8-OH-DPAT acts on both 5-HT1A and 5-HT7 receptors to induce hypothermia in rodents

Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
European Journal of Pharmacology (Impact Factor: 2.53). 04/2004; 487(1-3):125-32. DOI: 10.1016/j.ejphar.2004.01.031
Source: PubMed


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.

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Available from: Pascal Bonaventure, Sep 09, 2015
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    • "It has been proposed that 5-HT7 receptors, possessing the highest affinity for 5-HT, are activated by low doses of 5-HT and are responsible for the fine-tuning of body temperature. On the other hand, higher agonist concentrations activate 5-HT1A receptors, which might play a role as a defense against hyperthermia (Hedlund et al., 2004). "
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    • "One of them, 8-OH-DPAT, is an aminotetralin derivative which was developed in the 1980s and was one of the first major 5-HT 1A receptor agonists to be discovered [10]. 8-OH-DPAT has been extensively used in pharmacological studies characterizing 5-HT 1A [35], although it was later found to act as a 5-HT 7 receptor agonist [36]. Other compounds acting on 5-HT 1A receptors exhibit similar complex pharmacological profiles. "
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    • "In addition, (±)-8-OH-DPAT effectively alleviated the fluoxetine enhancement of haloperidol-induced EPS. Although (±)- 8-OH-DPAT has an affinity not only for 5-HT 1A receptors, but also for 5-HT 7 receptors (Hedlund et al., 2004), the reversal of the fluoxetine enhancement of EPS with (±)-8-OH-DPAT was abolished by the selective 5-HT 1A antagonist (S)-WAY-100135. The dosage (5–20 mg/kg) of fluoxetine used herein was in a range that reportedly inhibits 5-HT reuptake and increases the extracellular level of 5-HT (Paez and Leibowitz, 1993; Perry and Fuller, 1992). "
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