, Volume 195, Issue 2, pp 147–166 | Cite as

A pharmacological analysis of mice with a targeted disruption of the serotonin transporter

  • Meredith A. Fox
  • Anne M. Andrews
  • Jens R. Wendland
  • Klaus-Peter Lesch
  • Andrew Holmes
  • Dennis L. Murphy



Partial or complete ablation of serotonin transporter (SERT) expression in mice leads to altered responses to serotonin receptor agonists and other classes of drugs.


In the current report, we review and integrate many of the major behavioral, physiological, and neurochemical findings in the current literature regarding pharmacological assessments made in SERT mutant mice.


The absence of normal responses to serotonin reuptake inhibiting (SRI) antidepressants in SERT knockout (−/−) mice demonstrates that actions on SERT are a critical principle mechanism of action of members of this class of antidepressants. Drugs transported by SERT, (+)-3,4-methylenedioxymethamphetamine (MDMA) and 1-methyl-4-(2′-aminophenyl)-1,2,3,6-tetrahydropyridine (2′-NH2-MPTP), are also inactive in SERT −/− mice. Temperature, locomotor, and electrophysiological responses to various serotonin receptor agonists, including 8-hydroxy-2-(di-n-propylamino)-tetraline (8-OH-DPAT), ipsapirone, and RU24969, are reduced in SERT −/− mice, despite comparatively lesser reductions in Htr1a and Htr1b binding sites, G-proteins, and other signaling molecules. SERT −/− mice exhibit an ∼90% reduction in head twitches in response to the Htr2a/2c agonist (+/−)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), associated with a profound reduction in arachidonic acid signaling, yet only modest changes in Htr2a and Htr2c binding sites. SERT −/− mice also exhibit altered behavioral responses to cocaine and ethanol, related to abnormal serotonin, and possibly dopamine and norepinephrine, homeostasis.


Together, these studies demonstrate a complex and varied array of modified drug responses after constitutive deletion of SERT and provide insight into the role of serotonin, and in particular, its transporter, in the modulation of complex behavior and in the pharmacological actions of therapeutic agents and drugs of abuse.


Serotonin Serotonin transporter (SERT) Knockout mice Pharmacology 


  1. Adrien J (2002) Neurobiological bases for the relation between sleep and depression. Sleep Med Rev 6:341–351PubMedGoogle Scholar
  2. Alexandre C, Popa D, Fabre V, Bouali S, Venault P, Lesch KP, Hamon M, Adrien J (2006) Early life blockade of 5-hydroxytryptamine 1A receptors normalizes sleep and depression-like behavior in adult knock-out mice lacking the serotonin transporter. J Neurosci 26:5554–5564PubMedGoogle Scholar
  3. Andrews AM, Murphy DL (1993a) 2′-NH2-MPTP in Swiss Webster mice: evidence for long-term (6-month) depletions in cortical and hippocampal serotonin and norepinephrine, differential protection by selective uptake inhibitors or clorgyline and functional changes in central serotonin neurotransmission. J Pharmacol Exp Ther 267:1432–1439PubMedGoogle Scholar
  4. Andrews AM, Murphy DL (1993b) Fluoxetine and desipramine selectively attenuate 2′-NH2-MPTP-induced depletions in serotonin and norepinephrine. Eur J Pharmacol 250:215–221PubMedGoogle Scholar
  5. Andrews AM, Murphy DL (1993c) Sustained depletion of cortical and hippocampal serotonin and norepinephrine but not striatal dopamine by 1-methyl-4-(2′-aminophenyl)-1,2,3,6-tetrahydropyridine (2′-NH2-MPTP): a comparative study with 2′-CH3-MPTP and MPTP. J Neurochem 60:1167–1170PubMedGoogle Scholar
  6. Ansorge MS, Zhou M, Lira A, Hen R, Gingrich JA (2004) Early-life blockade of the 5-HT transporter alters emotional behavior in adult mice. Science 306:879–881PubMedGoogle Scholar
  7. Bagdy G (1996) Role of the hypothalamic paraventricular nucleus in 5-HT1A, 5-HT2A and 5-HT2C receptor-mediated oxytocin, prolactin and ACTH/corticosterone responses. Behav Brain Res 73:277–280PubMedGoogle Scholar
  8. Bengel D, Johren O, Andrews AM, Heils A, Mossner R, Sanvitto GL, Saavedra JM, Lesch KP, Murphy DL (1997) Cellular localization and expression of the serotonin transporter in mouse brain. Brain Res 778:338–345PubMedGoogle Scholar
  9. Bengel D, Murphy DL, Andrews AM, Wichems CH, Feltner D, Heils A, Mossner R, Westphal H, Lesch KP (1998) Altered brain serotonin homeostasis and locomotor insensitivity to 3, 4-methylenedioxymethamphetamine (“Ecstasy”) in serotonin transporter-deficient mice. Mol Pharmacol 53:649–655PubMedGoogle Scholar
  10. Bill DJ, Knight M, Forster EA, Fletcher A (1991) Direct evidence for an important species difference in the mechanism of 8-OH-DPAT-induced hypothermia. Br J Pharmacol 103:1857–1864PubMedGoogle Scholar
  11. Bonaventure P, Umans L, Bakker MH, Cras P, Langlois X, Luyten WH, Megens AA, Serneels L, Van Leuven F, Leysen JE (1999) Humanization of mouse 5-hydroxytryptamine1B receptor gene by homologous recombination: in vitro and in vivo characterization. Mol Pharmacol 56:54–67PubMedGoogle Scholar
  12. Bouali S, Evrard A, Chastanet M, Lesch KP, Hamon M, Adrien J (2003) Sex hormone-dependent desensitization of 5-HT1A autoreceptors in knockout mice deficient in the 5-HT transporter. Eur J Neurosci 18:2203–2212PubMedGoogle Scholar
  13. Boyce-Rustay JM, Wiedholz LM, Millstein RA, Carroll J, Murphy DL, Daws LC, Holmes A (2006) Ethanol-related behaviors in serotonin transporter knockout mice. Alcohol Clin Exp Res 30:1957–1965PubMedGoogle Scholar
  14. Cryan JF, Holmes A (2005) The ascent of mouse: advances in modelling human depression and anxiety. Nat Rev Drug Discov 4:775–790PubMedGoogle Scholar
  15. D’Amato RJ, Blue ME, Largent BL, Lynch DR, Ledbetter DJ, Molliver ME, Snyder SH (1987) Ontogeny of the serotonergic projection to rat neocortex: transient expression of a dense innervation to primary sensory areas. Proc Natl Acad Sci U S A 84:4322–4326PubMedGoogle Scholar
  16. Dailey JW, Reith ME, Yan QS, Li MY, Jobe PC (1997a) Anticonvulsant doses of carbamazepine increase hippocampal extracellular serotonin in genetically epilepsy-prone rats: dose response relationships. Neurosci Lett 227:13–16PubMedGoogle Scholar
  17. Dailey JW, Reith ME, Yan QS, Li MY, Jobe PC (1997b) Carbamazepine increases extracellular serotonin concentration: lack of antagonism by tetrodotoxin or zero Ca2+. Eur J Pharmacol 328:153–162PubMedGoogle Scholar
  18. Daws LC, Montanez S, Munn JL, Owens WA, Baganz NL, Boyce-Rustay JM, Millstein RA, Wiedholz LM, Murphy DL, Holmes A (2006) Ethanol inhibits clearance of brain serotonin by a serotonin transporter-independent mechanism. J Neurosci 26:6431–6438PubMedGoogle Scholar
  19. Esaki T, Cook M, Shimoji K, Murphy DL, Sokoloff L, Holmes A (2005) Developmental disruption of serotonin transporter function impairs cerebral responses to whisker stimulation in mice. Proc Natl Acad Sci U S A 102:5582–5587PubMedGoogle Scholar
  20. Fabre V, Beaufour C, Evrard A, Rioux A, Hanoun N, Lesch KP, Murphy DL, Lanfumey L, Hamon M, Martres MP (2000) Altered expression and functions of serotonin 5-HT1A and 5-HT1B receptors in knock-out mice lacking the 5-HT transporter. Eur J Neurosci 12:2299–2310PubMedGoogle Scholar
  21. Fox MA, Jensen CL, Murphy DL (2006) Mediation of exaggerated serotonin syndrome-like behaviors and temperature responses in serotonin transporter knockout mice by 5-HT1A and 5-HT7 serotonin receptors: a possible model and mechanism for differential human vulnerability to the serotonin syndrome. Neuropsychopharmacology 31:S221–S222Google Scholar
  22. Fox MA, Murphy DL (2006) Exaggerated serotonin syndrome in serotonin transporter knockout mice. Int J Neuropsychopharmacol 9:S174–S175Google Scholar
  23. Garcia-Colunga J, Awad JN, Miledi R (1997) Blockage of muscle and neuronal nicotinic acetylcholine receptors by fluoxetine (Prozac). Proc Natl Acad Sci U S A 94:2041–2044PubMedGoogle Scholar
  24. Giros B, Jaber M, Jones SR, Wightman RM, Caron MG (1996) Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter. Nature 379:606–612PubMedGoogle Scholar
  25. Gobbi G, Murphy DL, Lesch K, Blier P (2001) Modifications of the serotonergic system in mice lacking serotonin transporters: an in vivo electrophysiological study. J Pharmacol Exp Ther 296:987–995PubMedGoogle Scholar
  26. González-Maeso J, Yuen T, Ebersole BJ, Wurmbach E, Lira A, Zhou M, Weisstaub N, Hen R, Gingrich JA, Sealfon SC (2003) Transcriptome fingerprints distinguish hallucinogenic and nonhallucinogenic 5-hydroxytryptamine 2A receptor agonist effects in mouse somatosensory cortex. J Neurosci 23:8836–8843PubMedGoogle Scholar
  27. Goodwin GM, De Souza RJ, Green AR (1985) The pharmacology of the hypothermic response in mice to 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). A model of presynaptic 5-HT1 function. Neuropharmacology 24:1187–1194PubMedGoogle Scholar
  28. Greenberg BD, Li Q, Lucas FR, Hu S, Sirota LA, Benjamin J, Lesch KP, Hamer D, Murphy DL (2000) Association between the serotonin transporter promoter polymorphism and personality traits in a primarily female population sample. Am J Med Genet 96:202–216PubMedGoogle Scholar
  29. Hall FS, Li XF, Sora I, Xu F, Caron M, Lesch KP, Murphy DL, Uhl GR (2002) Cocaine mechanisms: enhanced cocaine, fluoxetine and nisoxetine place preferences following monoamine transporter deletions. Neuroscience 115:153–161PubMedGoogle Scholar
  30. Hariri AR, Holmes A (2006) Genetics of emotional regulation: the role of the serotonin transporter in neural function. Trends Cogn Sci 10:182–191PubMedGoogle Scholar
  31. Heils A, Wichems C, Mossner R, Petri S, Glatz K, Bengel D, Murphy DL, Lesch KP (1998) Functional characterization of the murine serotonin transporter gene promoter in serotonergic raphe neurons. J Neurochem 70:932–939PubMedCrossRefGoogle Scholar
  32. Heydorn WE (1999) Paroxetine: a review of its pharmacology, pharmacokinetics and utility in the treatment of a variety of psychiatric disorders. Expert Opin Investig Drugs 8:417–441PubMedGoogle Scholar
  33. Holmes A, Murphy DL, Crawley JN (2002a) Reduced aggression in mice lacking the serotonin transporter. Psychopharmacology (Berl) 161:160–167Google Scholar
  34. Holmes A, Yang RJ, Murphy DL, Crawley JN (2002b) Evaluation of antidepressant-related behavioral responses in mice lacking the serotonin transporter. Neuropsychopharmacology 27:914–923PubMedGoogle Scholar
  35. Holmes A, Li Q, Murphy DL, Gold E, Crawley JN (2003a) Abnormal anxiety-related behavior in serotonin transporter null mutant mice: the influence of genetic background. Genes Brain Behav 2:365–380PubMedGoogle Scholar
  36. Holmes A, Murphy DL, Crawley JN (2003b) Abnormal behavioral phenotypes of serotonin transporter knockout mice: parallels with human anxiety and depression. Biol Psychiatry 54:953–959PubMedGoogle Scholar
  37. Holmes A, Yang RJ, Lesch KP, Crawley JN, Murphy DL (2003c) Mice lacking the serotonin transporter exhibit 5-HT(1A) receptor-mediated abnormalities in tests for anxiety-like behavior. Neuropsychopharmacology 28:2077–2088PubMedGoogle Scholar
  38. Hoyer D, Hannon JP, Martin GR (2002) Molecular, pharmacological and functional diversity of 5-HT receptors. Pharmacol Biochem Behav 71:533–554PubMedGoogle Scholar
  39. Hu XZ, Lipsky RH, Zhu G, Akhtar LA, Taubman J, Greenberg BD, Xu K, Arnold PD, Richter MA, Kennedy JL, Murphy DL, Goldman D (2006) Serotonin transporter promoter gain-of-function genotypes are linked to obsessive-compulsive disorder. Am J Hum Genet 78:815–826PubMedGoogle Scholar
  40. Jennings KA, Loder MK, Sheward WJ, Pei Q, Deacon RM, Benson MA, Olverman HJ, Hastie ND, Harmar AJ, Shen S, Sharp T (2006) Increased expression of the 5-HT transporter confers a low-anxiety phenotype linked to decreased 5-HT transmission. J Neurosci 26:8955–8964PubMedGoogle Scholar
  41. Jobe PC, Dailey JW, Wernicke JF (1999) A noradrenergic and serotonergic hypothesis of the linkage between epilepsy and affective disorders. Crit Rev Neurobiol 13:317–356PubMedGoogle Scholar
  42. Jones BJ, Blackburn TP (2002) The medical benefit of 5-HT research. Pharmacol Biochem Behav 71:555–568PubMedGoogle Scholar
  43. Kalueff AV, Fox MA, Gallagher PS, Murphy DL (2007) Hypolocomotion, anxiety and serotonin syndrome-like behavior contribute to the complex phenotype of serotonin transporter knockout mice. Genes Brain Behav 6:389–400PubMedGoogle Scholar
  44. Këlai S, Aissi F, Lesch KP, Cohen-Salmon C, Hamon M, Lanfumey L (2003) Alcohol intake after serotonin transporter inactivation in mice. Alcohol Alcohol 38:386–389PubMedGoogle Scholar
  45. Kim DK, Tolliver TJ, Huang SJ, Martin BJ, Andrews AM, Wichems C, Holmes A, Lesch KP, Murphy DL (2005) Altered serotonin synthesis, turnover and dynamic regulation in multiple brain regions of mice lacking the serotonin transporter. Neuropharmacology 49:798–810PubMedGoogle Scholar
  46. Kobayashi T, Washiyama K, Ikeda K (2003) Inhibition of G protein-activated inwardly rectifying K+ channels by fluoxetine (Prozac). Br J Pharmacol 138:1119–1128PubMedGoogle Scholar
  47. Lenkey N, Karoly R, Kiss JP, Szasz BK, Vizi ES, Mike A (2006) The mechanism of activity-dependent sodium channel inhibition by the antidepressants fluoxetine and desipramine. Mol Pharmacol 70:2052–2063PubMedGoogle Scholar
  48. Lesch KP, Balling U, Gross J, Strauss K, Wolozin BL, Murphy DL, Riederer P (1994) Organization of the human serotonin transporter gene. J Neural Transm Gen Sect 95:157–162PubMedGoogle Scholar
  49. Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S, Benjamin J, Muller CR, Hamer DH, Murphy DL (1996) Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 274:1527–1531PubMedGoogle Scholar
  50. Lesch KP, Meyer J, Glatz K, Flugge G, Hinney A, Hebebrand J, Klauck SM, Poustka A, Poustka F, Bengel D, Mossner R, Riederer P, Heils A (1997) The 5-HT transporter gene-linked polymorphic region (5-HTTLPR) in evolutionary perspective: alternative biallelic variation in rhesus monkeys. Rapid communication. J Neural Transm 104:1259–1266PubMedGoogle Scholar
  51. Li Q, Wichems C, Heils A, Van De Kar LD, Lesch KP, Murphy DL (1999) Reduction of 5-hydroxytryptamine (5-HT)(1A)-mediated temperature and neuroendocrine responses and 5-HT(1A) binding sites in 5-HT transporter knockout mice. J Pharmacol Exp Ther 291:999–1007PubMedGoogle Scholar
  52. Li Q, Wichems C, Heils A, Lesch KP, Murphy DL (2000) Reduction in the density and expression, but not G-protein coupling, of serotonin receptors (5-HT1A) in 5-HT transporter knock-out mice: gender and brain region differences. J Neurosci 20:7888–7895PubMedGoogle Scholar
  53. Li Q, Wichems CH, Ma L, Van de Kar LD, Garcia F, Murphy DL (2003) Brain region-specific alterations of 5-HT2A and 5-HT2C receptors in serotonin transporter knockout mice. J Neurochem 84:1256–1265PubMedGoogle Scholar
  54. Li Q, Holmes A, Ma L, Van de Kar LD, Garcia F, Murphy DL (2004a) Medial hypothalamic 5-hydroxytryptamine (5-HT)1A receptors regulate neuroendocrine responses to stress and exploratory locomotor activity: application of recombinant adenovirus containing 5-HT1A sequences. J Neurosci 24:10868–10877PubMedGoogle Scholar
  55. Li Q, Ma L, Innis RB, Seneca N, Ichise M, Huang H, Laruelle M, Murphy DL (2004b) Pharmacological and genetic characterization of two selective serotonin transporter ligands: 2-[2-(dimethylaminomethylphenylthio)]-5-fluoromethylphenylamine (AFM) and 3-amino-4-[2-(dimethylaminomethyl-phenylthio)]benzonitrile (DASB). J Pharmacol Exp Ther 308:481–486PubMedGoogle Scholar
  56. Lira A, Zhou M, Castanon N, Ansorge MS, Gordon JA, Francis JH, Bradley-Moore M, Lira J, Underwood MD, Arango V, Kung HF, Hofer MA, Hen R, Gingrich JA (2003) Altered depression-related behaviors and functional changes in the dorsal raphe nucleus of serotonin transporter-deficient mice. Biol Psychiatry 54:960–971PubMedGoogle Scholar
  57. Lu KT, Gean PW (1998) Endogenous serotonin inhibits epileptiform activity in rat hippocampal CA1 neurons via 5-hydroxytryptamine1A receptor activation. Neuroscience 86:729–737PubMedGoogle Scholar
  58. Mannoury la Cour C, Boni C, Hanoun N, Lesch KP, Hamon M, Lanfumey L (2001) Functional consequences of 5-HT transporter gene disruption on 5-HT(1a) receptor-mediated regulation of dorsal raphe and hippocampal cell activity. J Neurosci 21:2178–2185PubMedGoogle Scholar
  59. Mannoury la Cour C, Hanoun N, Melfort M, Hen R, Lesch KP, Hamon M, Lanfumey L (2004) GABA(B) receptors in 5-HT transporter- and 5-HT1A receptor-knock-out mice: further evidence of a transduction pathway shared with 5-HT1A receptors. J Neurochem 89:886–896PubMedGoogle Scholar
  60. Martin KF, Phillips I, Hearson M, Prow MR, Heal DJ (1992) Characterization of 8-OH-DPAT-induced hypothermia in mice as a 5-HT1A autoreceptor response and its evaluation as a model to selectively identify antidepressants. Br J Pharmacol 107:15–21PubMedGoogle Scholar
  61. Mathews TA, Fedele DE, Coppelli FM, Avila AM, Murphy DL, Andrews AM (2004) Gene dose-dependent alterations in extraneuronal serotonin but not dopamine in mice with reduced serotonin transporter expression. J Neurosci Methods 140:169–181PubMedGoogle Scholar
  62. Molteni R, Calabrese F, Bedogni F, Tongiorgi E, Fumagalli F, Racagni G, Riva MA (2006) Chronic treatment with fluoxetine up-regulates cellular BDNF mRNA expression in rat dopaminergic regions. Int J Neuropsychopharmacol 9:307–317PubMedGoogle Scholar
  63. Montañez S, Owens WA, Gould GG, Murphy DL, Daws LC (2003) Exaggerated effect of fluvoxamine in heterozygote serotonin transporter knockout mice. J Neurochem 86:210–219PubMedGoogle Scholar
  64. Mossner R, Schmitt A, Hennig T, Benninghoff J, Gerlach M, Riederer P, Deckert J, Lesch KP (2004) Quantitation of 5HT3 receptors in forebrain of serotonin transporter deficient mice. J Neural Transm 111:27–35PubMedGoogle Scholar
  65. Mossner R, Simantov R, Marx A, Lesch KP, Seif I (2006) Aberrant accumulation of serotonin in dopaminergic neurons. Neurosci Lett 401:49–54PubMedGoogle Scholar
  66. Murphy DL, Andrews AM, Wichems CH, Li Q, Tohda M, Greenberg B (1998) Brain serotonin neurotransmission: an overview and update with an emphasis on serotonin subsystem heterogeneity, multiple receptors, interactions with other neurotransmitter systems, and consequent implications for understanding the actions of serotonergic drugs. J Clin Psychiatry 59(Suppl 15):4–12PubMedGoogle Scholar
  67. Numis AL, Unger EL, Sheridan DL, Chisnell AC, Andrews AM (2004) The role of membrane and vesicular monoamine transporters in the neurotoxic and hypothermic effects of 1-methyl-4-(2′-aminophenyl)-1,2,3,6-tetrahydropyridine (2′-NH(2)-MPTP). Mol Pharmacol 66:718–727PubMedGoogle Scholar
  68. Palvimaki EP, Roth BL, Majasuo H, Laakso A, Kuoppamaki M, Syvalahti E, Hia J et al (1996) Interactions of selective serotonin reuptake inhibitors with the serotonin 5-HT2c receptor. Psychopharmacology (Berl) 126:234–240Google Scholar
  69. Pan Y, Gembom E, Peng W, Lesch KP, Mossner R, Simantov R (2001) Plasticity in serotonin uptake in primary neuronal cultures of serotonin transporter knockout mice. Brain Res Dev Brain Res 126:125–129PubMedGoogle Scholar
  70. Pasini A, Tortorella A, Gale K (1996) The anticonvulsant action of fluoxetine in substantia nigra is dependent upon endogenous serotonin. Brain Res 724:84–88PubMedGoogle Scholar
  71. Pattij T, Groenink L, Hijzen TH, Oosting RS, Maes RA, van der Gugten J, Olivier B (2002a) Autonomic changes associated with enhanced anxiety in 5-HT(1A) receptor knockout mice. Neuropsychopharmacology 27:380–390PubMedGoogle Scholar
  72. Pattij T, Groenink L, Oosting RS, van der Gugten J, Maes RA, Olivier B (2002b) GABA(A)-benzodiazepine receptor complex sensitivity in 5-HT(1A) receptor knockout mice on a 129/Sv background. Eur J Pharmacol 447:67–74PubMedGoogle Scholar
  73. Peng W, Simantov R (2003) Altered gene expression in frontal cortex and midbrain of 3,4-methylenedioxymethamphetamine (MDMA) treated mice: differential regulation of GABA transporter subtypes. J Neurosci Res 72:250–258PubMedGoogle Scholar
  74. Perez XA, Andrews AM (2005) Chronoamperometry to determine differential reductions in uptake in brain synaptosomes from serotonin transporter knockout mice. Anal Chem 77:818–826PubMedGoogle Scholar
  75. Perez XA, Bianco LE, Andrews AM (2006) Filtration disrupts synaptosomes during radiochemical analysis of serotonin uptake: comparison with chronoamperometry in SERT knockout mice. J Neurosci Methods 154:245–255PubMedGoogle Scholar
  76. Perrault G, Morel E, Zivkovic B, Sanger DJ (1992) Activity of litoxetine and other serotonin uptake inhibitors in the tail suspension test in mice. Pharmacol Biochem Behav 42:45–47PubMedGoogle Scholar
  77. Persico AM, Mengual E, Moessner R, Hall FS, Revay RS, Sora I, Arellano J, DeFelipe J, Gimenez-Amaya JM, Conciatori M, Marino R, Baldi A, Cabib S, Pascucci T, Uhl GR, Murphy DL, Lesch KP, Keller F (2001) Barrel pattern formation requires serotonin uptake by thalamocortical afferents, and not vesicular monoamine release. J Neurosci 21:6862–6873PubMedGoogle Scholar
  78. Porsolt RD (2000) Animal models of depression: utility for transgenic research. Rev Neurosci 11:53–58PubMedGoogle Scholar
  79. Porsolt RD, Le Pichon M, Jalfre M (1977) Depression: a new animal model sensitive to antidepressant treatments. Nature 266:730–732PubMedGoogle Scholar
  80. Qu Y, Villacreses N, Murphy DL, Rapoport SI (2005) 5-HT2A/2C receptor signaling via phospholipase A2 and arachidonic acid is attenuated in mice lacking the serotonin reuptake transporter. Psychopharmacology (Berl) 180:12–20Google Scholar
  81. Raap DK, Evans S, Garcia F, Li Q, Muma NA, Wolf WA, Battaglia G, Van De Kar LD (1999) Daily injections of fluoxetine induce dose-dependent desensitization of hypothalamic 5-HT1A receptors: reductions in neuroendocrine responses to 8-OH-DPAT and in levels of Gz and Gi proteins. J Pharmacol Exp Ther 288:98–106PubMedGoogle Scholar
  82. Ramamoorthy S, Bauman AL, Moore KR, Han H, Yang-Feng T, Chang AS, Ganapathy V, Blakely RD (1993) Antidepressant- and cocaine-sensitive human serotonin transporter: molecular cloning, expression, and chromosomal localization. Proc Natl Acad Sci U S A 90:2542–2546PubMedGoogle Scholar
  83. Rioux A, Fabre V, Lesch KP, Moessner R, Murphy DL, Lanfumey L, Hamon M, Martres MP (1999) Adaptive changes of serotonin 5-HT2A receptors in mice lacking the serotonin transporter. Neurosci Lett 262:113–116PubMedGoogle Scholar
  84. Rudnick G, Wall SC (1993) Non-neurotoxic amphetamine derivatives release serotonin through serotonin transporters. Mol Pharmacol 43:271–276PubMedGoogle Scholar
  85. Sakai K, Hasegawa C, Okura M, Morikawa O, Ueyama T, Shirai Y, Sakai N, Saito N (2003) Novel variants of murine serotonin transporter mRNA and the promoter activity of its upstream site. Neurosci Lett 342:175–178PubMedGoogle Scholar
  86. Salichon N, Gaspar P, Upton AL, Picaud S, Hanoun N, Hamon M, De Maeyer E, Murphy DL, Mossner R, Lesch KP, Hen R, Seif I (2001) Excessive activation of serotonin (5-HT) 1B receptors disrupts the formation of sensory maps in monoamine oxidase a and 5-ht transporter knock-out mice. J Neurosci 21:884–896PubMedGoogle Scholar
  87. Sanchez C, Hyttel J (1999) Comparison of the effects of antidepressants and their metabolites on reuptake of biogenic amines and on receptor binding. Cell Mol Neurobiol 19:467–489PubMedGoogle Scholar
  88. Schmitt A, Mossner R, Gossmann A, Fischer IG, Gorboulev V, Murphy DL, Koepsell H, Lesch KP (2003) Organic cation transporter capable of transporting serotonin is up-regulated in serotonin transporter-deficient mice. J Neurosci Res 71:701–709PubMedGoogle Scholar
  89. Serretti A, Kato M, De Ronchi D, Kinoshita T (2007) Meta-analysis of serotonin transporter gene promoter polymorphism (5-HTTLPR) association with selective serotonin reuptake inhibitor efficacy in depressed patients. Mol Psychiatry 12:247–257PubMedGoogle Scholar
  90. Shen HW, Hagino Y, Kobayashi H, Shinohara-Tanaka K, Ikeda K, Yamamoto H, Yamamoto T, Lesch KP, Murphy DL, Hall FS, Uhl GR, Sora I (2004) Regional differences in extracellular dopamine and serotonin assessed by in vivo microdialysis in mice lacking dopamine and/or serotonin transporters. Neuropsychopharmacology 29:1790–1799PubMedGoogle Scholar
  91. Sheridan DL, Wichems CH, Murphy DL, Andrews AM (1999) The effects of PCPA on monoamine neurotransmitter levels in mice with a disruption of the serotonin transporter gene. 29th Annual Meeting of the Society for NeuroscienceGoogle Scholar
  92. Shouse MN, Staba RJ, Ko PY, Saquib SF, Farber PR (2001) Monoamines and seizures: microdialysis findings in locus ceruleus and amygdala before and during amygdala kindling. Brain Res 892:176–192PubMedGoogle Scholar
  93. Sora I, Wichems C, Takahashi N, Li XF, Zeng Z, Revay R, Lesch KP, Murphy DL, Uhl GR (1998) Cocaine reward models: conditioned place preference can be established in dopamine- and in serotonin-transporter knockout mice. Proc Natl Acad Sci U S A 95:7699–7704PubMedGoogle Scholar
  94. Sora I, Hall FS, Andrews AM, Itokawa M, Li XF, Wei HB, Wichems C, Lesch KP, Murphy DL, Uhl GR (2001) Molecular mechanisms of cocaine reward: combined dopamine and serotonin transporter knockouts eliminate cocaine place preference. Proc Natl Acad Sci U S A 98:5300–5305PubMedGoogle Scholar
  95. Steru L, Chermat R, Thierry B, Simon P (1985) The tail suspension test: a new method for screening antidepressants in mice. Psychopharmacology (Berl) 85:367–370Google Scholar
  96. Strekalova T, Gorenkova N, Schunk E, Dolgov O, Bartsch D (2006) Selective effects of citalopram in a mouse model of stress-induced anhedonia with a control for chronic stress. Behav Pharmacol 17:271–287PubMedGoogle Scholar
  97. Tjurmina OA, Armando I, Saavedra JM, Goldstein DS, Murphy DL (2002) Exaggerated adrenomedullary response to immobilization in mice with targeted disruption of the serotonin transporter gene. Endocrinology 143:4520–4526PubMedGoogle Scholar
  98. Trigo JM, Renoir T, Lanfumey L, Hamon M, Lesch KP, Robledo P, Maldonado R (2007) 3,4-Methylenedioxymethamphetamine self-administration is abolished in serotonin transporter knockout mice. Biol Psychiatry (in press)Google Scholar
  99. Tzschentke TM (1998) Measuring reward with the conditioned place preference paradigm: a comprehensive review of drug effects, recent progress and new issues. Prog Neurobiol 56:613–672PubMedGoogle Scholar
  100. Unger EL, Mazzola-Pomietto P, Murphy DL, Andrews AM (2002) 2′-NH(2)-MPTP [1-methyl-4-(2′-aminophenyl)-1,2,3,6-tetrahydropyridine] depletes serotonin and norepinephrine in rats: a comparison with 2′-CH(3)-MPTP [1-methyl-4-(2′-methylphenyl)-1,2,3,6-tetrahydropyridine]. J Pharmacol Exp Ther 303:527–533PubMedGoogle Scholar
  101. van der Kooy D (1987) Place conditioning: a simple and effective method for assessing the motivational properties of drugs. In: Bozarth MA (ed) Methods of assessing the reinforcing properties of abused drugs. Springer, Berlin, pp 229–240Google Scholar
  102. Wendland JR, Lesch KP, Newman TK, Timme A, Gachot-Neveu H, Thierry B, Suomi SJ (2006) Differential functional variability of serotonin transporter and monoamine oxidase a genes in macaque species displaying contrasting levels of aggression-related behavior. Behav Genet 36:163–172PubMedGoogle Scholar
  103. Wichems CH, Andrews AM, Heils A, Li Q, Lesch KP, Murphy DL (1998) Spontaneous behavior differences and altered responses to psychomotor stimulants in mice lacking the serotonin transporter. 28th Annual Meeting of the Society for NeuroscienceGoogle Scholar
  104. Wichems CH, Li Q, Holmes A, Crawley JN, Tjurmina O, Goldstein D, Andrews AM, Lesch KP, Murphy DL (2000) Mechanisms mediating the increased anxiety-like and excessive responses to stress in mice lacking the serotonin transporter. 30th Annual Meeting of the Society for NeuroscienceGoogle Scholar
  105. Willins DL, Meltzer HY (1997) Direct injection of 5-HT2A receptor agonists into the medial prefrontal cortex produces a head-twitch response in rats. J Pharmacol Exp Ther 282:699–706PubMedGoogle Scholar
  106. Wisor JP, Wurts SW, Hall FS, Lesch KP, Murphy DL, Uhl GR, Edgar DM (2003) Altered rapid eye movement sleep timing in serotonin transporter knockout mice. Neuroreport 14:233–238PubMedGoogle Scholar
  107. Xu Y, Sari Y, Zhou FC (2004) Selective serotonin reuptake inhibitor disrupts organization of thalamocortical somatosensory barrels during development. Brain Res Dev Brain Res 150:151–161PubMedGoogle Scholar
  108. Zhang Y, Damjanoska KJ, Carrasco GA, Dudas B, D’Souza DN, Tetzlaff J, Garcia F, Hanley NR, Scripathirathan K, Petersen BR, Gray TS, Battaglia G, Muma NA, Van de Kar LD (2002) Evidence that 5-HT2A receptors in the hypothalamic paraventricular nucleus mediate neuroendocrine responses to (-)DOI. J Neurosci 22:9635–9642PubMedGoogle Scholar
  109. Zhao S, Edwards J, Carroll J, Wiedholz L, Millstein RA, Jaing C, Murphy DL, Lanthorn TH, Holmes A (2006) Insertion mutation at the C-terminus of the serotonin transporter disrupts brain serotonin function and emotion-related behaviors in mice. Neuroscience 140:321–334PubMedGoogle Scholar
  110. Zhou FC, Lesch KP, Murphy DL (2002) Serotonin uptake into dopamine neurons via dopamine transporters: a compensatory alternative. Brain Res 942:109–119PubMedGoogle Scholar
  111. Zhou FM, Liang Y, Salas R, Zhang L, De Biasi M, Dani JA (2005) Corelease of dopamine and serotonin from striatal dopamine terminals. Neuron 46:65–74PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Meredith A. Fox
    • 1
  • Anne M. Andrews
    • 2
  • Jens R. Wendland
    • 1
  • Klaus-Peter Lesch
    • 3
  • Andrew Holmes
    • 4
  • Dennis L. Murphy
    • 1
  1. 1.Laboratory of Clinical Science, National Institute of Mental HealthNational Institutes of HealthBethesdaUSA
  2. 2.Huck Institutes of the Life SciencesThe Pennsylvania State UniversityUniversity ParkUSA
  3. 3.Molecular and Clinical Psychobiology, Department of Psychiatry and PsychotherapyUniversity of WürzburgWürzburgGermany
  4. 4.Section on Behavioral Science and Genetics, Laboratory for Integrative Neuroscience, National Institute on Alcoholism and Alcohol AbuseNational Institutes of HealthBethesdaUSA

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