STRESS ACTIVATION OF MESOCORTICOLIMBIC DOPAMINE NEURONS - EFFECTS OF A GLYCINE NMDA RECEPTOR ANTAGONIST

Restraint of brief duration causes a metabolic activation of mesocorti cal and some mesolimbic dopaminergic systems with little effect on the nigrostriatal system. We have examined the ability of an antagonist o f the allosteric glycine site of the N-methyl-D-aspartate receptor com plex to block the stress-induced response in dopamine utilization. Thi rty minutes of restraint stress elevated dopamine metabolism, as measu red by the ratio between 3,4-dihydroxyphenylacetic acid (DOPAC) and do pamine, in both the medial prefrontal cortex and nucleus accumbens. An antagonist for the glycine/N-methyl-D -aspartate receptor complex, 1- hydroxy-3-aminopyrrolidone-2 ((+)-HA-966), given systemically or injec ted into the ventral tegmental area, prevents the stress-induced incre ase in dopamine metabolism in the prefrontal cortex without altering t he response in the nucleus accumbens. Similarly, systemic administrati on of the non-competitive antagonist for the N-methyl-D-aspartate rece ptor, dizocilpine ((+)-MK-801), blocked the stress-induced rise in dop amine metabolism in the medial prefrontal cortex but not the nucleus a ccumbens. The negative enantiomer of HA-966 did not produce a selectiv e antagonism of the stress-induced dopamine metabolism in the medial p refrontal cortex. These results support previous work which suggest th e mesocortical and mesoaccumbens dopamine neurons respond to excitator y input through different glutamate receptor mechanisms. Additionally, the specific blockade of the stress-induced change in dopamine metabo lism in the medial prefrontal cortex by a glycine antagonist implies a role for such an antagonist in treatment of disease states which may involve disruptions of N-methyl-D-aspartate receptor function.