Sharifi Hamdolah, Mohajjel Nayebia Alireza, Farajnia Safar
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tabriz University of Medical Sciences.Tabriz, Iran.
Adv Pharm Bull. 2013;3(1):203-6. doi: 10.5681/apb.2013.033. Epub 2013 Feb 7.
Progressive loss of dopaminergic neurons of the substantia nigra pars compacta (SNc) in Parkinson's disease (PD) leads to impairment of motor skills. Several evidences show that the role of serotonergic system in regulation of normal movement is pivotal and mediates via 5-HT1A receptors. Our previous study has shown that fluoxetine in acute injections able to attenuate catalepsy in 6-hydroxydopamine (6-OHDA)-lesioned rats. Since drugs are used chronically in clinic, in this study we attempted to evaluate effect of chronic administration of fluoxetine on 6-OHDA-induced catalepsy.
Catalepsy was induced by unilateral infusion of 6-OHDA (8 µg/2 µl/rat) into the central region of SNc and assayed by using bar-test. Fluoxetine (1, 2.5, 5 and 10 mg/kg) was injected intraperitonealy (ip) for 10 days and its anti-cataleptic effect was assessed at the 10th day.
Fluoxetine in high doses (5 and 10 mg/kg) worsened 6-OHDA-induced catalepsy while it had anti-cataleptic effect at the dose of 1mg/kg. The anti-cataleptic effect of fluoxetine (1mg/kg) was reversed by co-administration with NAN-190 (0.5 mg/kg, ip), as a5-HT1Areceptor antagonist.
According to the results it can be concluded that fluoxetine has anti-cataleptic effect in parkinsonian rats only at low doses, whereas at higher doses it worsens catalepsy. It's anti-cataleptic effect is exerted through affecting on 5-HT1Areceptors. However, at high doses other mechanisms may be involved. Further clinical studies are needed to prove it's possible clinical application as an adjuvant therapy in reducing catalepsy of PD.
帕金森病（PD）中黑质致密部（SNc）多巴胺能神经元的进行性丧失导致运动技能受损。多项证据表明，血清素能系统在正常运动调节中起关键作用，并通过5-HT1A受体介导。我们之前的研究表明，急性注射氟西汀能够减轻6-羟基多巴胺（6-OHDA）损伤大鼠的僵住症。由于药物在临床上是长期使用的，在本研究中，我们试图评估长期给予氟西汀对6-OHDA诱导的僵住症的影响。
通过向SNc中央区域单侧注入6-OHDA（8μg/2μl/只大鼠）诱导僵住症，并使用杆式试验进行测定。氟西汀（1、2.5、5和10mg/kg）腹腔注射（ip）10天，并在第10天评估其抗僵住症作用。
高剂量（5和10mg/kg）的氟西汀使6-OHDA诱导的僵住症恶化，而在1mg/kg剂量时具有抗僵住症作用。氟西汀（1mg/kg）的抗僵住症作用可被作为5-HT1A受体拮抗剂的NAN-190（0.5mg/kg，ip）共同给药所逆转。
根据结果可以得出结论，氟西汀仅在低剂量时对帕金森病大鼠具有抗僵住症作用，而在高剂量时会使僵住症恶化。其抗僵住症作用是通过影响5-HT1A受体发挥的。然而，在高剂量时可能涉及其他机制。需要进一步的临床研究来证明其作为辅助治疗减少PD僵住症的可能临床应用。
