The GABAB receptor positive modulator BHF177 attenuated anxiety, but not conditioned fear, in rats

NEUROPHARMACOLOGY

卷:97

Article

Li, Xia¹  Kaczanowska, Katarzyna²  Finn, M. G.³  Markou, Athina¹  Risbrough, Victoria B.^1,4 

[1] Univ Calif San Diego, Dept Psychiat, Hlth Sci, La Jolla, CA 92093 USA

[2] Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, La Jolla, CA 92093 USA

[3] Georgia Inst Technol, Sch Chem & Biochem, Atlanta, GA 30332 USA

[4] Vet Affairs Ctr Excellence Stress & Mental Hlth, La Jolla, CA USA

关键词: GABA(B) receptor;    Positive allosteric modulator;    Anxiety;    Fear;    Startle;   

DOI  :  10.1016/j.neuropharm.2015.05.001

来源: Elsevier

【 摘 要 】

GABA(B) (gamma-aminobutyric acid B) receptors may be a therapeutic target for anxiety disorders. Here we characterized the effects of the GABA(B) 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 GABA(B) 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 GABA(B) receptor PAMs may be promising compounds for alleviating increased anxiety seen in various psychiatric disorders with a superior side-effect profile compared GABA(B) receptor agonists. Published by Elsevier Ltd.

【 授权许可】

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