Anxiolytic effects of flesinoxan in the stress-induced hyperthermia paradigm in singly-housed mice are 5-HT 1A receptor mediated

Abstract

In the stress-induced hyperthermia paradigm in singly-housed male mice, two sequential rectal temperature measurements reveal the basal temperature ( T 1) and, 10 min later, an enhanced body temperature ( T 2), due to the stress of the first rectal measurement. The difference T 2− T 1 (Δ T) is the stress-induced hyperthermia and putatively reflects a stress-induced anxiogenic response. The full 5-HT 1A receptor agonist flesinoxan ((+)-enantiomer), its (−)-enantiomer and the racemic mixture reduced stress-induced hyperthermia effects, indicating putative anxiolytic properties. The ratio of their potencies to reduce stress-induced hyperthermia was similar to their potency in receptor binding affinities for 5-HT 1A receptors, supporting that the anti-hyperthermia effects are mediated by the 5-HT 1A receptor. This was further substantiated when the 5-HT 1A receptor antagonists WAY 100635 (( N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]- N-(2-pyridinyl) cyclo-hexane carboxamine trihydrochloride) and DU 125530 (2-[4-[4-(7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)-1-piperazinyl]butyl]-1,2-benzisothiazol-3(2H)-one-1,1-dioxide, monomesylate) both were able to antagonize the anti-stress-induced hyperthermia effects of flesinoxan. The stress-induced hyperthermia paradigm in singly-housed mice represents a simple and robust paradigm to measure putative anxiolytic effects of drugs.