5-HT1A receptor agonist 8-OH-DPAT improves motor complications in Parkinson' s disease / 中华神经科杂志

ABSTRACT

Objective To investigate cellular and behavioural effects of 5-HT1A receptor agonist 8- OH-DPAT in a rat model of levodopa-induced motor complications.Methods The hemi-parkinsonian rat model was produced by stereotaxically injecting 6-OHDA to right medial forebrain bundle(MFB).Two sets of experiments were performed.First,rats were intrapefitoneally treated with levodopa 50 mg/kg plus benserazide 12.5 mg/kg twice a day for 22 days.On day 23,rats intraperitoneally received either 8-OH- DPAT(1 mg/kg)or 8-OH-DPAT plus WAY-100635(0.1 mg/kg)or dissolvent with each levodopa dose as controls.In the second set,rats were intraperitoneally treated either with levodopa(50 mg/kg)plus 8-OH- DPAT(1 mg/kg)or levodopa 50 mg/kg plus dissolvent,administered twice daily for 22 consecutive days. Rotational duration and frequency of off period were estimated.After sacrificed,subcellualr distribution of GluR1 and GluR1Ser845 phosphorylation was observed by Western blot.Results 8-OH-DPAT,reversing the shortened rotational duration induced by levodopa,prolonged the rotational duration by 27.8%?6.1% and reduced the frequency of failures to levodopa by 7.2%?1.7%.Co-administration of WAY-100635,a 5-HT1A receptor antagonist,with 8-OH-DPAT eliminated the effect of 8-OH-DPAT on motor complications, indicating that the observed 8-OH-DPAT responses were probably mediated via the 5-HT1A autoreceptor. Moreover,8-OH-DPAT could regulate subcellular distribution of GluR1 and reduce hyperphosphorylation of GluR1 Ser845 by 22.1%?3.5%,which was closely associated with levodopa-induced motor complications. Conclusions These results suggest that pharmaceuticals stimulating 5-HT1A receptors could be useful in the treatment and prevention of the motor complications in parkinsonian patients.