Differential regulation of glutamate, aspartate and gamma-aminobutyrate release by N-methyl-D-aspartate receptors in rat striatum after partial and extensive lesions to the nigro-striatal dopamine pathway

The in vivo microdialysis methodology was used to assess the effect of N-me thyl-D-aspartate (NMDA) receptor ligands on glutamate (GLU), aspartate (ASP ) and gamma-aminobutyrate (GABA) extracellular levels in the striatum of an aesthetized rats, after damage to the dopamine (DA) nigrostriatal pathway b y injections of different doses of 6-hydroxydopamine (6-OH-DA) seven days e arlier. The 6-OH-DA treated rats were divided into two groups, correspondin g to animals with 20-80% (partial) and 85-99% (extensive) striatal DA tissu e depletion, respectively. In rats with partial DA depletion, the striatal extracellular ASP levels significantly increased after intrastriatal dialys is perfusion with MK-801 (100 mu M), an antagonist of NMDA receptors. In ad dition, a change in the pattern of local NMDA (500 mu M)- induced efflux of ASP was observed in the striatum of these rats. However, in these partiall y DA-depleted striata no changes were found in basal extracellular levels o f GLU, ASP and GABA or in NMDA- and MK-801-mediated effluxes of GLU and GAB A relative to striata from sham rats. In contrast, rats with extensive stri atal DA depletion exhibited a significant increase in ASP and GABA extracel lular striatal levels, after intrastriatal dialysis perfusion with NMDA. In addition, the MK-801-mediated stimulation of extracellular ASP levels was accentuated along with the appearance of a MK-801 mediated increase in extr acellular striatal GLU. Finally, basal extracellular levels of ASP, but not of GLU and GABA, were found to increase in extensive DA-depleted striata w hen compared to sham and partially DA-depleted striata. Thus, a differentia l regulation of basal and NMDA receptor-mediated release of transmitter ami no acids occur seven days after partial and extensive DA-depleted striatum by 6-OH-DA-induced lesions of the nigrostriatal DA pathway. These findings may have implications as regards the participation of NMDA r eceptors in the compensatory mechanisms associated with the progress of Par kinson's disease, as well as in the treatment of this neurological disorder . (C) 1999 Elsevier Science Ltd. All rights reserved.