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Vol. 291, Issue 3, 999-1007, December 1999
Laboratory of Clinical Science, National Institute of Mental
Health, National Institutes of Health Clinical Center, Bethesda,
Maryland (Q.L., C.W., A.H., D.L.M.); Department of Pharmacology,
Stritch School of Medicine, Loyola University of Chicago, Maywood,
Illinois (L.D.V. de K.); and Department of Psychiatry, University of
Wurzburg, Wurzburg, Germany (K.-P.L.)
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-HT1A agonist
8-hydroxy-2-(di-n-propylamino)tetraline (8-OH-DPAT) were
used to examine the function of 5-HT1A 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-HT1A 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. [3H]8-OH-DPAT-
and [125I]MPPI
[4-(2'-methoxyphenyl)-1-[2'-[N-(2"-pyridinyl)-iodobenzamido]ethyl]piperazine]-binding sites in the hypothalamus and [125I]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-HT1A receptor responses to 8-OH-DPAT,
which may be a consequence, at least in part, of the decrease in
density of 5-HT1A receptors in the hypothalamus and dorsal
raphe of 5-HTT/ mice.
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