Effects of the Serotonin 5-HT1A Receptor Biased Agonists, F13714 and F15599, on Striatal Neurotransmitter Levels Following l-DOPA Administration in Hemi-Parkinsonian Rats

Peak-dose dyskinesia is associated with the dramatic increase in striatal dopamine levels that follows l-DOPA administration. The ‘false neurotransmitter’ hypothesis postulates that the latter is likely due to an aberrant processing of l-DOPA by serotonergic neurons. In keeping with this hypothesis, two highly selective ‘biased agonists’ of 5-HT1A receptors—namely F13714 and F15599 (NLX-101)—were recently shown to exhibit exceptionally potent anti-dyskinetic activity without impairing l-DOPA therapeutic properties despite their differential targeting of 5-HT1A receptor sub-populations. In this study, we investigated whether these two compounds dampened peak l-DOPA-induced dopamine microdialysate levels in the striatum of hemi-parkinsonian rats. Acute administration of either F13714 (0.04 and 0.16 mg/kg i.p.) or F15599 (0.16 and 0.64 mg/kg, i.p.) blunted l-DOPA (2 mg/kg)-induced increases in dopamine microdialysate levels in the denervated striatum (following unilateral injection of 6-OHDA into the medial forebrain bundle). No significant changes were observed on the intact side of the brain. Concurrently, both drugs profoundly reduced striatal serotonin levels on both sides of the brain. In addition, F13714 and F15599, in the presence of l-DOPA, produced a dose-dependent increase in glutamate levels, but this effect was restricted to later time points. These finding support the interpretation that F13714 and F15599 mediate their anti-dyskinetic effects by blunting of the peak in dopamine levels via activation of somatodendritic serotonin 5-HT1A receptors and the consequent inhibition of serotonergic neurons. This study adds to the growing body of evidence supporting the development of a potent 5-HT1A receptor agonist for treatment of peak-dose dyskinesia.