Glutamate and dopamine transporter modulation: Implications for the treatment of Parkinson's disease and L-DOPA induced dyskinesia

Parkinson's disease (PD) is characterized by selective dopaminergic loss with excessive glutamatergic neurotransmission also contributing to the demise of these nigrostriatal neurons. As such, regulation of extracellular dopamine and glutamate are important components of PD pathophysiology and may alter or slow Parkinson's symptomatology or biochemical correlates. In order to examine pre-synaptic dynamics during PD progression more closely, we first sought to identify alterations that may occur in order to compensate for the loss of the dopamine transporter (DAT) in a 6-OHDA rodent model. A NE-sensitive transporter or NET is shown to be increased in 6-OHDA lesioned rats and may be mediating DA uptake in order to help counter the loss of DA regulatory proteins associated with PD. Additionally, L-DOPA blocking this observed DA reuptake poses an alternate mechanism by which exogenous L-DOPA may be alleviating motor symptoms in PD. Specifically, increased extracellular DA in the presence of L-DOPA may increase DA receptor activation and thus, locomotion. It remains uncertain however, if this decrease in DA reuptake with L-DOPA is also a mechanism for L-DOPA induced dyskinesia (LID), a debilitating complication that often occurs with patients receiving chronic L-DOPA therapy to mitigate their PD symptoms. To this end, we then sought to examine how chronic NET blockade by desipramine (DMI) may affect dyskinesia onset and expression in a 6.-OHDA LID rodent model. Worsening of dyskinesia with DMI suggests a dopaminergic component of LID that may be altered through the manipulation of NET.;In order to address the glutamatergic component of PD and LID, the beta-lactam antibiotic, ceftriaxone, increases the expression of glutamate transporter 1 (GLT-1), a glutamate transporter that plays a major role in glutamate clearance in CNS. When Ceftriaxone (CEF) is administered to a 6-OHDA model, we observed an attenuation of tyrosine hydroxylase (TH) loss was associated with increased glutamate uptake, increased GLT-1 expression, and reduced Serine 19 TH phosphorylation, a calcium-dependent target specific for nigrostriatal neurons. Applying cel'ttiaxone to a LID model, chronic CEF was also able to attenuate TH loss and ameliorate dyskinesia significantly compared to L-DOPA alone. Taken together, these data provide novel insights into how a potential therapeutic target, GLT- 1 and/or NET may be modulated in the treatment of Parkinson's disease as well as the prevention of L-DOPA induced dyskinesia.