DIFFERENTIAL INTERACTION OF COMPETITIVE NMDA AND AMPA ANTAGONISTS WITH SELECTIVE DOPAMINE D-1 AND D-2 AGONISTS IN A RAT MODEL OF PARKINSONS-DISEASE

Stimulation of the dopamine (DA) D-2 and D-1 receptors results in beha vioural activation (i.e., induction of contralateral rotations) in 6-h ydroxydopamine (6-OHDA) substantia nigra lesioned rats. Competitive N- methyl-D-aspartate (NMDA) antagonists as well as pha-amino-3-hydroxy-5 -methyl-4-isoxazolepropionate (AMPA) antagonists potentiate the stimul atory responses to threshold doses of L-DOPA or the mixed dopamine D-1 /D-2 agonist apomorphine in this model, indicating the potential of su ch combinations for the management of Parkinson's disease. Neuroanatom ic and electrophysiologic data indicate a differential distribution of DA D-1 and DA D-2 receptors within motor loops of the basal ganglia. DA D-1 receptors are preferentially located on GABAergic neurones proj ecting to the substantia nigra compacta (SNc) and to the substantia ni gra reticulata (SNr), whereas DA D-2 receptors are preferentially loca ted on neurones that innervate the external pallidum. NMDA receptors a re present in high densities within the striatum, whereas AMPA recepto rs are enriched in the entopeduncular nucleus/internal pallidum and th e SNr. To further characterise the functional interaction between DA a nd glutamate receptors, we tested the competitive NMDA antagonist +/-) -2-carboxypiperstzin-4-yl)-propyl-1-phosphonic acid (CPP) and the AMPA antagonist -dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline (NBQX) following systemic administration in combination with the DA D-2 selec tive agonist quinpirole or the DAD-1 selective agonist A68 930 1R,3S)- 1-aminomethyl-5,6-dihydroxy-3-phenylisochro man) in rats with chronic 6-OHDA lesions of the SNc. CPP potentiated quinpirole-induced rotation s and did not affect those induced by the D-1 agonist A 68930. By cont rast, NBQX had no effect on quinpirole-induced rotations, whereas syne rgism was seen with A 68930. These results suggest that rotations indu ced by combined treatment with glutamate antagonists and DA agonists a re mediated by different pathways within the basal ganglia, depending on which subtype of receptor is involved. AMPA antagonists could act p referentially by activating the direct motor pathway, whereas NMDA ant agonists could modulate the indirect loop. (C) 1997 Wiley-Liss, Inc.