13- cis -Retinoic Acid Alters Intracellular Serotonin,Increases 5-HT 1A Receptor,and Serotonin Reuptake Transporter Levels In Vitro

Abstract

In addition to their established role in nervous system development, vitamin A and related retinoids are emerging as regulators of adult brain function. Accutane (13-cis-retinoic acid, isotretinoin) treatment has been reported to increase depression in humans. Recently, we showed that chronic administration of 13-cis-retinoic acid (13-cis-RA) to adolescent male mice increased depression-related behaviors. Here, we have examined whether 13-cis-RA regulates components involved in serotonergic neurotransmission in vitro. We used the RN46A-B14 cell line, derived from rat embryonic raphe nuclei. This cell line synthesizes serotonin (5-hydroxytryptamine, 5-HT) and expresses the 5-HT_1A receptor and the serotonin reuptake transporter (SERT). Cells were treated with 0, 2.5, or 10 μM 13-cis-RA for 48 or 96 hrs, and the levels of 5-HT; its metabolite, 5-hydroxyindoleacetic acid (5HIAA); 5-HT_1A receptor; and SERT were determined. Treatment with 13-cis-RA for 96 hrs increased the intracellular levels of 5-HT and tended to increase intra-cellular 5HIAA levels. Furthermore, 48 hrs of treatment with 2.5 and 10 μM 13-cis-RA significantly increased 5-HT_1A protein to 168.5 ± 20.0% and 148.7 ± 2.2% of control respectively. SERT protein levels were significantly increased to 142.5 ± 11.1% and 119.2 ± 3.6% of control by 48 hrs of treatment with 2.5 and 10 μM of 13-cis-RA respectively. Increases in both 5-HT_1A receptor and SERT proteins may lead to decreased serotonin availability at synapses. Such an effect of 13-cis-RA could contribute to the increased depression-related behaviors we have shown in mice.

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References

Hull PR, D’Arcy C. Isotretinoin use and subsequent depression and suicide. Am J Clin Dermatol 4:493–505, 2003.

Chai C, Lane W, Chibnall J, Allen A, Siegfried E. Isotretinoin therapy and mood changes in adolescents with moderate to severe acne: a cohort study. Arch Dermatol 141, 2005.

Jacobs B, Praag H, Gage F. Adult brain neurogenesis and psychiatry: a novel theory of depression. Mol Psychiatry 5:262–269, 2000.

O’Connell KA, Wilkin JK, Pitts M. Isotretinoin (Accutane) and serious psychiatric adverse events. J Am Acad Dermatol 48:306–308; author reply 308, 2003.

O’Donnell J. Overview of existing research and information linking isotretinoin (Accutane), depression, psychosis, and suicide. Am J Ther 10:148–159, 2003.

Soprano D, Qin P, Soprano K. Retinoic acid receptors and cancer. Annu Rev Nutr 24:201–221, 2004.

Idres N, Marill J, Flexor MA, Chabot GG. Activation of retinoic acid receptor-dependent transcription by all-trans-retinoic acid metabolites and isomers. J Bio Chem 277:31491–31498, 2002.

Tsukada M, Schroder M, Roos TC, Chandraratna RAS, Reichert U, Mark HF, Orfanos CE, Zouboulis CC. 13-Cis-retinoic acid exerts its specific activity on human sebocytes through selective intracellular isomerization to all-trans retinoic acid and binding to retinoic acid receptors. J Invest Dermatol 115:321–327, 2000.

Lane MA, Bailey SJ. Role of retinoid signaling in the adult brain. Prog Neurobiol 72:275–293, 2005.

10.

Motomura K, Mitsuru O, Satre M, Tsukamoto H. Destabilization of TNF-alpha mRNA by retinoic acid in hepatic macrophages: implications for alcoholic liver disease. Am J Physiol Endocrinol Metab 281: E420–E429, 2001.

11.

Crowe D. Retinoic acid mediates post-transcriptional regulation of keratin 19 mRNA levels. J Cell Sci 106:183–188, 1993.

12.

Qin P, Haberbusch J, Soprano D, Soprano K. Retinoic acid regulates the expression of PBX1, PBX2, and PBX3 in P19 cells both transcriptionally and post-translationally. J Cell Biochem 92:147–163, 2004.

13.

Bremner JD, Fani N, Ashraf A, Votaw JR, Brummer ME, Cummins T, Vaccarino V, Goodman MM, Reed L, Siddiq S, Nemeroff CB. Functional brain imaging alterations in acne patients treated with isotretinoin. Am J Psychiatry 162:983–991, 2005.

14.

Crandall J, Sakai Y, Zhang J, Koul O, Mineur Y, Crusio WE, McCaffery PJ. 13-Cis-retinoic acid suppresses hippocampal cell division and hippocampal-dependent learning in mice. Proc Natl Acad Sci U S A 101:5111–5116, 2004.

15.

O’Reilly K, Shumake J, Gonzalez-Lima F, Lane MA, Bailey SJ. Chronic administration of 13-cis-retinoic acid increases depression-related behavior in mice. Neuropsychopharmacology 31:1919–1927, 2006.

16.

Detke MJ, Rickels M, Lucki I. Active behaviors in the rat forced swimming test differentially produced by serotonergic and noradrenergic antidepressants. Psychopharmacology (Berl) 121:66–72, 1995.

17.

Blier P, de Montigny C. Current advances and trends in the treatment of depression. Trends Pharmacol Sci 15:220–226, 1994.

18.

Blier P, Pineyro G, el Mansari M, Bergeron R, de Montigny C. Role of somatodendritic 5-HT autoreceptors in modulating 5-HT neurotrans-mission. Ann N Y Acad Sci 861:204–216, 1998.

19.

Lemonde S, Turecki G, Bakish D, Du L, Hrdina PD, Bown CD, Sequeira A, Kushwaha N, Morris SJ, Basak A, Ou XM, Albert PR. Impaired repression at a 5-hydroxytryptamine 1A receptor gene polymorphism associated with major depression and suicide. J Neurosci 23:8788–8799, 2003.

20.

Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S, Benjamin J, Muller CR, Hamer DH, Murphy DL. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 274:1527–1531, 1996.

21.

Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H, McClay J, Mill J, Martin J, Braithwaite A, Poulton R. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 301:386–389, 2003.

22.

Neumeister A, Young T, Stastny J. Implications of genetic research on the role of the serotonin in depression: emphasis on the serotonin type 1A receptor and the serotonin transporter. Psychopharmacology 174:512–524, 2004.

23.

Eaton MJ, Staley JK, Globus MYT, Whittemore SR. Developmental regulation of early serotonergic neuronal differentiation: the role of brain-derived neurotrophic factor and membrane depolarization. Dev Bio 170:169–182, 1995.

24.

Eaton MJ, Whittemore SR. Autocrine BDNF secretion enhances the survival and serotonergic differentiation of raphe neuronal precursor cells grafted into the adult rat CNS. Exp Neurol 140:105–114, 1996.

25.

White LA, Eaton MJ, Castro MC, Klose KJ, Globus MY, Shaw G, Whittemore SR. Distinct regulatory pathways control neurofilament expression and neurotransmitter synthesis in immortalized serotonergic neurons. J Neurosci 14:6744–6753, 1994.

26.

Bai F, Lau S, Monks T. Glutathione and N-acetylcysteine conjugates of alpha-methyldopamine produce serotonergic neurotoxicity: possible role in methylenedioxyamphetamine-mediated neurotoxicity. Chem Res Toxicol 12:1150–1157, 1999.

27.

Pierce P, Xie B, Levine J, Peroutka S. 5-Hydroxytrypramine receptor subtype messenger RNAs in rat peripheral sensory and sympathetic ganglia: a polymerase chain reaction study. Neuroscience 70:553–559, 1996.

28.

Collins F, Team M. Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proc Natl Acad Sci U S A 99:16899–16903, 2002.

29.

Ozsarac N, Santha E, Hoffman B. Alternative non-coding exons support serotonin transporter mRNA expression in the brain and gut. J Neurochem 82:336–344, 2002.

30.

Lane M, Chen A, Roman S, Derguini F, Gudas L. Removal of LIF (leukemia inhibitory factor) results in increased vitamin A (retinol) metabolism to 4-oxoretinol in embryonic stem cells. Proc Natl Acad Sci U S A 96:13524–13529, 1999.

31.

Bry K, Lappalainen U. Pathogenesis of bronchopulmonary dysplasia; the role of interleukin 1 beta in the regulation of inflammation-mediated pulmonary retinoic acid pathways in transgenic mice. Semin Perinatol 30:121–128, 2006.

32.

Nishizawa H, Manabe N, Morita M, Sugimoto M, Imanishi S, Miyamoto H. Effects of in utero exposure to bisphenol A on expression of RARalpha and RXRalpha mRNAs in murine embryos. J Reprod Dev 4:539–545, 2003.

33.

Husson M, Enderlin V, Alfos S, Feart C, Higueret P, Pallet V. T3 administration reverses vitamin A deficiency related hypoexpression of RA and T3 nuclear receptors and of RC3 in rat brain. Br J Nutr 90:191–198, 2003.

34.

Ferguson S, Cisneros F, Gough B, Ali S. Four weeks of oral isotretinoin treatment causes few signs of general toxicity in male and female Sprague-Dawley rats. Food Chem Toxicol 43:1289–1296, 2005.

35.

Arias B, Arranz M, Gasto C, Catalan R, Pintor L, Gutierrez B, Kerwin R, Fananas L. Analysis of structural polymorphisms and C-1018G promoter variant of the 5-HT(1A) receptor gene as putative risk factors in major depression. Mol Psychiatry 7:930–932, 2002.

36.

Olivier B, Pattij T, Wood S, Oosting R, Sarnyai Z, Toth M. The 5-HT(1A) receptor knockout mouse and anxiety. Behav Pharmacol 12:439–450, 2001.

37.

Richer M, Hen R, Blier P. Modification of serotonin neuron properties in mice lacking 5-HT1A receptors. Eur J Pharmacol 435:195–203, 2002.

38.

Parsons LH, Kerr T, Tecott LH. 5-HT(1A) receptor mutant mice exhibit enhanced tonic, stress-induced and fluoxetine-induced serotonergic neurotransmission. J Neurochem 77:607–617, 2001.

39.

He M, Sibille E, Benjamin D, Toth M, Shippenberg T. Differential effects of 5-HT1A receptor deletion upon basal and fluoxetine-evoked 5-HT concentrations as revealed by in vivo microdialysis. Brain Res 902:11–17, 2001.

40.

Serretti A, Benedetti F, Zanardi R, Smeraldi E. The influence of Serotonin Transporter Promoter Polymorphism (SERTPR) and other polymorphisms of the serotonin pathway on the efficacy of anti-depressant treatments. Prog Neuropsychopharmacol Biol Psychiatry 29:1074–1084, 2005.

41.

Greenberg BD, Tolliver T, Huang S, Li Q, Bengel D, Murphy DL. Genetic variation in the serotonin transporter promoter region affects serotonin uptake in human blood platelets. Am J Med Genet 88:83–87, 1999.

42.

Little K, McLaughlin D, Zhang L, Livermore C, Dalack G, McFinton P, DelProposto Z, Hill E, Cassin B, Watson S, Cook E. Cocaine, ethanol, and genotype effects on human midbrain serotonin transporter binding sites and mRNA levels. Am J Psychiatry 155:207–213, 1998.

43.

Collier D, Stober G, Li T, Heils A, Catalano M, Di Bella D, Arranz M, Murray R, Vallada H, Bengel D, Muller CR, Roberts G, Smeraldi E, Kirov G, Sham P, Lesch KP. A novel functional polymorphism within the promoter of the serotonin transporter gene: possible role in susceptibility to affective disorders. Mol Psychiatry 1:453–460, 1996.

44.

Lira A, Zhou M, Castanon N, Ansorge M, Gordon J, Francis J, Bradley-Moore M, Lira J, Underwood M, Arango V, Kung H, Hofer M, Hen R, Gingrich J. Altered depression-related behaviors and functional changes in the dorsal raphe nucleus of serotonin transporter deficient mice. Biol Psychiatry 54:960–971, 2003.

45.

Thacker D, Natt F, Husken D, van der Putten H, Maier R, Hoyer D, Cryan J. siRNA-mediated knockdown of the serotonin transporter in the adult mouse brain. Mol Psychiatry 10:782–789, 2005.

46.

Bengel D, Murphy DL, Andrews A, Wichems C, Feltner D, Heils A, Mossner R, Westphal H, Lesch KP. Altered brain serotonin homeo-stasis and locomotor insensitivity to 3,4-methylenedioxymethamphetamine (“Ecstasy”) in serotonin transporter-deficient mice. Mol Pharmacol 53:649–655, 1998.

47.

Montanez S, Owens W, Gould G, Murphy DL, Daws L. Exaggerated effect of fluvoxamine in heterozygote serotonin transporter knockout mice. J Neurochem 86:210–219, 2003.

48.

Mathews T, Fedele D, Coppelli F, Aviala A, Murphy DL, Andrews A. Gene dose-dependent alterations in extraneuronal serotonin but not dopamine in mice with reduced serotonin transporter expression. J Neurosci Methods 140:169–181, 2004.