MK-801 interaction with the 5-HT transporter: A real-time study in brain slices using fast cyclic voltammetry

The effects of a noncompetitive N-methyl-D-aspartate (NMDA) receptor antago nist dizocilpine ((+)-MK-801) and a competitive NMDA antagonist, (+/-)-3-2- carboxypiperazin-4-yl-propyl-1-phosphonic acid (CPP) were compared in elect rically evoked 5-HT release in the brain slices incorporating the substanti a nigra pars reticulata (SNr) or the dorsal raphe nucleus (DRN) using fast cyclic voltammetry (FCV). Electrical stimulation of either the SNr or the D RN with 50 pulses at frequencies greater than 10 Hz generated signals that were indistinguishable from 5-HT. In the SNr, 0.6-60 mu M MK-801 concentrat ion dependently potentiated stimulated 5-HT release. CPP 20 mu M or NMDA 10 0 mu M had no effect on 5-HT release evoked by electrical stimulation. In t he SNr, 1 mu M fluvoxamine or 0.6-60 mu M MK-801 potentiated electrically e voked release of 5-HT. Pre-exposure to 20 mu M MK-801 inhibited the enhanci ng effects of 1 mu M fluvoxamine on electrically evoked 5-HT release in the SNr. In the DRN, the presence of 1 mu M fluvoxamine or 20 PM MK-801 weakly potentiated 5-HT release. In the presence of 1 PM methiothepin (a nonselec tive 5-HT1-2 antagonist), 1 mu M fluvoxamine or 20 mu M MK-801 were equipot ent in potentiating the,concentration of 5-HT released in response to elect rical stimulation. The T-1/2 values for 5-HT release following MK-801 or fl uvoxamine administration were significantly increased. Potentiation of 5-HT release by MK-801 in the SNr and the DRN and lack of effect of either CPP or NMDA on 5-HT release or uptake argues against a role for NMDA receptors in modulation of 5-HT release. Inhibition of fluvoxamine induced potentiati on of 5-HT signal in the presence of MK-801 suggests that MK-801 and fluvox amine may interact at the level of the 5-HT transporter. (C) 1999 Wiley-Lis s, Inc.