Recent studies suggest that l-3,4 dihydroxyphenylalanine (l-DOPA)-induced dyskinesia (LID), a severe complication of conventional l-DOPA therapy of Parkinson's disease, may be caused by dopamine (DA) release originating in serotonergic neurons. To evaluate the in vivo effect of a 5-HT 1A agonist [(±)-8-hydroxy-2-(dipropylamino) tetralin hydrobromide, 8-OHDPAT] on the l-DOPA-induced increase in extracellular DA and decrease in [ 11C]raclopride binding in an animal model of advanced Parkinson's disease and LID, we measured extracellular DA in response to l-DOPA or a combination of l-DOPA and the 5-HT 1A agonist, 8-OHDPAT, with microdialysis, and determined [ 11C]raclopride binding to DA receptors, with micro-positron emission tomography, as the surrogate marker of DA release. Rats with unilateral 6-hydroxydopamine lesions had micro-positron emission tomography scans with [ 11C]raclopride at baseline and after two pharmacological challenges with l-DOPA + benserazide with or without 8-OHDPAT co-treatment. Identical challenge regimens were used with the subsequent microdialysis concomitant with ratings of LID severity. The baseline increase of [ 11C]raclopride-binding potential (BP ND) in lesioned striatum was eliminated by the l-DOPA challenge, while the concurrent administration of 8-OHDPAT prevented this l-DOPA-induced displacement of [ 11C]raclopride significantly in lesioned ventral striatum and near significantly in the dorsal striatum. With microdialysis, the l-DOPA challenge raised the extracellular DA in parallel with the emergence of strong LID. Co-treatment with 8-OHDPAT significantly attenuated the release of extracellular DA and LID. The 8-OHDPAT co-treatment reversed the l-DOPA-induced decrease of [ 11C]raclopride binding and increase of extracellular DA and reduced the severity of LID. The reversal of the effect of l-DOPA on [ 11C]raclopride binding, extracellular DA and LID by 5-HT agonist administration is consistent with the notion that part of the DA increase associated with LID originates in serotonergic neurons.
- 5-HT receptor agonist
- Parkinson's disease
- l -DOPA induced dyskinesia
- micro-positron emission tomography and microdialysis
ASJC Scopus subject areas
- Cellular and Molecular Neuroscience