Contribution of the Striatum to the Effects of 5-HT1A Receptor Stimulation in L-DOPA-treated Hemiparkinsonian Rats

Clinical and experimental studies implicate the use of serotonin (5-HT)1A receptor agonists for the reduction of i-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID). Although raphe nuclei likely play a role in these antidyskinetic effects, an unexplored population of striatal 5-HT1A receptors (5-HT1AR) may also contribute. To better characterize this mechanism, L-DOPA-primed hemiparkinsonian rats received the 5-HT1AR agonist +/- 8-OH-DPAT (0, 0.1, 1.0 mg/kg, i.p.) with or without cotreatment with the 5-HT1AR antagonist WAY100635 (0.5 mg/kg, i.p.) 5 min after L-DOPA, after which abnormal involuntary movements (AIMs), rotations, and forelimb akinesia were quantified. To establish the effects of 5-HT1AR stimulation on L-DOPA-induced c-fos and preprodynorphin (PPD) mRNA within the dopamine-depleted striatum, immunohistochemistry and real-time reverse transcription polymerase chain reaction, respectively, were used. Finally, to determine the contribution of striatal 5-HT1AR to these effects, L-DOPA-primed hemiparkinsonian rats received bilateral intrastriatal microinfusions of +/- 8-OH-DPAT (0, 5, or 10 mu g/side), WAY100635 (5 mu g/side), or both (10 mu g + 5 mu g/side) 5 min after L-DOPA, after which AIMs and rotations were examined. Systemic 8-OH-DPAT close- and receptor-dependently attenuated L-DOPA-mediated AIMs and improved forelimb akinesia. Striatal c-fos immunoreactivity and PPD mRNA ipsilateral to the lesion were strongly induced by L-DOPA, while 8-OH-DPAT suppressed these effects. Finally, intrastriatal infusions of 8-OH-DPAT reduced AIMs while coinfusion of WAY100635 reversed its antidyskinetic effect. Collectively, these results support the hypothesis that the cellular and behavioral properties of 5-HT1AR agonists are conveyed in part via a population of functional 5-HT1AR within the striatum. (C) 2008 Wiley-Liss, Inc.