個體在胎兒期暴露在抗憂鬱劑之下，日後出生時會出現少數生理上的不良後果，但還未有充足的研究證實是否有長期的影響。本研究之目的：讓小鼠在胎兒期暴露於四種作用在不同神經傳導物質的抗憂鬱劑，分別為bupropion (正腎上腺素與多巴胺回收抑制劑)，trazodone (血清素突觸後接受拮抗與回收抑制劑), citalopra和fluvoxamine (血清素回收抑制劑)。我們欲研究小鼠成年後的活動量、焦慮程度，以及對古柯鹼的上癮行為強度。在小鼠懷孕第三週於皮下注射抗憂鬱劑，控制組則注射等量的生理食鹽水。待小鼠成年後，以紅外線偵測儀器進行三分鐘的活動量評估；接著以具高度的十字迷津評估小鼠的焦慮程度；最後以三天的配對程序建立小鼠古柯鹼的上癮行為，記錄其場地制約偏好的強度。研究結果發現小鼠在胎兒期暴露於trazodone出生後有較高的死亡率。再者，胎兒期暴露於劑量25mg/kg的bupropion，產生較高的場地制約偏好，表示其有較強的古柯鹼上癮行為，然而當劑量減半時此顯著差異便消失。後續研究需針對bupropion在胎兒期注射母鼠體內，對其後代小鼠的中樞神經相關的神經傳導物發生之影響做進一步的探討。

　Although minor, negative finding on birth outcome of prenatal antidepressant exposure have been reported, the long-lasting effects are suspected in this regard. In this study, four antidepressants targeting varied neurotransmitter, bupropion (norepinephrine and dopamine reuptake inhibitor), trazodone (5-HT2 antagonists and serotonin reuptake inhibitor), citalopram and fluvoxamine (selective serotonin reuptake inhibitor) were used to assess the prenatal exposure effects of these antidepressants on cocaine reward, locomotion and naïve anxiety level in adult mice. Female C57BL/6J mice were treated with daily subcutaneous bupropion (25 or 12.5mg/kg), citalopram (5mg/kg), fluvoxamine (10mg/kg), trazodone (20mg/kg), or saline during their third trimester of gestation. On the postpartum day 56, mice were evaluated their locomotor activity and native anxiety using elevated plus maze. Then they underwent conditioned place preference (CPP) trainings to associate the euphoric effects of cocaine (5 mg/kg, i. p.) in a 3-day paring protocol. We found that trazodone pretreatment produced a higher mortality rate. Moreover, our result revealed that prenatal antidepressant exposure did not affect the locomotor activity and native anxiety. Mice prenatal exposure of citalopram, fluvoxamine, trazodone or saline all showed indistinct cocaine-associated CPP. However, mice prenatal exposed to bupropion at 25 mg/kg showed higher level of the cocaine-associated CPP as compared to the saline group, but those with 12.5 mg/kg did not reveal such elevation. Further studies are needed to investigate the effects of prenatal bupropion exposure on the brain neurotransmitters.

Andersen S. L., Arvanitogiannis A., Pliakas A. M., LeBlanc C. and Carlezon W.
　A. Altered responsiveness to cocaine in rats exposed to methylphenidate
　during development. Nature Neuroscience, 5(1), 13-14. 2001.
Allikmets L., Matto V. and Harro J. Do the antidepressants have anxiogenic
　action? Biological Psychiatry, 39(7), 626. 1996.
Boshier A., Wilton L. V., and Shakir S. A. W. Evaluation of the safety of
　bupropion (Zyban) for smoking cessation from experience gained in general
　practice use in England in 2000. Pharmacoepidemiology and Prescription, 59,
　767-773. 2003.
Cabrera-Vera T.M. and Battaglia G. Prenatal exposure to fluoxetine (Prozac)
　produces site-specific and age-dependent alterations in brain serotonin
　transporters in rat progeny: evidence from autoradiographic studies. Journal
　of Pharmacology & Experimental Therapeutics, 286(3), 1474-1481. 1998.
Carrasco M. C., Vicens P., Vidal J. and Redolat R. Effects of acute
　administration of bupropion on behavior in the elevated plus-maze test by
　NMRI mice. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 28,
　1135-1141.2004.
Carroll M. E., Lac S. T., Asencio M. and Kragh R. Fluoxetine reduces
　intravenous cocaine self-administration in rats. Pharmacology, Biochemistry &
　Behavior, 35, 237-244. 1990.
Chambers C. D., Johnson K. A., Dick L. M., Felix R. J. and Jones K. L. Birth
　outcomes in pregnant women taking fluoxetine. The New England Journal of
　Medicine, 335(14), 1010-1015. 1996.
Christensen H. D., Rayburn W. F., Gonzalez C. L. Chronic prenatal exposure to
　paroxetine (Paxil) and cognitive development of mice offspring.
　Neurotoxicology and Teratology, 22, 733-739. 2000.
Cohen L. S. and Rosenbaum J. F. Psychotropic drug use during pregnancy:
　weighing the risks. Journal of Clinical Psychiatry, 59 (suppl 2), 18-28. 1998.
Cohen L. S., Heller V. L., Bailey J. W., Grush L., Ablon J. S. and bouffard S.
　M. Birth outcomes following prenatal exposure to fluoxetine. Biological
　Psychiatry, 48, 996-1000. 2000.
Coleman F. H., Christensen H. D., Gonzalez C. L. and Rayburn W. F. Behavioral c
　changes in developing mice after prenatal exposure to paroxetine (Paxil).
　American Journal of Obstetrics and Gynecology, 181(5), 1166-1171. 1999.
DaSilva V. A., Altenburg S. P., Malherios L. R., Thomaz T. G.. and Lindsey C.
　J. Postnatal development of rats exposed to fluvoxetine or venlafaxine during
　the third week of pregnancy. Brazilian Journal of medical & biological
　research, 32(1), 93-98. 1999.
Eninarson A., Bonari L., Voyer-Lavigne S., Addis A., Matsi D., Johnson Y. and
　Koren G. A multicentre prospective controlled study to determine the safety
　of trazodone and nefazodone use during pregnancy. The Canadian Journal of
　Psychiatry, 48(2), 106-110. 2003.
Feighner J. P., Mechanism of action of antidepressant medications. Journal of
　Clinical Psychiatry, 60 (suppl 4), 4-11. Fraser A. D. (1998) Urine drug
　testing for social service agencies in Nova Scotia, Canada. Journal of Forensic Sciences, 43(1), 194-196. 1999.Goldstein D. J. Effects of third
　trimester fluoxetine exposure on the newborn. Journal of Clinical
　Psychopharmacology, 15(6), 417-420. 1995.
Gotlib I. H., Whiffen V. E. and Mount J. H. Prevalence rates demographic
　characteristics associated with depression in pregnancy and postpartum.
　Journal of Consulting and Clinical Psychology, 57(2), 269-274. 1989.
Gregory E. S., Michael L. C. and Robert L. D. Outcomes of Prenatal
　antidepressant Exposure. American journal of psychiatry, 159(12), 2055-2061. 　2002.
Hachisu M. and Ichimaru Y. Pharmacological and clinical aspects of fluvoxamine
　(Depromel), the first selective serotonin reuptake inhibitor approved for
　clinical use employed in Japan. Nippon Yakurigaku Zasshi - Folia
　Pharmacologica Japonica, 115(5), 271-279. 2000.
Hall F. S., Li X. F., Sora L., Xu F., Caron M., Lesch K. P., Murphy D. L. and
　Uhl G. R. Cocaine mechanisms: enhanced cocaine, fluoxetine and nisoxetine
　place preference following monoamine transporter deletions. Neuroscience, 115
　(1), 153-161. 2002.
Hendrick V., Stowe Z. N., Altshuler L. L., Hwang S., Lee E. and Haynes D.
　Placental passage of antidepressant medications. American Journal of
　Psychiatry, 160(5), 993-996. 2003.
Hogg S. A review of the validity and variability of the elevated plus-maze as
　an animal model of anxiety. Pharmacology, Biochemistry & Behavior, 54(1), 21-
　30. 1996
Holcomb W. L., Stone L. S., Lustman P. J., Gavard J. A. and Mostello D. J.
　Screening for depression in pregnancy: characteristics of the Bech depression
　inventory. International Journal of Gynecology & Obstetrics, 88(6), 1021-
　1025. 1996.
Horst W. D. and Preskorn S. H. Mechanisms of action and clinical
　characteristics of three atypical antidepressants: venlafaxine, nefazodone,
　bupropion. Journal of Affective Disorders, 51, 237-254. 1998.
Kandel D., Chen K., Warner L. A., Kessler R. C. and Grant B. (1997) Prevalence
　and demographic correlates of symptoms of last dependence alcohol, nicotine,
　marijuana and cocaine in the U.S. population. Drug and Alcohol Dependence,
　44, 11-29. 1997.
Katz J. L., Izenwasser S. and Terry P. Relationships among dopamine transporter
　affinities and cocaine-like discriminative-stimulus effects.
　Psychopharmacology, 148, 90-98. 2000.
Kulin N. A., Pastuszak A., Sage S. R., Schick-Boschetto B., Spivey G., Feldkamp
　M., Ormond K., Matsui D., Stein-Schechman A. K., Cook L., Brochu J., Rieder
　M. and Koren G. Pregnancy outcome following maternal use of the new selective
　serotonin reuptake inhibitors: a prospective control multicenter study.
　Journal of the American Medical Association, 279(8), 609-610. 1998.
Lee K. and Kornetsky C. Acute and chronic fluoxetine treatment decreases the
　sensitivity of rats to rewarding brain stimulation. Pharmacology,
　Biochemistry & Behavior, 60(2), 539-544. 1998.
Lister R. G., The use of a plus-maze to measure anxiety in the mouse.
　Psychopharmacology, 92, 180-185. 1987.
Marcoli M. Maura G., Tortarolo M. and Raiteri M. Trazodone is a potent agonist
　at 5-HT2c Receptor mediateing inhibition of the N-Methyl-D-Aspartate/Nitric
　Oxide/Cyclic GMP pathway in rat cerebellum. The Journal of Pharmacology and
　Experimental Therapeutics, 285(3), 983-986. 1998.
Marcus S. M., Barry K. L., Glynn H.A., Tandon R. and Greden J. F. Treatment
　guidelines for depression in pregnancy. Internal Journal of Gynecology &
　Obstetrics, 72, 61-70. 2001.
Marek G. J., Mcdougle C. J., Price L. H. and Seiden L. S. (1992) A comparison
　of trazodone and fluoxetine: implications for a serotonergic mechanism of
　antidepressant action. Psychopharmacology, 109(1-2), 2-11. 1992.
Nowakowska E., Chodera A. and Kus K. The influence of fluoxetine on memory,
　anxiolytic activity and locomotor function in rats. European
　Neuropsychopharmacology, 6(suppl 3), 190. 1996.
Nulman I., Bovet J., Stewart D. E., Wolpin J., Gardner H. A., Theis J. G. W.,
　Kulin N. and Koren G. Neurodevelopment of children exposed in utero to
　antidepressant drugs. The New England Journal of Medicine, 336(4), 258-262.
　1997.
Oncken C. A. and Kranzler H. R. Pharmacotherapies to enhance smoking cessation
　during pregnancy. Drug and Alcohol Review, 22, 191-202. 2003.
Pohland R. C., Byrd T. K., Hamilton M. and Koons J. R. Placental transfer and
　fetal distribution of fluoxetine in the rat. Toxicology and Applied
　Pharmacology, 98(2), 198-205. 1989.
Preskorn S.H. and Othmer S. C. Evaluation of bupropion hydrochloride: the first
　of a new class of atypical antidepressants. Psychopharmacology, 4(1), 20-34.
　1984.
Rogerio R. and Takahashi R. N. Anxiogenic properties of cocaine in the rat
　evaluated with the elevated plus-maze. Pharmacology, Biochemistry & Behavior,
　43, 631-633. 1992.
Sadock B. J. and Sadock V. A. Kaplan & Sadock’s synosis of psychiatry:
　behavioral sciences, clinical psychiatry 9th ed. Lippincott Williams &
　Wilkins, PA, USA, 565-569. 2003.
Sasaki-Adams, D.M. and Kelley, A.E. Serotonin-dopamine interactions in the
　control of conditioned reinforcement and motor behavior.
　Neuropsychopharmacology, 25:440-452. 2001.
Singh Y., Jaiswal A. K. and Bhattacharya S. K. Effect of prenatal diazepam,
　Phenobarbital, haloperidol and fluoxetine exposure on foot shock induced
　aggression in rats. Indian Journal of Experimental Biology, 36(10), 1023-
　1024. 1998.
Sora I., Wichems C., Takahashi N., Li X-F., Zeng Z., Revay R., Lesch K. P.,
　Murphy D.L. and Uhl G. R. Cocaine reward models: conditioned place preference
　can be established in dopamine- and serotonin-transporter knockout mice.
　Proceedings of the National Academy of Sciences of the United States of
　America, 95, 7699-7704. 1998.
Stephen M. S. Selecting an antidepressant by using mechanism of action to
　enhance efficacy and avoid side effects. Journal of Clinical Psychiatry, 59
　(suppl 18), 23-29. 1998.
Tirelli E., Laviola G. and Adriani W. Ontogenesis of behavioral sensitization
　and conditioned place preference induced by psychostimulants in laboratory
　rodents. Neuroscience & Biobehavioral Reviews, 27(1-2), 163-78. 2003.
Tzschentke T. M. Mesureing reward with the conditioned place preference
　paradigm: a comprehensive review of drug effects, recent progress and
　new issues. Progress in Neurobiology, 56, 613-672. 1998.
Vorhee C. V., Acuff-Smith K. D., Schiling M. A., Fisher J. E., Moran M. S. and
　Buelke-Sam J. A Developmental neurotoxicity evaluation of the effects of
　prenatal exposure to fluoxetine in rats. Fundamental and Applied Toxicology,
　23, 194-205. 1994.