THE NMDA GLYCINE SITE ANTAGONIST (-HA-966 SELECTIVELY REGULATES CONDITIONED STRESS-INDUCED METABOLIC-ACTIVATION OF THE MESOPREFRONTAL CORTICAL DOPAMINE BUT NOT SEROTONIN SYSTEMS - A BEHAVIORAL, NEUROENDOCRINE,AND NEUROCHEMICAL STUDY IN THE RAT())

Animals confronting threatening stimuli respond with a coordinated set of autonomic, neuroendocrine, neurochemical, and behavioral responses that constitute the stress response. The role of the NMDA receptor an d its glycine modulatory site was investigated in a rat conditioned st ress model. Behavioral, neuroendocrine, and neurochemical analyses wer e conducted. Regional dopamine (DA) and serotonin (5-HT) utilization w as assessed by postmortem tissue measurements of metabolite-to-parent neurotransmitter ratios. Rats were conditioned to fear a tone previous ly paired with footshock. The following day, rats were systemically ad ministered saline or the NMDA glycine site antagonist (+)-HA-966 befor e exposure to thirty minutes of conditioned stress. Conditioned stress resulted in a selective increase in medial prefrontal cortical DA and 5-HT utilization, elevation in serum corticosterone, and freezing beh avior in control animals. The conditioned stress-induced increase in D A utilization in control animals was also detected in the lateral pref rontal cortex and nucleus accumbens, whereas DA utilization was not af fected in the perirhinal or cingulate cortices, lateral-basolateral am ygdaloid complex, anterior ventromedial caudatoputamen, or posterior d orsolateral caudatoputamen. Pretreatment with (+)-HA-966 at 15 mg/kg c ompletely abolished the conditioned stress-induced increase in DA util ization in the medial and lateral prefrontal cortices. This effect was regionally specific since (+)-HA-966 pretreatment did not block incre ased DA utilization in the nucleus accumbens. This effect was also neu rochemically specific since the stress-induced increase in 5-HT utiliz ation in the medial prefrontal cortex was not affected by (+)-HA-966 p retreatment. Pretreatment with (+)-HA-966 did not affect stress-induce d serum corticosterone elevation but did attenuate the freezing respon se. Control experiments demonstrated that (+)-HA-966 pretreatment did not (1) induce sedation, (2) interfere with habituation to a novel env ironment, (3) alter basal DA, 5-HT, or serum corticosterone levels, or (4) block acquisition of aversive memories. These data suggest that t he NMDA receptor complex and associated glycine modulatory site may pl ay an important role in the afferent control of the mesoprefrontal cor tical DA system during conditioned stress. The relevance of these find ings to schizophrenia and human anxiety disorders such as post-traumat ic stress disorder are discussed.