THE IMPACT OF A COMPETITIVE AND A NONCOMPETITIVE NMDA RECEPTOR ANTAGONIST ON DOPAMINERGIC NEUROTRANSMISSION IN THE RAT VENTRAL TEGMENTAL AREA AND SUBSTANTIA-NIGRA

The study compares effects of the competitive and non-competitive NMDA receptor antagonists, CGP 40116 and MK-801 respectively, on the metab olism of dopamine and on the density of D-1 and D-2 dopaminergic recep tors in the rat ventral tegmental area and substantia nigra. The effec ts of CGP 40116 were tested in a range of doses which either were devo id of or had locomotor- or stereotypy-stimulating effects. It was foun d that (1) CGP 40116 given in a dose of 5 mg/kg enhanced the locomotor activity of rats and evoked a stereotypy-like activity; doses of 1.25 and 2.5 mg/kg were devoid of such effects; (2) CGP 40116 (5 mg/kg) en hanced the concentrations of dopamine, DOPAC and HVA in the ventral te gmental area, whereas the lowest dose, 1.25 mg/kg was without effect; a dose of 2.5 mg/kg increased the concentration of dopamine only; the only effect of CGP 40116 (5 mg/kg) observed increase dopamine 1.25 and 2.5 mg/kg were ineffective. (3) MK-801 (0.2 and 0.4 mg/kg) enhanced t he concentrations of dopamine, DOPAC and HVA in both structures. A dos e of 0.1 mg/kg increased the dopamine concentration only. The effects of MK-801 in substantia nigra were quantitatively weaker than those ob served in ventral tegmental area. (4) Both CGP 40116 (5 mg/kg) and MK- 801 (0.4 mg/kg) evoked alterations in the density of dopaminergic rece ptors. D-2 receptors, were up-regulated by MK-801 in ventral tegmental area and subregions of substantia nigra, i.e. pars compacta and pars reticulata, whereas CGP 40116 evoked similar effects in ventral tegmen tal area only. D-1 receptors in pars compacta and pars reticulata of s ubstantia nigra were down-regulated after administration of either dru g. It is concluded that competitive NMDA receptor antagonists in doses which evoke hyperlocomotion and substantia nigra, was an concentratio n; its doses of stereotypy-like activity, may have a substantial impac t on the dopaminergic neurotransmission in the rat ventral tegmental a rea and substantia nigra, similar to that described for MK-801, a non- competitive NMDA receptor antagonist. The obtained results may suggest that CGP 40116 and, possibly, other competitive NMDA antagonists may have dopaminomimetic properties, and that their clinical potentials ma y be limited by the risk of evoking dopamine-dependent psychotomimetic and abusing effects, similar to those described for MK-801.