Differential induction of 5-HT(1A)-mediated responses in vivo by three chemically dissimilar 5-HT(1A) agonists

In the rat, activation of 5-hydroxytryptamine(1A) (5-HT(1A)) receptors causes hypothermia and the 5-HT syndrome. The effects of three chemically dissimilar 5-HT(1A) agonists administered s.c. [8-hydroxy-2-(di-n- propylamino)tetralin (8-OH-DPAT), gepirone, and (+) 4-[n-5-(methoxychroman- 3-yl)n-propylamino]butyl-8-azaspiro[4,5]decane-7,adione ((+) S-20499)] on both of these responses were studied. The same maximal drop in body temperature (~2.5°C) was elicited by all three agonists, 8-OH-DPAT being the most potent (EC₅₀ = 0.05 mg/kg), followed by gepirone (1.8 mg/kg) and (+) S-20499 (8 mg/kg). Both pindolol, a nonselective 5-HT(1A) receptor/β adrenoceptor antagonist and n-t-butyl,-3-[1-[4-(2- methoxy)phenyl]piperazinyl]-1-phenylpropionamide [(+) WAY 100135], a more selective 5-HT(1A) receptor antagonist, dose dependently attenuated the hypothermia induced by all three agonists. From these data, we inferred that all three agonists caused hypothermia via activation of 5-HT(1A) receptors. The syndrome was observed reliably in rats at doses of 2 to 4 mg/kg 8-OH- DPAT; doses up to 100 mg/kg of gepirone or (+) S-20499 did not produce the syndrome. In reserpine-pretreated animals, 8-OH-DPAT (maximal effect at 2-4 mg/kg) and 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) (5 mg/kg) induced forepaw treading, whereas gepirone (10 mg/kg) and (+) S-20499 (75 mg/kg) did not. (+) WAY 100135 competitively antagonized the forepaw treading caused by 8-OH-DPAT in reserpine-pretreated rats. This indicates that forepaw treading, like hypothermia, is mediated by activation of 5-HT(1A) receptors. Gepirone (5-10 mg/kg) attenuated the forepaw treading induced by either 8-OH-DPAT (4 mg/kg) or 5-MeODMT (5 mg/kg); by contrast, (+) S-20499, at doses up to 75 mg/kg, did not attenuate the forepaw treading induced by either 8-OH-DPAT or 5-MeODMT. The inability of (+) S-20499 either to induce the 5-HT syndrome or forepaw treading or to attenuate the forepaw treading induced by other agonists could be due to several factors, one of which is that different subtypes of the 5-HT(1A) receptor mediate hypothermia and the 5-HT syndrome.