Midbrain serotonin transporter binding potential measured with [ 11C]DASB is affected by serotonin transporter genotype Article First Online: 18 January 2007 Received: 08 September 2006 Accepted: 02 November 2006 DOI:
Cite this article as: Reimold, M., Smolka, M., Schumann, G. et al. J Neural Transm (2007) 114: 635. doi:10.1007/s00702-006-0609-0 Summary Background. Homozygote carriers of two long ( L) alleles of the serotonin transporter (5-HTT) regulatory region displayed in vitro a twofold increase in 5-HTT expression compared with carriers of one or two short ( S) alleles. However, in vivo imaging studies yielded contradictory results. Recently, an A > G exchange leading to differential transcriptional activation of 5-HTT mRNA in lymphobalstoid cell lines was discovered in the 5-HTT regulatory region. In vitro and in vivo evidence suggests that [ 11C]DASB, a new 5-HTT ligand offers some advantages over the ligands used in previous studies in measuring 5-HTT density independent of synaptic levels of serotonin. Method. We assessed 5-HTT binding potential ( BP 2) in the midbrain of 19 healthy subjects with positron emission tomography and [ 11C]DASB. Accounting for the hypothesized functional similarity of L G and S in driving 5-HTT transcription, we assessed whether L A L A homozygotes display increased midbrain BP 2 compared with carriers of at least one S allele. Results. BP 2 in the midbrain was significantly increased in L A L A homozygotes compared with carriers of at least one S allele. Interestingly, the genotype effect on the midbrain was significantly different from that on the thalamus and the amygdala where no group differences were detected. Conclusions. This in vivo study provides further evidence that subjects homozygous for the L A allele display increased expression of 5-HTT in the midbrain, the origin of central serotonergic projections. Keywords: 5-HTT, SCL6A4, PET, DASB
First (MR) and second author (MNS) contributed equally to this work.
References Callicott, JH, Egan, MF, Bertolino, A, Mattay, VS, Langheim, FJ, Frank, JA, Weinberger, DR 1998 Hippocampal N-acetyl aspartate in unaffected siblings of patients with schizophrenia: a possible intermediate neurobiological phenotype Biol Psychiatry 44 941 950 PubMed CrossRef Google Scholar Caspi, A, Sugden, K, Moffitt, TE, Taylor, A, Craigh, IW, Harrington, H, McClay, J, Mill, J, Martin, J, Braithwaite, A, Poulton, R 2003 Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene Science 301 386 389 PubMed CrossRef Google Scholar Delgado, PL 2004 How antidepressants help depression: mechanisms of action and clinical response J Clin Psych 65 25 30 Google Scholar First, MB, Spitzer, RL, Gibbon, M, Williams, J 1997Structured Clinical Interview for DSM-IV Personality Disorders (SCID-II) American Psychiatric Press Washington, DC Google Scholar
First MB, Spitzer RL, Gibbon M, Williams J (2001) Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version, Patient Edition With Psychotic Screen. Biometrics Research, New York State Psychiatric Institute, New York
Frankle, G, Huang, Y, Hwang, R-D, Talbot, PS, Slifstein, M, van Heertum, R, Abi-Dargham, A, Laruelle, M 2004 Comparative evaluation of serotonin transporter radioligands 11C-DASB and 11C-McN 5652 in Healthy Humans J Nucl Med 45 682 694 PubMed Google Scholar Garpenstrand, H, Annas, P, Ekblom, J, Oreland, L, Fredrikson, M 2001 Human fear conditioning is related to dopaminergic and serotonergic biological markers Behav Neurosci 115 358 364 PubMed CrossRef Google Scholar Hariri, AR, Mattay, VS, Tessitore, A, Kolachana, B, Fera, F, Goldman, D, Egan, MF, Weinberger, DR 2002 Serotonin transporter genetic variation and the response of the human amygdala Science 297 400 403 PubMed CrossRef Google Scholar Hariri, AR, Drabant, EM, Munoz, KE, Kolachana, BS, Mattay, VS, Egan, MF, Weinberger, DR 2005 A susceptibility gene for affective disorders and the response of the human amygdala Arch Gen Psychiatry 62 146 152 PubMed CrossRef Google Scholar Heinz, A, Jones, DW, Mazzanti, C, Goldman, D, Ragan, P, Hommer, D, Linnoila, M, Weinberger, DR 2000 Serotonin transporter genotype interacts with in vivo protein expression and chronic alcohol intake Biol Psychiatry 47 643 649 PubMed CrossRef Google Scholar Heinz, A, Jones, DW, Zajicek, K, Gorey, JG, Juckel, G, Higley, JD, Weinberger, DR 2004 Depletion and restoration of endogenous monoamines affects beta-CIT binding to serotonin but not dopamine transporters in non-human primates J Neural Transm Suppl 68 29 38 Google Scholar Heinz, A, Braus, DF, Smolka, MN, Wrase, J, Hermann, D, Klein, S, Grüsser, SM, Flor, H, Schumann, G, Mann, K, Büchel, C 2005 Amygdala-prefrontal coupling depends on a genetic variation of the serotonin transporter Nat Neurosci 8 20 21 PubMed CrossRef Google Scholar Houle, S, Ginovart, N, Hussey, D, Meyer, JH, Wilson, AA 2000 Imaging the serotonin transporter with positron emission tomography: initial human studies with [ 11C]DAPP and [ 11C]DASB Eur J Nucl Med 27 1719 1722 PubMed CrossRef Google Scholar Hu, XZ, Oroszi, G, Chun, J, Smith, TL, Goldman, D, Schuckit, MA 2005 An expanded evaluation of the relationship of four alleles to the level of response to alcohol and the alcoholism risk Alcohol Clin Exp Res 29 8 16 PubMed CrossRef 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 promotor gain-of-function genotypes are linked to obsessive-compulsive disorder Am J Hum Genet 78 815 826 PubMed CrossRef Google Scholar Hummerich, R, Reischl, G, Ehrlichmann, W, Machulla, HJ, Heinz, A, Schloss, P 2004 DASB – in vitro binding characteristics on human recombinant monoamine transporters with regard to its potential as a PET tracer J Neurochem 90 1218 1226 PubMed CrossRef Google Scholar Hummerich, R, Schulze, O, Radler, T, Mikecz, P, Reimold, M, Brenner, W, Clausen, M, Schloss, P, Buchert, R 2006 Inhibition of serotonin transport by (+)McN5652 is noncompetitive Nucl Med Biol 33 317 323 PubMed CrossRef Google Scholar Ichise, M, Liow, J-S, Lu, J-Q, Takano, A, Model, K, Toyama, H, Suhara, T, Suzuki, K, Innis, RB, Carson, RE 2003 Linearized reference tissue parametric imaging methods: application to [ 11C]DASB positron emission tomography studies of the serotonin transporter in human brain J Cereb Blood Flow Metab 23 1096 1112 PubMed CrossRef Google Scholar Kraft, JB, Slager, SL, McGrath, PJ, Hamilton, SP 2005 Sequence analysis of the serotonin transporter and associations with antidepressant response Biol Psychiatry 58 374 381 PubMed CrossRef Google Scholar Laruelle, M, Baldwin, R, Malison, R, Zea-Ponce, Y, Zoghbi, S, Al-Tikriti, M, Sybirska, E, Zimmermann, R, Wisniewski, G, Neumeyer, J, Milius, R, Wang, S, Smith, E, Roth, R, Charney, D, Hoffer, P, Innis, R 1993 SPECT imaging of dopamine and serotonin transporters with [ 123I]β-CIT: pharmacological characterization of brain uptake in non-human primates Synapse 13 295 309 PubMed CrossRef Google Scholar Leibenluft, E, Charney, DS, Towbin, KE, Bhangoo, RK, Pine, DS 2004 Defining clinical phenotypes of juvenile mania Am J Psychiatry 160 430 437 CrossRef Google Scholar Lesch, KP, Bengel, D, Heils, A, Sabol, SZ, Greenberg, D, Petri, S, Benjamin, J, Müller, 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 CrossRef Google Scholar Little, KY, McLaughlin, DP, Zhang, L, Livermore, CS, Dalack, GW, McFinton, PR, DelProposto, ZS, Hill, E, Cassin, BJ, Watson, SJ, Cook, EH 1998 Cocaine, ethanol and genotype effects on human midbrain serotonin transporter binding sites and mRNA levels Am J Psychiatry 155 207 213 PubMed Google Scholar Malison, RT, Price, LH, Berman, R, van Dyck, CH, Pelton, GH, Carpenter, L, Sanacora, G, Owens, MJ, Nemeroff, CB, Rajeevan, N, Baldwin, RM, Seibyl, P, Innis, RB, Charney, DS 1998 Reduced brain serotonin transsporter availability in major depression as measured by [ 123I]-2β-carbomethoxy-3β-(4-iodophenyl)tropane and single photon emission computed tomography Biol Psychiatry 44 1090 1098 PubMed CrossRef Google Scholar Meltzer, CC, Price, JC, Mathis, CA, Butters, MA, Ziolko, SK, Moses-Kolko, E, Mazumdar, S, Mulsant, BH, Houck, PR, Lopresti, BJ, Weissfeld, LA, Reynolds, CF 2004 Serotonin 1A receptor binding and treatment response in late-life depression Neuropsychopharmacology 29 2258 2265 PubMed CrossRef Google Scholar Nakamura, M, Ueno, S, Sano, A, Tanabe, H 2000 The human serotonin transporter gene linked polymorphism (5-HTTLPR) shows ten novel allelic variants Mol Psychiatry 5 32 38 PubMed CrossRef Google Scholar Parsey, RV, Hastings, RS, Oquendo, MA, Hu, X, Goldman, D, Huang, YY, Simpson, N, Arcement, J, Huang, Y, Ogden, RT, Van Heertum, RL, Arango, V, Mann, JJ 2006 Effect of a triallelic functional polymorphism of the serotonin-transporter-linked promoter region on expression of serotonin transporter in the human brain Am J Psychiatry 163 48 51 PubMed CrossRef Google Scholar Praschak-Rieder, N, Wilson, AA, Hussey, D, Carella, A, Wei, C, Ginovart, N, Schwarz, MJ, Zach, J, Houle, S, Meyer, JH 2005 Effects of tryptophan depletion on the serotonin transporter in healthy humans Biol Psychiatry 58 825 830 PubMed CrossRef Google Scholar Shioe, K, Ichimiya, T, Suhara, T, Takano, A, Sudo, Y, Yasuno, F, Hirano, M, Shinohara, M, Kagami, M, Okubo, Y, Nankai, M, Kanba, S 2003 No association between genotype of the promoter region of serotonin transporter gene and serotonin transporter binding in human brain measured by PET Synapse 48 184 188 PubMed CrossRef Google Scholar Solbach, C, Reischl, G, Machulla, H-J 2004 Determination of reaction parameters for the synthesis of the serotonin transporter ligand [ 11C]DASB and application in a remote-controlled high yield synthesis Radiochim Acta 92 341 344 CrossRef Google Scholar Talbot, PS, Frankle, WG, Hwang, DR, Huang, Y, Suckow, RF, Slifstein, M, Abi-Dargham, A, Laruelle, M 2005 Effects of reduced endogenous 5-HT on the in vivo binding of the serotonin transporter radioligand 11C-DASB in healthy humans Synapse 55 164 175 PubMed CrossRef Google Scholar van Dyck, CH, Malison, RT, Staley, JK, Jacobsen, LK, Seibyl, JP, Laruelle, M, Baldwin, RM, Innis, RB, Gelernter, J 2004 Central serotonin transporter availability measured with [ 123I]beta-CIT SPECT in relation to serotonin transporter genotype Am J Psychiatry 161 525 531 PubMed CrossRef Google Scholar