Regional effects of MK-801 on dopamine release: effects of competitive NMDA or 5-HT2A receptor blockade

The open channel N-methyl-D-aspartate (NMDA) receptor antagonists dizocilpine (MK-801) and phencyclidine (PCP) increase the firing rate of both A9 and A10 dopaminergic neurons in the rat. In the A10 nucleus, this effect of MK-801 is reportedly prevented by either competitive NMDA antagonists or serotonin2 (5-HT2) antagonists. The present study examined the neurochemical correlates of these effects using the technique of in vivo microdialysis in conscious rats. In contrast to its reported electrophysiological effects at the cell body level, MK-801 (2 mg/kg, i.p.) has divergent effects on dopamine release in the terminal fields of the A9 and A10 systems. MK-801 stimulated dopamine release in both the medial prefrontal cortex and the nucleus accumbens but tended to decrease release in the striatum. Stimulated dopamine release in the nucleus accumbens was selectively blocked by either the competitive NMDA receptor antagonist, MDL 100,453 or the 5-HT2A receptor antagonist, MDL 100,907. Neither MDL 100,453 nor MDL 100,907 affected MK-801-induced release in the medial prefrontal cortex. The results illustrate the complex regulation of the forebrain dopaminergic systems by glutamate and indicate that the serotonergic system, via the 5-HT2A receptor, may play an important role in this regulation.