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The interaction of escitalopram and R-citalopram at the human serotonin transporter investigated in the mouse
- 作者:Jacob P. R. Jacobsen (1)
Per Plenge (2) Benjamin D. Sachs (1) Alan L. Pehrson (3) Manuel Cajina (3) Yunzhi Du (1) Wendy Roberts (1) Meghan L. Rudder (1) Prachiti Dalvi (1) Taylor J. Robinson (1) Sharon P. O’Neill (4) King S. Khoo (4) Connie Sanchez Morillo (3) Xiaodong Zhang (4) Marc G. Caron (1)
- 关键词:5 ; HT ; Allosteric ; Antidepressant ; Escitalopram ; R ; citalopram ; Microdialysis
- 刊名:Psychopharmacology
- 出版年:2014
- 出版时间:December 2014
- 年:2014
- 卷:231
- 期:23
- 页码:4527-4540
- 全文大小:3,210 KB
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2. Artigas F, Romero L, de Montigny C, Blier P (1996) Acceleration of the effect of selected antidepressant drugs in major depression by 5-HT1A antagonists. Trends Neurosci 19:378-83 g/10.1016/S0166-2236(96)10037-0" target="_blank" title="It opens in new window">CrossRef 3. Barker EL, Kimmel HL, Blakely RD (1994) Chimeric human and rat serotonin transporters reveal domains involved in recognition of transporter ligands. Mol Pharmacol 46:799-07 4. Beaulieu JM, Zhang X, Rodriguiz RM, Sotnikova TD, Cools MJ, Wetsel WC, Gainetdinov RR, Caron MG (2008) Role of GSK3 beta in behavioral abnormalities induced by serotonin deficiency. Proc Natl Acad Sci U S A 105:1333-338 g/10.1073/pnas.0711496105" target="_blank" title="It opens in new window">CrossRef 5. Binneman B, Feltner D, Kolluri S, Shi Y, Qiu R, Stiger T (2008) A 6-week randomized, placebo-controlled trial of CP-316,311 (a selective CRH1 antagonist) in the treatment of major depression. Am J Psychiatry 165:617-20 g/10.1176/appi.ajp.2008.07071199" target="_blank" title="It opens in new window">CrossRef 6. Blakely RD, Berson HE, Fremeau RT Jr, Caron MG, Peek MM, Prince HK, Bradley CC (1991) Cloning and expression of a functional serotonin transporter from rat brain. Nature 354:66-0 g/10.1038/354066a0" target="_blank" title="It opens in new window">CrossRef 7. Blier P (2003) The pharmacology of putative early-onset antidepressant strategies. Eur Neuropsychopharmacol 13:57-6 g/10.1016/S0924-977X(02)00173-6" target="_blank" title="It opens in new window">CrossRef 8. Borsini F, Podhorna J, Marazziti D (2002) Do animal models of anxiety predict anxiolytic-like effects of antidepressants? Psychopharmacology 163:121-41 g/10.1007/s00213-002-1155-6" target="_blank" title="It opens in new window">CrossRef 9. Brosen K, Naranjo CA (2001) Review of pharmacokinetic and pharmacodynamic interaction studies with citalopram. Eur Neuropsychopharmacol 11:275-83 g/10.1016/S0924-977X(01)00101-8" target="_blank" title="It opens in new window">CrossRef 10. Bunin MA, Wightman RM (1998) Quantitative evaluation of 5-hydroxytryptamine (serotonin) neuronal release and uptake: an investigation of extrasynaptic transmission. J Neurosci 18:4854-860 11. Cervo L, Canetta A, Calcagno E, Burbassi S, Sacchetti G, Caccia S, Fracasso C, Albani D, Forloni G, Invernizzi RW (2005) Genotype-dependent activity of tryptophan hydroxylase-2 determines the response to citalopram in a mouse model of depression. J Neurosci 25:8165-172 g/10.1523/JNEUROSCI.1816-05.2005" target="_blank" title="It opens in new window">CrossRef 12. Chang AS, Chang SM, Starnes DM, Schroeter S, Bauman AL, Blakely RD (1996) Cloning and expression of the mouse serotonin transporter. Brain Res Mol Brain Res 43:185-92 g/10.1016/S0169-328X(96)00172-6" target="_blank" title="It opens in new window">CrossRef 13. Chen F, Larsen MB, Sanchez C, Wiborg O (2005) The S-enantiomer of R, S-citalopram, increases inhibitor binding to the human serotonin transporter by an allosteric mechanism. Comparison with other serotonin transporter inhibitors. Eur Neuropsychopharmacol 15:193-98 g/10.1016/j.euroneuro.2004.08.008" target="_blank" title="It opens in new window">CrossRef 14. Colonna L, Andersen HF, Reines EH (2005) A randomized, double-blind, 24-week study of escitalopram (10?mg/day) versus citalopram (20?mg/day) in primary care patients with major depressive disorder. Curr Med Res Opin 21:1659-668 g/10.1185/030079905X65484" target="_blank" title="It opens in new window">CrossRef 15. Cristalli G, Lambertucci C, Marucci G, Volpini R, Dal Ben D (2008) A2A adenosine receptor and its modulators: overview on a druggable GPCR and on structure–activity relationship analysis and binding requirements of agonists and antagonists. Curr Pharm Des 14:1525-552 g/10.2174/138161208784480081" target="_blank" title="It opens in new window">CrossRef 16. Crowley JJ, Blendy JA, Lucki I (2005) Strain-dependent antidepressant-like effects of citalopram in the mouse tail suspension test. Psychopharmacology 183:257-64 g/10.1007/s00213 - 作者单位:Jacob P. R. Jacobsen (1)
Per Plenge (2) Benjamin D. Sachs (1) Alan L. Pehrson (3) Manuel Cajina (3) Yunzhi Du (1) Wendy Roberts (1) Meghan L. Rudder (1) Prachiti Dalvi (1) Taylor J. Robinson (1) Sharon P. O’Neill (4) King S. Khoo (4) Connie Sanchez Morillo (3) Xiaodong Zhang (4) Marc G. Caron (1)
1. Department of Cell Biology, Duke University Medical Center, PO Box 3287, Durham, NC, 27710, USA 2. Department of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen, Denmark 3. Lundbeck Research USA, Paramus, NJ, USA 4. Neuroscience and Behavioral Disorders Program, Duke-NUS Graduate Medical School Singapore, Singapore, Singapore
- ISSN:1432-2072
文摘
Rationale Escitalopram appears to be a superior antidepressant to racemic citalopram. It has been hypothesized that binding of R-citalopram to the serotonin transporter (SERT) antagonizes escitalopram binding to and inhibition of the SERT, thereby?curtailing the elevation of extracellular 5-hydroxytryptamine (5-HTExt), and hence?antidepressant efficacy. Further, it has been suggested that a putative allosteric binding site is important for binding of escitalopram to the primary, orthosteric, site, and for R-citalopram’s inhibition hereof. Objectives Primary: Investigate at the human (h)SERT, at clinical relevant doses, whether R-citalopram antagonizes escitalopram-induced 5-HTExt elevation. Secondary: Investigate whether abolishing the putative allosteric site affects escitalopram-induced 5-HTExt elevation and/or modulates the effect of R-citalopram. Methods Recombinant generation of hSERT transgenic mice; in vivo microdialysis; SERT binding; pharmacokinetics; 5-HT sensitive behaviors (tail suspension, marble burying). Results We generated mice expressing either the wild-type human SERT (hSERTWT) or hSERT carrying amino acid substitutions (A505V, L506F, I507L, S574T and I575T) collectively abolishing the putative allosteric site (hSERTALI/VFL+SI/TT). One mg/kg escitalopram yielded clinical relevant plasma levels and brain levels consistent with therapeutic SERT occupancy. The hSERT mice showed normal basal 5-HTExt levels. Escitalopram-induced 5-HTExt elevation was not decreased by R-citalopram co-treatment and was unaffected by loss of the allosteric site. The behavioral effects of the clinically relevant escitalopram dose were small and?tended?to be enhanced by R-citalopram co-administration. Conclusions We find no evidence that R-citalopram directly antagonizes escitalopram or that the putative allosteric site is important for hSERT inhibition by escitalopram.
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