title: The GABA(B) receptor positive modulator BHF177 attenuated anxiety, but not conditioned fear, in rats.
abstract: GABAB (γ-aminobutyric acid B) receptors may be a therapeutic target for anxiety disorders. Here we characterized the effects of the GABAB receptor positive allosteric modulator (PAM) BHF177 on conditioned and unconditioned physiological responses to threat in the light-enhanced startle (LES), stress-induced hyperthermia, and fear-potentiated startle (FPS) procedures in rats. The effects of BHF177 on LES were compared with those of the GABAB receptor agonists baclofen and CGP44532, and the positive control buspirone, a 5-HT1A receptor partial agonist with anxiolytic activity in humans. Baclofen (0.4, 0.9 and 1.25 mg/kg) and CGP44532 (0.065, 0.125 and 0.25 mg/kg) administration had significant sedative, but not anxiolytic, activity reflected in overall decrease in the startle response in the LES tests. BHF177 (10, 20 and 40 mg/kg) had no effect on LES, nor did it produce an overall sedative effect. Interesting, however, when rats were grouped by high and low LES responses, BHF177 had anxiolytic-like effects only on LES in high, but not low, LES responding rats. BHF177 also blocked stress-induced hyperthermia, but had no effect on conditioned fear responses in the FPS test. Buspirone (1 and 3 mg/kg) had an anxiolytic-like profile in both LES and FPS tests. These results indicate that BHF177 may specifically attenuate unconditioned anxiety in individuals that exhibit a high anxiety state, and has fewer sedative effects than direct agonists. Thus, BHF177 or other GABAB receptor PAMs may be promising compounds for alleviating increased anxiety seen in various psychiatric disorders with a superior side-effect profile compared to GABAB receptor agonists.
authors.affiliation: Department of Psychiatry, Health Sciences, University of California San Diego, La Jolla, CA, USA.
authors.forename: Xia
authors.initials: X
authors.lastname: Li
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kaczanowska
authors.affiliation: School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332, USA.
authors.forename: M G
authors.initials: MG
authors.lastname: Finn
authors.affiliation: Department of Psychiatry, Health Sciences, University of California San Diego, La Jolla, CA, USA.
authors.forename: Athina
authors.initials: A
authors.lastname: Markou
authors.affiliation: Department of Psychiatry, Health Sciences, University of California San Diego, La Jolla, CA, USA; Veterans Affairs Center of Excellence for Stress and Mental Health, La Jolla, CA, USA. Electronic address: vrisbrough@ucsd.edu.
authors.forename: Victoria B
authors.initials: VB
authors.lastname: Risbrough
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D001007:Anxiety / Q000188:drug therapy* / Q000503:physiopathology; D001418:Baclofen / Q000494:pharmacology; D002065:Buspirone / Q000494:pharmacology; D003214:Conditioning, Classical / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005239:Fear / Q000187:drug effects* / Q000502:physiology; D005334:Fever / Q000188:drug therapy / Q000503:physiopathology; D018757:GABA Modulators / Q000494:pharmacology*; D008297:Male; D009636:Norbornanes / Q000494:pharmacology*; D010721:Phosphinic Acids / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology*; D017208:Rats, Wistar; D018080:Receptors, GABA-B / Q000378:metabolism; D013216:Reflex, Startle / Q000187:drug effects* / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C112036:3-amino-2-(S)-hydroxypropyl-methyl-phosphinic acid; D014151:Anti-Anxiety Agents; D018757:GABA Modulators; C560183:N-(bicyclo(2.2.1)hept-2-yl)-2-methyl-5-(4-(trifluoromethyl)phenyl)-4-pyrimidinamine; D009636:Norbornanes; D010721:Phosphinic Acids; D011743:Pyrimidines; D018080:Receptors, GABA-B; D005680:gamma-Aminobutyric Acid; D001418:Baclofen; D002065:Buspirone
keywords: Anxiety; Fear; GABA(B) receptor; Positive allosteric modulator; Startle