In vitro and in vivo pharmacology of trans- and cis-(+-)-1-amino-1,3-cyclopentanedicarboxylic acid: dissociation of metabotropic and ionotropic excitatory amino acid receptor effects.
This study explored further the function of the metabotropic excitatory amino acid receptor in the rat brain. The trans and cis isomers of (+-)-1-amino-1,3-cyclopentane-dicarboxylic acid (ACPD) were characterized for relative affinities at ionotropic and metabotropic excitatory amino acid receptors in vitro, as well as ability to produce in vivo excitatory or excitotoxic effects in rats. trans-ACPD was about 12 times more potent in vitro as an agonist for metabotropic excitatory amino acid receptors when compared to its ability to displace N-methyl-D-aspartate (NMDA) ([3H]CGS-19755) receptor binding, cis-ACPD was about 30 times more potent as a displacer of [3H]CGS-19755 binding than as a stimulant of phosphoinositide hydrolysis. When administered intraperitoneally to neonatal rats, both cis- and trans-ACPD produced convulsions that were prevented by the competitive NMDA receptor antagonists, LY233053 and LY274614. cis-ACPD was six times more potent as a convulsant when compared to trans-ACPD. Both compounds were examined for excitotoxic effects in vivo following stereotaxic injection into the mature or neonatal rat striatum. Doses of trans-ACPD of up to 5,000 or 1,200 nmol produced few signs of striatal neuronal degeneration in the mature or neonatal brain, respectively. However, cis-ACPD produced extensive dose-related neuronal degeneration at doses of 100-1,000 nmol in the mature brain and 50-200 nmol in the neonatal brain. These studies suggest that, unlike the ionotropic excitatory amino acid receptors, activation of the metabotropic excitatory amino acid receptor does not result directly in excitatory effects, such as excitotoxicity.
Schoepp
D D
DD
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46256.
Johnson
B G
BG
Salhoff
C R
CR
McDonald
J W
JW
Johnston
M V
MV
D000818:Animals; D000831:Animals, Newborn; D000927:Anticonvulsants / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D003342:Corpus Striatum / Q000201:enzymology; D003515:Cycloleucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005968:Glutamate Decarboxylase / Q000378:metabolism; D007267:Injections; D007477:Ions; D008297:Male; D009410:Nerve Degeneration; D009498:Neurotoxins / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D017459:Receptors, Amino Acid; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000502:physiology*; D012640:Seizures / Q000139:chemically induced; D013237:Stereoisomerism
D000927:Anticonvulsants; D007477:Ions; D009498:Neurotoxins; D017459:Receptors, Amino Acid; D011956:Receptors, Cell Surface; D003515:Cycloleucine; C036361:1-amino-1,3-dicarboxycyclopentane; D002795:Choline O-Acetyltransferase; D005968:Glutamate Decarboxylase