Blockade of NMDA receptors in the nucleus accumbens elicits spontaneous tail-flicks in rats

The open channel blocker at N-methyl-D-aspartate (NMDA) receptors, dizocilpine, stereospecifically elicited spontaneous tail-flicks in rats - a reaction similar to those elicited by other drugs (tenocyclidine, phencyclidine and ketamine) acting as open channel blockers. Their relative potencies were strongly correlated with affinities at NMDA binding sites and labeled by [H-3]dizocilpine in the frontal cortex(r = 0.94) and, as determined previously [Millan, M.J., Seguin, L., 1994. Chemically-diverse ligands at the glycine B site coupled to N-methyl-D-aspartate (NMDA) receptors selectively block the late phase of formalin-induced pain in mice, Neurosci. Lett., 178 (1994) 139-143], potency for eliciting antinociception (0.93). The competitive antagonists at the NMDA receptor recognition site, (+/-)3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP). 4-phosphonomethyl-2-piperidine carboxylic acid (CGS19755), D,L-(E)-2-amino-4-methylphosphono-3-pentanoic acid (CGP37849) and (3E)- 1-ethylester-2-amino-3-methyl-5-phosphono-3-pentenoic acid (CGP39551), likewise dose-dependently evoked spontaneous tail-flick. In contrast, antagonists/weak partial agonists at the coupled, glycine B site, 7-chloro-4-hydroxy-3-(3-phenoxy) phenyl-2(H)-quinolinone (L7101,324), (+)-1-hydroxy-3-aminopyrrolidine-2-one ((+)-HA966), (3R,4R)-3-amino-2-hydroxy-4-methyl-2-pyrrolidinone (L687,414), (6,7-dichloro-1,4-dihydro-5-nitro, 2,3 quinoxalinedione (ACEA1021) and 2-carboxy-4,6-dichloro (1H)-indole-3-propanoic acid (MDL29,951), were inactive. NMDA abolished induction of spontaneous tail-flick by CPP and CGS19755, but not by dizocilpine. Upon bilateral injection into the nucleus accumbens, dizocilpine immediately and dose-dependently elicited spontaneous tail-flick, but it was ineffective in the ventrotegmental area and striatum. Similarly, injection of CPP into the nucleus accumbens elicited spontaneous tail-flick. Neither dizocilpine nor CPP elicited spontaneous tail-flick upon administration onto lumbar spinal cord. In conclusion, a pharmacologically specific spontaneous tail-flick-response is elicited by both open channel blockers and recognition site antagonists, but not glycine B site antagonists, at NMDA receptors. Their actions, mediated in the nucleus accumbens, may be differentiated by their respective resistance and sensitivity to NMDA. (C) 2000 Elsevier Science B.V. All rights reserved.