LY354740, a potent group II metabotropic glutamate receptor agonist prevents lactate-induced panic-like response in panic-prone rats.
LY354740 is a potent and selective agonist at the group II metabotropic glutamate receptors and is shown to be an effective inhibitor of glutamate release with significant anxiolytic and drug withdrawal alleviating properties in certain animal models. Rats with chronic inhibition of GABA synthesis in the dorsomedial hypothalamus (DMH) are highly anxious and exhibit panic-like responses to peripheral lactate infusions similar to patients with panic disorder. Using these panic-prone rats, we tested the efficacy of LY354740 in preventing the lactate-induced panic-like response, comparing it to alprazolam, a clinically effective anti-panic drug. Rats were fitted with femoral arterial and venous catheters and implanted with Alzet pumps infusing the GABA synthesis inhibitor L-allylglycine into the DMH. After four days of recovery, they were confirmed to be panic-prone to lactate infusions as indicated by increases in heart rate, blood pressure, respiratory rate and "anxiety" measured in the social interaction test. Next, they were pretreated with either vehicle, LY354740 (0.3 and 0.6 mg/kg) or alprazolam (0.5 and 1.0 mg/kg) and re-challenged with lactate infusions. LY354740 treatment was equally efficacious as alprazolam in preventing lactate-induced panic attacks in this model. These data suggest that LY354740 could be a novel anti-panic drug, as effective as alprazolam in acute treatment.
Shekhar
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Department of Psychiatry, Pharmacology and Toxicology and Program in Medical Neurobiology, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis 46202, USA. ashekhar@iupui.edu
Keim
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D000501:Allylglycine / Q000494:pharmacology; D000525:Alprazolam / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001794:Blood Pressure / Q000187:drug effects; D001643:Bridged Bicyclo Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D018690:Excitatory Amino Acid Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D018757:GABA Modulators / Q000008:administration & dosage / Q000494:pharmacology; D005968:Glutamate Decarboxylase / Q000037:antagonists & inhibitors; D006339:Heart Rate / Q000187:drug effects; D007033:Hypothalamus, Middle / Q000502:physiology; D007261:Infusions, Intra-Arterial; D007398:Interpersonal Relations; D019344:Lactic Acid / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D008297:Male; D010200:Panic / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists*; D015656:Respiratory Mechanics / Q000187:drug effects
D001643:Bridged Bicyclo Compounds; D018690:Excitatory Amino Acid Agonists; D018757:GABA Modulators; D018094:Receptors, Metabotropic Glutamate; D000501:Allylglycine; D019344:Lactic Acid; D005968:Glutamate Decarboxylase; C104753:eglumetad; D000525:Alprazolam