LAUSR

L-3,4-dihydroxyphenylalanine (L-DOPA) is the mainstay treatment for Parkinson's disease, but its effectiveness during early disease is marred by the eventual development of L-DOPA induced dyskinesia. In hemi-parkinsonian rats, the serotonin type 3 (5-HT3) antagonists ondansetron and granisetron alleviated dyskinesia induced by L-DOPA without impeding its anti-parkinsonian action; in parkinsonian marmosets, ondansetron alleviated dyskinesia and enhanced L-DOPA anti-parkinsonian action. Here, we sought to gain insight into the mechanisms governing the anti-dyskinetic action of 5-HT3 antagonists and measured their levels across different brain, using [3H]GR65630 autoradiographic binding. Brain sections were chosen from 6-hydroxydopamine (6-OHDA)-lesioned rats exhibiting abnormal involuntary movements (AIMs), as well as L-DOPA-naïve 6-OHDA and sham-lesioned animals. [3H]GR65630 binding increased in the ipsilateral subthalamic nucleus of 6-OHDA-lesioned rats with mild and severe AIMs, (3-fold changes, P < 0.001). [3H]GR65630 binding also increased in the ipsilateral entopeduncular nucleus and thalamus of 6-OHDA-lesioned rats with severe AIMs (75% and 88%, P < 0.05). AIMs scores negatively correlated with [3H]GR65630 binding in the ipsilateral dorsolateral striatum and contralateral subthalamic nucleus (P < 0.05). These results suggest that alterations in 5-HT3 mediated neurotransmission may contribute to the pathophysiology of L-DOPA induced dyskinesia.