Selective activation of
5-HT1 receptors has been shown to produce near to full suppression of
L-DOPA-induced
dyskinesia (LID) in animal models of
Parkinson's disease; however, a reduction of the
therapeutic effect of
L-DOPA has been reported in several studies. Conversely, we recently found that increasing the serotonergic tone with chronic administration of the
serotonin precursor 5-hydroxy-tryptophan (5-HTP) can reduce LID in 6-OHDA-lesioned rats, without affecting
L-DOPA efficacy. To directly compare the effects of selective versus non-selective
serotonin receptor activation, here we first tested different acute doses of the 5-HT1A/1B receptor agonist
eltoprazine and
5-HTP on LID in order to identify doses of the individual compounds showing similar anti-dyskinetic efficacy in
L-DOPA-primed dyskinetic rats. About 50% reduction of LID was observed with 0.1 mg/kg and 24 mg/kg of
eltoprazine and
5-HTP, respectively; we then compared the effect of the two drugs, individually and in combination, on
L-DOPA-induced stepping test in
L-DOPA-naïve parkinsonian animals and LID over three weeks of
L-DOPA treatment. Results showed that
eltoprazine induced significant worsening of
L-DOPA-mediated performance in the stepping test, while
5-HTP did not. Interestingly, combination of
5-HTP with
eltoprazine prevented the reduction in the forelimb use induced by
eltoprazine. Moreover,
5-HTP and
eltoprazine given individually showed similar efficacy also upon chronic treatment, and had additive effect in dampening the appearance of LID when given in combination. Finally, chronic administration of
eltoprazine and/or
5-HTP did not affect striatal
serotonin innervation, compared to
l-DOPA alone, as measured by
serotonin transporter expression.