J. Arnt et al., DIFFERENTIATION OF IN-VIVO EFFECTS OF AMPA AND NMDA RECEPTOR LIGANDS USING DRUG DISCRIMINATION METHODS AND CONVULSANT ANTICONVULSANT ACTIVITY/, European journal of pharmacology, 285(3), 1995, pp. 289-297
The discriminative stimulus properties of the AMPA amino-3-(3-hydroxy-
5-methylisoxazol-4-yl)propionic acid) receptor agonist ATPA o-3-(3-hyd
roxy-5-tert-butylisoxazol-4-yl)propionic acid) and NMDA (N-methyl-D-as
partic acid) in rats have been characterized. It is suggested that the
cues are mediated by separate mechanisms in the central nervous syste
m. The ATPA cue is not mimicked by NMDA or an NMDA receptor agonist, a
nd is inhibited by the AMPA receptor antagonist (R)-APPA amino-3-(3-hy
droxy-5-phenylisoxazol-4-yl)propionic acid) but not the AMPA receptor
antagonist ATOA carboxymethoxy-5-tert-butylisoxazol-4-yl)propionic aci
d) or the NMDA receptor antagonist CPP ((RS)-3-(2-carboxypiperazin-4-y
l)propyl)phosphonic acid). The ATPA cue is not mimicked by AMPA which
is believed not to penetrate the blood-brain barrier. In contrast, ATP
A does not generalize to the NMDA cue, which is mimicked by some NMDA
receptor agonists (tetrazol-5-yl-gylcine and AMAA -2-amino-2-(3-hydrox
y-5-methylisoxazol-4-yl)acetic acid)) and is inhibited by the NMDA rec
eptor antagonist CPP. Highly potent convulsant activity was demonstrat
ed in mice with all AMPA and NMDA receptor agonists after intracerebro
ventricular (i.c.v.) injection, whereas weaker or no effects were foun
d after subcutaneous (s.c.) or intravenous injection. Only (RS)-tetraz
ol-5-yl-glycine had a potent effect after s.c. administration. I.c.v.
ATOA and CPP inhibited convulsions induced by i.c.v. injection of AMPA
or NMDA, while (R)-APPA was ineffective. These results indicate that
there are differences in the structure-activity relations in the drug
discrimination and convulsant/anticonvulsant models, even when effects
after i.c.v. and s.c. injection are taken into consideration. The con
vulsion models are rapid tests which can give an indication of central
nervous system penetration, but are less pharmacologically specific w
ith respect to differentiation between AMPA and NMDA ligands where cue
models demonstrate clear differences in effects of ligands with selec
tivity for receptor subtypes.