l-DOPA is the standard treatment for
Parkinson's disease (PD), but chronic treatment typically leads to abnormal
involuntary movement or
dyskinesia (LID) development. Although poorly understood, dyskinetic mechanisms involve a complex interaction between the remaining
dopamine system and the semi-homologous
serotonin and
norepinephrine systems.
Serotonin and
norepinephrine transporters (SERT and NET, respectively) have affinity for
dopamine uptake especially when
dopamine transporters (DAT) are scant. Monoamine reuptake inhibitors have been reported to modulate
l-DOPA's anti-parkinsonian effects, but DAT, SERT, and NET's contribution to
dyskinesia has not been well delineated. The current investigation sought to uncover the differential expression and function of DAT, SERT, and NET in the
l-DOPA-treated hemi-parkinsonian rat.
Protein analysis of striatal monoamine transporters in unilateral
sham or 6-hydroxydopamine-lesioned rats treated with
l-DOPA (0 or 6 mg/kg) showed lesion-induced DAT loss and
l-DOPA-induced gain in SERT:DAT and NET:DAT ratios in lesioned rats which positively correlated with
dyskinesia expression, suggesting functional shifts among monoamine transporters in the dyskinetic state. SERT blockade with
citalopram (3, 5 mg/kg) reduced LID while DAT and NET blockade with
GBR-12909 (5, 10 mg/kg) and
nisoxetine (5, 10 mg/kg), respectively, mildly exacerbated
dyskinesia expression. Transporter inhibition did not significantly alter
l-DOPA's ability to reverse motor deficit. Overall, DA and DAT loss with
l-DOPA treatment appear to precipitate gain in SERT and NET function. Strong correlations with LID and direct behavioral comparisons of selective transporter blockade reveal novel implications for SERT, DAT, and NET as potential
biomarkers and therapeutic targets in the hemi-parkinsonian model and dyskinetic PD patients.