TY - JOUR T1 - Altered Brain Serotonin Homeostasis and Locomotor Insensitivity to 3,4-Methylenedioxymethamphetamine (“Ecstasy”) in Serotonin Transporter-Deficient Mice JF - Molecular Pharmacology JO - Mol Pharmacol SP - 649 LP - 655 DO - 10.1124/mol.53.4.649 VL - 53 IS - 4 AU - Dietmar Bengel AU - Dennis L. Murphy AU - Anne M. Andrews AU - Christine H. Wichems AU - Douglas Feltner AU - Armin Heils AU - Rainald Mössner AU - Heiner Westphal AU - Klaus-Peter Lesch Y1 - 1998/04/01 UR - http://molpharm.aspetjournals.org/content/53/4/649.abstract N2 - 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]3β-(4′-iodophenyl)tropan-2β-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. ER -