Excessive cerebrocortical release of acetylcholine induced by NMDA antagonists is reduced by GABAergic and alpha(2)-adrenergic agonists

N-methyl-D-aspartate (NMDA) glutamate (Glu) receptor antagonists (eg MK-801 , ketamine, phencyclidine [PCP]) injure cerebrocortical neurons in the post erior cingulate and retrosplenial cortex (PC/RSC). We have proposed that th e neurotoxic action of these agents is mediated in part by a complex polysy naptic mechanism involving an interference in GABAergic inhibition resultin g in excessive release of acetylcholine (ACh). Previously we have found tha t the systemic injection of GABAergic agents and alpha(2)-adrenergic agonis ts can block this neurotoxicity. In the present study we tested the hypothe sis that NMDA antagonists trigger release of ACh in PC/RSC and that this ac tion of NMDA antagonists is suppressed by GABAergic agents or alpha(2)-adre nergic agonists. The effect of MK-801 and ketamine on PC/RSC ACh output (an d the ability of pentobarbital, diazepam and clonidine to modify MK-801-ind uced ACh release) was studied in adult female rats using in vivo microdialy sis. Both MK-801 and ketamine caused a significant rise in PC/RSC ACh outpu t compared to basal levels. Pentobarbital, diazepam and clonidine suppresse d MK-801's effect on ACh release. Exploratory studies indicated that the si te of action of these agents was outside of the PC/RSC. The microdialysis r esults are consistent with several aspects of the circuitry proposed to med iate the neurotoxic action of NMDA antagonists.