title: A selective, non-peptide CRF receptor 1 antagonist prevents sodium lactate-induced acute panic-like responses.
abstract: Corticotropin releasing factor (CRF) is implicated in a variety of stress-related disorders such as depression and anxiety, and blocking CRF receptors is a putative strategy for treating such disorders. Using a well-studied animal model of panic, we tested the efficacy of JNJ19567470/CRA5626, a selective, non-peptidergic CRF type 1 receptor (CRF1) antagonist (3, 10 and 40 mg/kg intraperitoneal injection), in preventing the sodium lactate (NaLac)-induced panic-like behavioural and cardiovascular responses. Adult male rats with chronic reduction of GABA levels (by inhibition of GABA synthesis with l-allyglycine, a glutamic acid decarboxylase inhibitor) in the dorsomedial/perifornical hypothalamus are highly anxious and exhibit physiological and behavioural responses to intravenous NaLac infusions similar to patients with panic disorder. These 'panic-prone' rats pre-treated with vehicle injections displayed NaLac-induced increases in autonomic responses (i.e. tachycardia and hypertensive responses), anxiety-like behaviour in the social interaction test, and flight-like increases in locomotor activity. However, systemically injecting such panic-prone rats with the highest dose of CRF1 receptor antagonist prior to NaLac infusions blocked all NaLac-induced behaviour and cardiovascular responses. These data suggest that selective CRF1 receptor antagonists could be a novel target for developing anti-panic drugs that are as effective as benzodiazepines in acute treatment of a panic attack without the deleterious side-effects (e.g. sedation and cognitive impairment) associated with benzodiazepines.
authors.affiliation: Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA. ashekhar@iupui.edu
authors.forename: Anantha
authors.initials: A
authors.lastname: Shekhar
authors.forename: Philip L
authors.initials: PL
authors.lastname: Johnson
authors.forename: Stephanie D
authors.initials: SD
authors.lastname: Fitz
authors.forename: Atsuro
authors.initials: A
authors.lastname: Nakazato
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Chaki
authors.forename: Thomas
authors.initials: T
authors.lastname: Steckler
authors.forename: Mark
authors.initials: M
authors.lastname: Schmidt
mesh_terms: D000818:Animals; D001007:Anxiety / Q000503:physiopathology; D001522:Behavior, Animal / Q000187:drug effects*; D002320:Cardiovascular Physiological Phenomena / Q000187:drug effects*; D004302:Dorsomedial Hypothalamic Nucleus / Q000187:drug effects* / Q000503:physiopathology; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D007398:Interpersonal Relations; D008297:Male; D010200:Panic / Q000187:drug effects* / Q000502:physiology; D016584:Panic Disorder / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D010455:Peptides / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019354:Sodium Lactate; D005680:gamma-Aminobutyric Acid / Q000378:metabolism; D000099052:CRF Receptor, Type 1
chemical_list: D010455:Peptides; D018019:Receptors, Corticotropin-Releasing Hormone; D005680:gamma-Aminobutyric Acid; D000099052:CRF Receptor, Type 1; D005998:Glycine; D019354:Sodium Lactate