Skip to main content
SpringerLink
Log in

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

  • Review
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

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

Objectives

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.

Results

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.

Conclusions

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  • Adrien J (2002) Neurobiological bases for the relation between sleep and depression. Sleep Med Rev 6:341–351

    PubMed  Google Scholar 

  • 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 26:5554–5564

    PubMed  CAS  Google Scholar 

  • 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 267:1432–1439

    PubMed  CAS  Google Scholar 

  • Andrews AM, Murphy DL (1993b) Fluoxetine and desipramine selectively attenuate 2′-NH2-MPTP-induced depletions in serotonin and norepinephrine. Eur J Pharmacol 250:215–221

    PubMed  CAS  Google Scholar 

  • 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 60:1167–1170

    PubMed  CAS  Google Scholar 

  • 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 306:879–881

    PubMed  CAS  Google Scholar 

  • 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 73:277–280

    PubMed  CAS  Google Scholar 

  • 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 778:338–345

    PubMed  CAS  Google Scholar 

  • 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 53:649–655

    PubMed  CAS  Google Scholar 

  • 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 103:1857–1864

    PubMed  CAS  Google Scholar 

  • 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 56:54–67

    PubMed  CAS  Google Scholar 

  • 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 18:2203–2212

    PubMed  Google Scholar 

  • 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 30:1957–1965

    PubMed  CAS  Google Scholar 

  • Cryan JF, Holmes A (2005) The ascent of mouse: advances in modelling human depression and anxiety. Nat Rev Drug Discov 4:775–790

    PubMed  CAS  Google Scholar 

  • 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 84:4322–4326

    PubMed  CAS  Google Scholar 

  • 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 227:13–16

    PubMed  CAS  Google Scholar 

  • 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 328:153–162

    PubMed  CAS  Google Scholar 

  • 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 26:6431–6438

    PubMed  CAS  Google Scholar 

  • 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 102:5582–5587

    PubMed  CAS  Google Scholar 

  • 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 12:2299–2310

    PubMed  CAS  Google Scholar 

  • 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–S222

    Google Scholar 

  • Fox MA, Murphy DL (2006) Exaggerated serotonin syndrome in serotonin transporter knockout mice. Int J Neuropsychopharmacol 9:S174–S175

    Google Scholar 

  • 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 94:2041–2044

    PubMed  CAS  Google Scholar 

  • 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 379:606–612

    PubMed  CAS  Google Scholar 

  • 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 296:987–995

    PubMed  CAS  Google Scholar 

  • 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 23:8836–8843

    PubMed  Google Scholar 

  • 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 24:1187–1194

    PubMed  CAS  Google Scholar 

  • 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 96:202–216

    PubMed  CAS  Google Scholar 

  • 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 115:153–161

    PubMed  CAS  Google Scholar 

  • Hariri AR, Holmes A (2006) Genetics of emotional regulation: the role of the serotonin transporter in neural function. Trends Cogn Sci 10:182–191

    PubMed  Google Scholar 

  • 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 70:932–939

    Article  PubMed  CAS  Google Scholar 

  • 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 8:417–441

    PubMed  CAS  Google Scholar 

  • Holmes A, Murphy DL, Crawley JN (2002a) Reduced aggression in mice lacking the serotonin transporter. Psychopharmacology (Berl) 161:160–167

    CAS  Google Scholar 

  • Holmes A, Yang RJ, Murphy DL, Crawley JN (2002b) Evaluation of antidepressant-related behavioral responses in mice lacking the serotonin transporter. Neuropsychopharmacology 27:914–923

    PubMed  CAS  Google Scholar 

  • 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 2:365–380

    PubMed  CAS  Google Scholar 

  • Holmes A, Murphy DL, Crawley JN (2003b) Abnormal behavioral phenotypes of serotonin transporter knockout mice: parallels with human anxiety and depression. Biol Psychiatry 54:953–959

    PubMed  CAS  Google Scholar 

  • 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 28:2077–2088

    PubMed  CAS  Google Scholar 

  • Hoyer D, Hannon JP, Martin GR (2002) Molecular, pharmacological and functional diversity of 5-HT receptors. Pharmacol Biochem Behav 71:533–554

    PubMed  CAS  Google Scholar 

  • 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 78:815–826

    PubMed  CAS  Google Scholar 

  • 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 26:8955–8964

    PubMed  CAS  Google Scholar 

  • Jobe PC, Dailey JW, Wernicke JF (1999) A noradrenergic and serotonergic hypothesis of the linkage between epilepsy and affective disorders. Crit Rev Neurobiol 13:317–356

    PubMed  CAS  Google Scholar 

  • Jones BJ, Blackburn TP (2002) The medical benefit of 5-HT research. Pharmacol Biochem Behav 71:555–568

    PubMed  CAS  Google Scholar 

  • 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 6:389–400

    PubMed  CAS  Google Scholar 

  • Këlai S, Aissi F, Lesch KP, Cohen-Salmon C, Hamon M, Lanfumey L (2003) Alcohol intake after serotonin transporter inactivation in mice. Alcohol Alcohol 38:386–389

    PubMed  Google Scholar 

  • 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 49:798–810

    PubMed  CAS  Google Scholar 

  • Kobayashi T, Washiyama K, Ikeda K (2003) Inhibition of G protein-activated inwardly rectifying K+ channels by fluoxetine (Prozac). Br J Pharmacol 138:1119–1128

    PubMed  CAS  Google Scholar 

  • 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 70:2052–2063

    PubMed  CAS  Google Scholar 

  • 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 95:157–162

    PubMed  CAS  Google Scholar 

  • 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 274:1527–1531

    PubMed  CAS  Google Scholar 

  • 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 104:1259–1266

    PubMed  CAS  Google Scholar 

  • 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 291:999–1007

    PubMed  CAS  Google Scholar 

  • 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 20:7888–7895

    PubMed  CAS  Google Scholar 

  • 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 84:1256–1265

    PubMed  CAS  Google Scholar 

  • 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 24:10868–10877

    PubMed  CAS  Google Scholar 

  • 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 308:481–486

    PubMed  CAS  Google Scholar 

  • 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 54:960–971

    PubMed  CAS  Google Scholar 

  • Lu KT, Gean PW (1998) Endogenous serotonin inhibits epileptiform activity in rat hippocampal CA1 neurons via 5-hydroxytryptamine1A receptor activation. Neuroscience 86:729–737

    PubMed  CAS  Google Scholar 

  • 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 21:2178–2185

    PubMed  CAS  Google Scholar 

  • 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 89:886–896

    PubMed  Google Scholar 

  • 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 107:15–21

    PubMed  CAS  Google Scholar 

  • 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 140:169–181

    PubMed  CAS  Google Scholar 

  • 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 9:307–317

    PubMed  CAS  Google Scholar 

  • Montañez S, Owens WA, Gould GG, Murphy DL, Daws LC (2003) Exaggerated effect of fluvoxamine in heterozygote serotonin transporter knockout mice. J Neurochem 86:210–219

    PubMed  Google Scholar 

  • 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 111:27–35

    PubMed  CAS  Google Scholar 

  • Mossner R, Simantov R, Marx A, Lesch KP, Seif I (2006) Aberrant accumulation of serotonin in dopaminergic neurons. Neurosci Lett 401:49–54

    PubMed  Google Scholar 

  • 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):4–12

    PubMed  CAS  Google Scholar 

  • 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 66:718–727

    PubMed  CAS  Google Scholar 

  • 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) 126:234–240

    CAS  Google Scholar 

  • 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 126:125–129

    PubMed  CAS  Google Scholar 

  • Pasini A, Tortorella A, Gale K (1996) The anticonvulsant action of fluoxetine in substantia nigra is dependent upon endogenous serotonin. Brain Res 724:84–88

    PubMed  CAS  Google Scholar 

  • 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 27:380–390

    PubMed  CAS  Google Scholar 

  • 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 447:67–74

    PubMed  CAS  Google Scholar 

  • 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 72:250–258

    PubMed  CAS  Google Scholar 

  • Perez XA, Andrews AM (2005) Chronoamperometry to determine differential reductions in uptake in brain synaptosomes from serotonin transporter knockout mice. Anal Chem 77:818–826

    PubMed  CAS  Google Scholar 

  • 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 154:245–255

    PubMed  CAS  Google Scholar 

  • 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 42:45–47

    PubMed  CAS  Google Scholar 

  • 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 21:6862–6873

    PubMed  CAS  Google Scholar 

  • Porsolt RD (2000) Animal models of depression: utility for transgenic research. Rev Neurosci 11:53–58

    PubMed  CAS  Google Scholar 

  • Porsolt RD, Le Pichon M, Jalfre M (1977) Depression: a new animal model sensitive to antidepressant treatments. Nature 266:730–732

    PubMed  CAS  Google Scholar 

  • 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) 180:12–20

    CAS  Google Scholar 

  • 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 288:98–106

    PubMed  CAS  Google Scholar 

  • 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 90:2542–2546

    PubMed  CAS  Google Scholar 

  • 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 262:113–116

    PubMed  CAS  Google Scholar 

  • Rudnick G, Wall SC (1993) Non-neurotoxic amphetamine derivatives release serotonin through serotonin transporters. Mol Pharmacol 43:271–276

    PubMed  CAS  Google Scholar 

  • 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 342:175–178

    PubMed  CAS  Google Scholar 

  • 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 21:884–896

    PubMed  CAS  Google Scholar 

  • 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 19:467–489

    PubMed  CAS  Google Scholar 

  • 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 71:701–709

    PubMed  CAS  Google Scholar 

  • 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 12:247–257

    PubMed  CAS  Google Scholar 

  • 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 29:1790–1799

    PubMed  CAS  Google Scholar 

  • 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 Neuroscience

  • 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 892:176–192

    PubMed  CAS  Google Scholar 

  • 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 95:7699–7704

    PubMed  CAS  Google Scholar 

  • 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 98:5300–5305

    PubMed  CAS  Google Scholar 

  • Steru L, Chermat R, Thierry B, Simon P (1985) The tail suspension test: a new method for screening antidepressants in mice. Psychopharmacology (Berl) 85:367–370

    CAS  Google Scholar 

  • 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 17:271–287

    PubMed  CAS  Google Scholar 

  • 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 143:4520–4526

    PubMed  CAS  Google Scholar 

  • 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)

  • Tzschentke TM (1998) Measuring reward with the conditioned place preference paradigm: a comprehensive review of drug effects, recent progress and new issues. Prog Neurobiol 56:613–672

    PubMed  CAS  Google Scholar 

  • 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 303:527–533

    PubMed  CAS  Google Scholar 

  • 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 229–240

    Google Scholar 

  • 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 36:163–172

    PubMed  Google Scholar 

  • 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 Neuroscience

  • 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 Neuroscience

  • 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 282:699–706

    PubMed  CAS  Google Scholar 

  • 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 14:233–238

    PubMed  CAS  Google Scholar 

  • Xu Y, Sari Y, Zhou FC (2004) Selective serotonin reuptake inhibitor disrupts organization of thalamocortical somatosensory barrels during development. Brain Res Dev Brain Res 150:151–161

    PubMed  CAS  Google Scholar 

  • 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 22:9635–9642

    PubMed  CAS  Google Scholar 

  • 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 140:321–334

    PubMed  CAS  Google Scholar 

  • Zhou FC, Lesch KP, Murphy DL (2002) Serotonin uptake into dopamine neurons via dopamine transporters: a compensatory alternative. Brain Res 942:109–119

    PubMed  CAS  Google Scholar 

  • Zhou FM, Liang Y, Salas R, Zhang L, De Biasi M, Dani JA (2005) Corelease of dopamine and serotonin from striatal dopamine terminals. Neuron 46:65–74

    PubMed  CAS  Google Scholar 

Download references

Acknowledgment

This research was supported by the NIMH Intramural Research program. The authors wish to thank our many collaborators and colleagues throughout the world whose studies provided the basis for this review, and especially Teresa Tolliver, Sharon Engel, and Christine Wichems for contributions to initial studies of these mice, and also Theresa Deguzman for very helpful assistance with the preparation of this manuscript.

Author information

Authors and Affiliations

  1. Laboratory of Clinical Science, National Institute of Mental Health, National Institutes of Health, Building 10, Room 3D41, Bethesda, MD, 20892, USA

    Meredith A. Fox, Jens R. Wendland & Dennis L. Murphy

  2. Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, PA, 16802, USA

    Anne M. Andrews

  3. Molecular and Clinical Psychobiology, Department of Psychiatry and Psychotherapy, University of Würzburg, 97080, Würzburg, Germany

    Klaus-Peter Lesch

  4. Section on Behavioral Science and Genetics, Laboratory for Integrative Neuroscience, National Institute on Alcoholism and Alcohol Abuse, National Institutes of Health, Bethesda, MD, 20852, USA

    Andrew Holmes

Authors
  1. Meredith A. Fox
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anne M. Andrews
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jens R. Wendland
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Klaus-Peter Lesch
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Andrew Holmes
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Dennis L. Murphy
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Meredith A. Fox.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fox, M.A., Andrews, A.M., Wendland, J.R. et al. A pharmacological analysis of mice with a targeted disruption of the serotonin transporter. Psychopharmacology 195, 147–166 (2007). https://doi.org/10.1007/s00213-007-0910-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-007-0910-0

Keywords

Search

Navigation