated all levodopa-induced dyskinesias including axial, limb, and orolingual subtypes.


CONCLUSIONS
These results suggest that the STN is a target structure for the antidyskinetic action of sarizotan and indicate that drug-mediated modulation of STN activity may be an alternative option for the treatment of levodopa-induced dyskinesias in Parkinson's disease.
Marin
C
C
Laboratori de Neurologia Experimental, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain. cmarin@clinic.ub.es
Aguilar
E
E
Rodríguez-Oroz
M C
MC
Bartoszyk
G D
GD
Obeso
J A
JA
D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D001545:Benserazide / Q000494:pharmacology; D015259:Dopamine Agents / Q000633:toxicity*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy* / Q000523:psychology; D007150:Immunohistochemistry; D007980:Levodopa / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D008297:Male; D008845:Microinjections; D009930:Organic Chemicals / Q000008:administration & dosage / Q000494:pharmacology; D016627:Oxidopamine; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects; D012399:Rotation; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D013239:Stereotyped Behavior / Q000187:drug effects; D020531:Subthalamic Nucleus / Q000502:physiology*; D013563:Sympathectomy, Chemical; D013565:Sympatholytics
D015259:Dopamine Agents; D050483:Dopamine Plasma Membrane Transport Proteins; D009930:Organic Chemicals; D017366:Serotonin Receptor Agonists; D013565:Sympatholytics; D044282:Receptor, Serotonin, 5-HT1A; D007980:Levodopa; C443959:sarizotan; D001545:Benserazide; D016627:Oxidopamine; D001058:Apomorphine