NMDA receptor complex antagonists have potential anxiolytic effects as measured with separation-induced ultrasonic vocalizations.
Pre-weaning rat pups emit ultrasonic vocalizations when removed from the litter. These 'separation-induced vocalizations' (SIV) are suppressed by classical benzodiazepine anxiolytics and by non-benzodiazepine anxiolytics which lack muscle relaxant and sedative properties. The present study used the SIV model to assess potential anxiolytic properties of compounds which target different sites associated with the NMDA receptor complex. Comparison was made to drugs which affect benzodiazepine or serotonin (5-HT) receptors. Muscle relaxant potential was assessed using 'TIP' (time on an inclined plane), the amount of time a pup was able to retain its position on a steeply inclined surface. Mephenesin, a centrally acting muscle relaxant, significantly suppressed TIP but not SIV. The benzodiazepine agonist diazepam suppressed both SIV and TIP, whereas the 5-HT1A partial agonists, buspirone and MDL 73,005EF, suppressed SIV without affecting TIP. The 5-HT2 antagonist MDL 11,939 suppressed TIP but not SIV, whereas neither measure was affected by the 5-HT3 antagonist MDL 73,147EF. SIV was suppressed by NMDA antagonists including those acting at the glutamate recognition site (D,L-amino-phosphonovaleric acid (AP5) and MDL 100,453) or at the ion channel (MK-801), or by the strychnine-insensitive glycine antagonist 5,7-dichlorokynurenic acid (5,7-DCKA). TIP was suppressed even more potently by AP5, MDL 100,453 and MK-801, whereas 5,7-DCKA was inactive on this measure. Thus, antagonists acting at different sites present on the glutamate recognition site exhibit potential anxiolytic activity, but the glycine antagonist was unusual in its lack of prominent muscle relaxant side effects.
Marion Merrel Dow Research Institute, Cincinnati, OH 45219.
J H
JH
Kehne
T C
TC
McCloskey
B M
BM
Baron
E M
EM
Chi
B L
BL
Harrison
J P
JP
Whitten
M G
MG
Palfreyman
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001010:Anxiety, Separation / Q000188:drug therapy; D001522:Behavior, Animal / Q000187:drug effects*; D002065:Buspirone / Q000494:pharmacology; D003975:Diazepam / Q000494:pharmacology; D004147:Dioxins / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D007211:Indoles / Q000494:pharmacology; D007736:Kynurenic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D008426:Maternal Deprivation; D008615:Mephenesin / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011807:Quinolizines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D011985:Receptors, Serotonin / Q000187:drug effects / Q000502:physiology; D012702:Serotonin Antagonists / Q000494:pharmacology; D013141:Spiro Compounds / Q000494:pharmacology; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D014828:Vocalization, Animal / Q000187:drug effects*
D014151:Anti-Anxiety Agents; D004147:Dioxins; D007211:Indoles; D010880:Piperidines; D011807:Quinolizines; D016194:Receptors, N-Methyl-D-Aspartate; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D013141:Spiro Compounds; C066169:alpha-phenyl-1-(2-phenylethyl)-4-piperidinemethanol; C066280:4-oxo-5-phosphononorvaline; C063249:binospirone mesylate; D016291:Dizocilpine Maleate; D015763:2-Amino-5-phosphonovalerate; D008615:Mephenesin; C060344:dolasetron; D007736:Kynurenic Acid; D014633:Valine; D003975:Diazepam; C066192:5,7-dichlorokynurenic acid; D002065:Buspirone