NON-NMDA EXCITATORY AMINO-ACID RECEPTORS IN THE VENTRAL TEGMENTAL AREA MEDIATE SYSTEMIC DIZOCILPINE (MK-801) INDUCED HYPERLOCOMOTION AND DOPAMINE RELEASE IN THE NUCLEUS-ACCUMBENS

This study investigated the putative role of non-NMDA excitatory amino acid (EAA) receptors in the ventral tegmental area (VTA) for the incr ease in dopamine (DA) release in the nucleus accumbens (NAG) and behav ioral stimulation induced by systemically administered dizocilpine (MK -801). Microdialysis was utilized in freely moving rats implanted with probes in the VTA and NAG. Dialysates from the NAC were analyzed with high-performance liquid chromatography for DA and its metabolites, Th e VTA was perfused with the AMPA and kainate receptor antagonist CNQX (0.3 or 1 mM) or vehicle. Forty min after onset of CNQX or vehicle per fusion of the VTA, MK-801 (0.1 mg/kg) was injected subcutaneously. Sub sequently, typical MK-801 induced behaviors were also assessed in the same animals by direct observation, MK-801 induced hyperlocomotion was associated with a 50% increase of DA levels in NAC dialysates. Both t he MK-801 evoked hyperlocomotion and DA release in the NAC was antagon ized by CNQX perfusion of the VTA in a concentration-dependent manner, None of the other rated MK-801 evoked behaviors, e.g. head weaving or sniffing, were affected by CNQX perfusion of the VTA, By itself the C NQX or vehicle perfusion of the VTA alone did not affect DA levels in NAC or any of the rated behaviors, These results indicate that MK-801 induced hyperlocomotion and DA release in the NAC are largely elicited within the VTA via activation of non-NMDA EAA receptors, tentatively caused by increased EAA release. Thus, the locomotor stimulation induc ed by psychotomimetic NMDA receptor antagonists may not only reflect i mpaired NMDA receptor function, but also enhanced AMPA and/or kainate receptor activation in brain, e.g., in the VTA, In view of their capac ity to largely antagonize the behavioral stimulation induced by psycho tomimetic drugs, such as MK-801, AMPA, and/or kainate receptor antagon ists may possess antipsychotic efficacy. (C) 1998 Wiley-Liss, Inc.