Anxiolytic effects of flesinoxan in the stress-induced hyperthermia paradigm in singly-housed mice are 5-HT1A receptor mediated.
In the stress-induced hyperthermia paradigm in singly-housed male mice, two sequential rectal temperature measurements reveal the basal temperature (T1) and, 10 min later, an enhanced body temperature (T2), due to the stress of the first rectal measurement. The difference T2 - T1 (deltaT) is the stress-induced hyperthermia and putatively reflects a stress-induced anxiogenic response. The full 5-HT1A 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-HT1A receptors, supporting that the anti-hyperthermia effects are mediated by the 5-HT1A receptor. This was further substantiated when the 5-HT1A 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.
Olivier
B
B
CNS-Pharmacology, Solvay Pharmaceuticals, Weesp, The Netherlands. berend.olivier@solvay.com
Zethof
T J
TJ
Ronken
E
E
van der Heyden
J A
JA
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001831:Body Temperature / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006979:Hyperthermia, Induced; D008297:Male; D051379:Mice; D010879:Piperazines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D011985:Receptors, Serotonin / Q000187:drug effects / Q000502:physiology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D012934:Social Isolation; D013237:Stereoisomerism; D013315:Stress, Psychological / Q000503:physiopathology*; D013844:Thiazoles / Q000494:pharmacology
D014151:Anti-Anxiety Agents; D010879:Piperazines; D011725:Pyridines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D013844:Thiazoles; C056895:flesinoxan; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; C106973:1,2-benzisothiazol-3(2H)-one, 2-(4-(4-(7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)-1-piperazinyl)butyl)-, 1,1-dioxide