Reduction of 5-hydroxytryptamine (5-HT)(1A)-mediated temperature and neuroendocrine responses and 5-HT(1A) binding sites in 5-HT transporter knockout mice.

Abstract

The aim of the present study was to determine whether alterations in 5-hydroxytryptamine (5-HT)(1A) receptors would be found in knockout mice lacking the serotonin transporter (5-HTT). Hypothermic and neuroendocrine responses to the 5-HT(1A) agonist 8-hydroxy-2-(di-n-propylamino)tetraline (8-OH-DPAT) were used to examine the function of 5-HT(1A) receptors. Initial studies evaluated the dose-response and time course of 8-OH-DPAT-induced hypothermia and hormone secretion in normal CD-1 mice (the background strain of the 5-HTT knockout mice). 8-OH-DPAT dose-dependently produced hypothermic responses that peaked at 20 min postinjection. 8-OH-DPAT-induced hypothermia was blocked by the 5-HT(1A) antagonist WAY-100635. 8-OH-DPAT dose-dependently increased the concentrations of plasma oxytocin, corticotropin, and corticosterone. In the 5-HTT knockout (-/-) mice, the hypothermic response to 8-OH-DPAT (0.1 mg/kg s.c.) was completely abolished. Furthermore, 5-HTT-/- mice had significantly attenuated plasma oxytocin and corticosterone responses to 8-OH-DPAT. No significant changes in the hypothermic or hormonal responses to 8-OH-DPAT were observed in heterozygous (5-HTT+/-) mice. [(3)H]8-OH-DPAT- and [(125)I]MPPI [4-(2'-methoxyphenyl)-1-[2'-[N-(2"-pyridinyl)-iodobenzamido]ethyl] pip erazine]-binding sites in the hypothalamus and [(125)I]MPPI-binding sites in the dorsal raphe were significantly decreased in 5-HTT-/- mice. The results indicate that lack of the 5-HTT is associated with a functional desensitization of 5-HT(1A) receptor responses to 8-OH-DPAT, which may be a consequence, at least in part, of the decrease in density of 5-HT(1A) receptors in the hypothalamus and dorsal raphe of 5-HTT-/- mice.

• Authors: Q Li, C Wichems, A Heils, L D Van De Kar, K P Lesch, D L Murphy
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 291 Issue 3 Pg. 999-1007 (Dec 1999) ISSN: 0022-3565 [Print] United States
• PMID: 10565817 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Aminopyridines
• Carrier Proteins
• Membrane Glycoproteins
• Membrane Transport Proteins
• Nerve Tissue Proteins
• Piperazines
• Pyridines
• Receptors, Serotonin
• Receptors, Serotonin, 5-HT1
• Serotonin Antagonists
• Serotonin Plasma Membrane Transport Proteins
• Serotonin Receptor Agonists
• Slc6a4 protein, mouse
• 4-(2'-methoxyphenyl)-1-(2'-(N-(2''-pyridinyl)-4-iodobenzamido)ethyl)piperazine
• Serotonin
• Oxytocin
• N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide
• 8-Hydroxy-2-(di-n-propylamino)tetralin
• Adrenocorticotropic Hormone
• Corticosterone

Topics

• 8-Hydroxy-2-(di-n-propylamino)tetralin (pharmacology)
• Adrenocorticotropic Hormone (blood)
• Aminopyridines (pharmacokinetics)
• Animals
• Autoradiography
• Body Temperature (drug effects)
• Carrier Proteins (genetics, metabolism)
• Corticosterone (blood)
• Dose-Response Relationship, Drug
• Hypothalamus (drug effects, metabolism)
• Membrane Glycoproteins (genetics, metabolism)
• Membrane Transport Proteins
• Mice
• Mice, Knockout
• Nerve Tissue Proteins
• Neurosecretory Systems (drug effects, metabolism)
• Oxytocin (blood)
• Piperazines (pharmacokinetics, pharmacology)
• Pyridines (pharmacology)
• Raphe Nuclei (drug effects, metabolism)
• Receptors, Serotonin (drug effects, genetics)
• Receptors, Serotonin, 5-HT1
• Serotonin (metabolism)
• Serotonin Antagonists (pharmacology)
• Serotonin Plasma Membrane Transport Proteins
• Serotonin Receptor Agonists (pharmacology)
• Time Factors