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Vol. 53, Issue 4, 649-655, April 1998
Laboratory of Clinical Science, National Institute of Mental
Health, Bethesda, Maryland 20892-1264 (D.B., D.L.M., A.M.A., C.H.W.),
Laboratory of Mammalian Genes and Development, National Institute of
Child Health and Human Development, Bethesda, Maryland 20982 (D.F.,
H.W.),
Department of Psychiatry, University of Würzburg, 97080 Würzburg, Germany (A.H., R.M., K.-P.L.)
The sodium-dependent, high affinity serotonin [5-hydroxytryptamine
(5-HT)] transporter (5-HTT) provides the primary mechanism for
inactivation of 5-HT after its release into the synaptic cleft. To
further evaluate the function of the 5-HTT, the murine gene was
disrupted by homologous recombination. Despite evidence that excess
extracellular 5-HT during embryonic development, including that
produced by drugs that inhibit the 5-HTT, may lead to severe craniofacial and cardiac malformations, no obvious developmental phenotype was observed in the 5-HTT
/ mice. High
affinity [3H]5-HT uptake was completely absent in
5-HTT/ mice, confirming a physiologically effective
knockout of the 5-HTT gene. 5-HTT binding sites labeled with
[125I]3
-(4'-iodophenyl)tropan-2-carboxylic acid
methyl ester were reduced in a gene dose-dependent manner, with no
demonstrable binding in 5-HTT/ mutants. In adult
5-HTT/ mice, marked reductions (60-80%) in 5-HT
concentrations were measured in several brain regions. While
(+)-amphetamine-induced hyperactivity did not differ across genotypes,
the locomotor enhancing effects of
(+)-3,4-methylenedioxymethamphetamine, a substituted amphetamine that
releases 5-HT via a transporter-dependent mechanism, was completely
absent in 5-HTT/ mutants. Together, these data suggest
that the presence of a functional 5-HTT is essential for brain
5-HT homeostasis and for 3,4-methylenedioxymethamphetamine-induced
hyperactivity.
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