8-OH-DPAT acts on both 5-HT1A and 5-HT7 receptors to induce hypothermia in rodents.
ABSTRACT Studies using selective drugs and knockout mice have demonstrated that the 5-HT(7) receptor plays an instrumental role in serotonin-induced hypothermia. There is also evidence supporting an involvement of the 5-HT(1A) receptor, although mainly from studies using 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT), a 5-HT(1A/7) receptor agonist. Here we studied the effects of 8-OH-DPAT and selective antagonists for the 5-HT(1A) and 5-HT(7) receptors on body temperature in rats, wild-type (5-HT(7)(+/+)) mice and knockout (5-HT(7)(-/-)) mice. At lower doses (0.3-0.6 mg/kg, i.p.), 8-OH-DPAT decreased body temperature in 5-HT(7)(+/+) mice but not in 5-HT(7)(-/-) mice. At a higher dose (1 mg/kg, i.p.) 8-OH-DPAT induced hypothermia in both 5-HT(7)(-/-) and 5-HT(7)(+/+) mice. The 5-HT(1A) receptor antagonist (S)-N-tert-butyl-3-(4-(2-methoxyphenyl)piperazine-1-yl)-2-phenylpropanamide (WAY-100135) (10 mg/kg, i.p.) inhibited the effect of 8-OH-DPAT at all doses in rats and mice. In 5-HT(7)(+/+) mice the selective 5-HT(7) receptor antagonist (R)-3-(2-(2-(4-methylpiperidin-1-yl)-ethyl)pyrrolidine-1-sulfonyl)phenol (SB-269970) (10 mg/kg, i.p.) fully inhibited the hypothermia induced by 0.3 mg/kg 8-OH-DPAT, but not that of higher doses. In rats, SB-269970 caused a 60% inhibition of the hypothermia induced by 0.3 mg/kg 8-OH-DPAT. Thus, both 5-HT(7) and 5-HT(1A) receptors are involved in a complex manner in thermoregulation, with the 5-HT(7) receptor being more important at lower, possibly more physiological, concentrations.
- Journal of Neurochemistry - J NEUROCHEM. 01/2002; 68(4):1372-1381.
- [show abstract] [hide abstract]
ABSTRACT: In vivo microdialysis measuring 5-hydroxytryptamine (5-HT) levels in the ventral hippocampus of chloral hydrate-anaesthetised rats was used to characterise further the recently described 5-HT1A receptor antagonists (S)-WAY100135 ((S)-N-tert-butyl-3-(4-(2-methoxyphenyl)piperazine-1-yl)-2- phenylpropanamide) and WAY100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl] ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide). In addition, binding experiments were performed to determine the affinity of the compounds for 5-HT1A receptors and for alpha 1-adrenoceptors. Both (S)-WAY100135 and WAY100635 exhibited high affinity for 5-HT1A receptors and moderate affinity for alpha 1-adrenoceptors. The effects of (S)-WAY100135 (0.63-20 mg/kg) and of WAY100635 (0.0025-0.16 mg/kg) on 5-HT levels were examined alone, and in combination with the 5-HT1A receptor agonist, (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). Both compounds dose-dependently reversed the 8-OH-DPAT-induced decrease in extracellular 5-HT levels with ED50 values of approximately 3.3 and 0.03 mg/kg, respectively. When given alone, WAY100635 did not alter 5-HT levels. (S)-WAY100135, however, induced, by itself, a transient but significant and dose-dependent decrease in 5-HT levels. WAY100635 (0.16 mg/kg) prevented the decrease induced by (S)-WAY100135 (10 mg/kg), but did not reverse the decrease induced by the alpha 1-adrenoceptor antagonist, prazosin (0.16 mg/kg). These results are further evidence that (S)-WAY100135 may modulate the release of 5-HT by acting as a partial agonist at somatodendritic 5-HT1A receptors. In contrast, WAY100635 acts as a potent and selective 5-HT1A receptor antagonist.European Journal of Pharmacology 06/1996; 304(1-3):15-21. · 2.59 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: We report the cloning and characterization of a novel serotonin receptor, designated as 5-HT7, which is coupled to the stimulation of adenylyl cyclase. 5-HT7 mRNA is expressed discretely throughout the CNS, predominantly in the thalamus and hypothalamus. 5-HT7 has a unique pharmacological profile that redefines agonist and antagonist classification of ligands previously thought to be "selective." The circadian phase of spontaneous neuronal activity of the rat suprachiasmatic nucleus of the hypothalamus advances in response to serotonin ligands with a pharmacological profile consistent exclusively with that of 5-HT7. These findings suggest a physiological role in the regulation of circadian rhythms for one subtype of serotonin receptor, 5-HT7, and provide a pharmacological test to evaluate its role in other neuronal systems.Neuron 10/1993; 11(3):449-58. · 15.77 Impact Factor