In vitro and in vivo studies in rats with LY293558 suggest AMPA/kainate receptor blockade as a novel potential mechanism for the therapeutic treatment of anxiety disorders.
BACKGROUND
Although convergent evidence exists for a role of glutamate in the regulation of anxiety, the involvement of specific glutamate receptor subtypes has yet to be defined.


OBJECTIVE
To evaluate the potential for blockade of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)/kainate receptors to produce anxioltyic-like effects with the AMPA/GLU(K5) (kainate) antagonist (3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5yl)ethyl]decahydroisoquinoline-3carboxylic acid (LY293558)


METHODS
Punished responding of rats was used to determine the efficacy of LY293558. Other in vivo and in vitro studies further characterized the specificity of LY293558 for AMPA/kainate receptors.


RESULTS
LY293558 had a rank order of potency of GLU(K5) > or = GLU(K5/6) approximately GLU(A2i) approximately GLU(K2/5) approximately GLU(A1i) approximately GLU(A2o) approximately GLU(A3i) approximately GLU(A1o) > or = GLU(A3o) > or = GLU(A4i) approximately GLU(A4o) and >100 microM affinity for rat cortical GABA(A) receptors. Comparison of the blockade of AMPA- vs N-methyl-D-aspartate (NMDA)-induced inward currents demonstrated that LY293558 was five-fold more potent as an antagonist at AMPA vs NMDA receptors in vitro. In keeping with the low affinity of LY293558 for NMDA receptors, LY293558 was not effective in preventing NMDA-induced seizures in mice. LY293558 increased punished responding, a preclinical predictor of anxiolytic efficacy, at a dose that decreased unpunished responding (10 mg/kg, i.p.). Chlordiazepoxide produced comparable increases in both punished and unpunished responding. The NMDA antagonist dizocilpine [(+)-MK-801] also increased both punished and unpunished responding.


CONCLUSIONS
These data along with those in the literature suggest that AMPA and/or kainate receptor blockade may be an important component to producing anxiolytic-like effects and may therefore be a target for compounds with efficacy in the therapeutic treatment of anxiety disorders.
Neuroscience Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA.
Andrew
A
Alt
Brianne
B
Weiss
Ann Marie
AM
Ogden
Xia
X
Li
Scott D
SD
Gleason
David O
DO
Calligaro
David
D
Bleakman
Jeffrey M
JM
Witkin
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D002264:Carboxylic Acids / Q000494:pharmacology*; D002478:Cells, Cultured; D002707:Chlordiazepoxide / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D016202:N-Methylaspartate; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D021122:Protein Subunits / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors* / Q000502:physiology; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors* / Q000502:physiology; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy; D013777:Tetrazoles / Q000494:pharmacology*
D014151:Anti-Anxiety Agents; D002264:Carboxylic Acids; D002707:Chlordiazepoxide; D007546:Isoquinolines; D016202:N-Methylaspartate; D021122:Protein Subunits; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; D013777:Tetrazoles; C082309:tezampanel