Translated Titles

Possible Role of Glutamatergic System in Depressive Disorder: Evidence of Data from Olfactory Bulbectomized Rats




何應瑞(Ying-Jui Ho);蔡元奮(Yuan-Feen Tsai)

Key Words

憂鬱症 ; 杏仁核 ; 動物模式 ; 麩胺酸神經系統 ; depression ; amygdala ; animal model ; glutamatergic system



Volume or Term/Year and Month of Publication

19卷1期(2005 / 03 / 01)

Page #

5 - 18

Content Language


Chinese Abstract

憂鬱症是盛行率相當高的精神疾病,由於不容易直接測量病患腦部之神經活性,因此藉由可資模擬的動物模式所得的研究結果,或將有助於瞭解形成憂鬱症可能的神經機轉。壓力是誘發憂鬱症的重要因子,研究上發現「噢球被切除之大鼠」(olfactory bulbectomized rats; OBX 大鼠)在受到壓力的環境中,其神經、免疫及內分泌反應之特徵與憂鬱症患者頗為相似,而且以抗憂鬱劑長期處理可以改善其生理及行為症狀,所以 OBX大鼠常作為研究憂鬱症的動物模式,其行為表現亦被廣泛作為篩選抗憂鬱劑之用。過去半個世紀以來,已經有相當多的研究探討大鼠的單肢類(monoamine)神經系統在嗅球被切除之後的變化。而近20無之研究結果亦發現麩膠酸(glutamate)神經系統在此動物模式中扮演著重要的角色。大鼠的嗅球投射麩腔酸神經纖維到杏仁核(amygdale),而杏仁核也有複雜的麩胺酸神經系統聯繫其他腦區,並且參與動物對壓力之反應。以電流刺激噢球,會抑制杏仁核內神經元之放電;若將嗅球切除,則會增加杏仁核內神經元的活性,並且降低杏仁核與大腦皮質內N-methyl-D-aspartate受體的密度。OBX大鼠在行為上會出現過度劇烈的壓力反應,同時其紋狀體(striatum)內麩胺酸之釋放量亦增加。若以全身性給藥或將藥物局部投入杏仁核內以阻斷麩胺酸神經訊遞,則可以改善其行為異常的症狀,這些結果顯示OBX大鼠出現對壓力的異常反應可能係杏仁核及麩胺酸神經系統功能的變化所導致,吾人據此推測人類的憂鬱症或其他對壓力反應異常疾病的病理機轉可能與此有關。

English Abstract

Direct investigation of the neuronal mechanism of depression in the human brain is difficult. Previous research has employed animal models to explore this issue. Stress is recognized as one of the important factors that can induce depression. The neuronal, immune, and endocrine responses of the olfactory bulbectomized (OBX) rats in a stressful environment have been shown to be similar to those in patients with depression. Since these responses in OBX rats can be alleviated by chronic treatment with antidepressants, this animal model of depression has been used to screen for the antidepressant-like activity of drugs. In the past half century, research in OBX rats have focused on the monoaminergic system, but data from the recent two decades indicate that the glutamatergic system plays an important role in depression. The amygdala is involved in the stress response. It not only receives the glutamatergic fibers from olfactory bulbs but also projects such fibers to a wide brain area. Electrical stimulation in the olfactory bulbs attenuates while olfactory bulbectomy increases the neuronal firing in the amygdala. A decreased N-methyl-D-aspartate receptor density in the cerebral cortex and the amygdala as well as an exaggerated behavioral response to the stress, accompanied by an enhanced striatal glutamate release, are observed in OBX rats. These abnormalities in behavior can be suppressed by systemic or locally drug treatment in the amygdala which antagonizes glutamatergic transmission. These findings suggest that the amygdala and the glutamatergic system are involved in the dysfunction of stress response in OBX rats, and that the similar systems play a role in the pathology of human depression and disorders of stress response. (Full text in Chinese)

Topic Category 醫藥衛生 > 社會醫學
  1. Adamec RE,Burton P,Shallow T,Budgell J(1999).Unilateral block of NMDA receptors in the amygdala prevents predator stress-induced lasting increases in anxiety-like behavior and unconditioned startle--effective hemisphere depends on the behavior.Physiol Behav,65,739-751.
  2. Alberts JR,Friedman MI(1972).Olfactory bulb removal but not anosmia increases emotionality and mouse killing.Nature,238,454-455.
  3. Armony JL,LeDoux JE,Gazzaniga M (Ed.)(2000).The new cognitive neurosciences.Cambridge:PIT Press.
  4. Bagley J,Moghaddam B(1997).Temporal dynamics of glutamate efflux in the prefrontal cortex and in the hippocampus following repeated stress: effects of pretreatment with saline or diazepam.Neuroscience,77,65-73.
  5. Barros DM,Izquierdo LA,Mello e Souza T(2000).Molecular signalling pathways in the cerebral cortex are required for retrieval of one-trial avoidance learning in rats.Behav Brain Res,114,183-192.
  6. Beauchemin V,Lavoie N,Dennis T(1994).Quantitative autoradiographic studies of the effects of bilateral olfactory bulbectomy in the rat brain: central- and peripheral-type benzodiazepine receptors.Neuroscience,58,527-537.
  7. Brecht S,Martin-Villalba A,Zuschratter W,Bravo R,Herdegen T(1995).Transection of rat fimbria-for-nix induces lasting expression of c-Jun protein in axotomized septal neurons immunonegative for choline acetyltransferase and nitric oxide synthase.Exp Neurol,134,112-125.
  8. Bunney WE,Davis JM(1965).Norepinephrine in depressive research.Arch Gen Psychiatry,13,483.
  9. Cahill L,McGaugh JL(1998).Mechanisms of emotional arousal and lasting declarative memory.Trends Neurosci,21,294-299.
  10. Caimcross KD,Cox B,Forster C,Wren AF(1979).Olfactory projection systems, drugs and behaviour: a review.Psychoneuroendocrinology,4,253-272.
  11. Cairncross KD,Wren A,Cox B,Schnieden H(1977).Effects of olfactory bulbectomy and domicile on stress-induced corticosterone release in the rat.Physiol Behav,19,485-487.
  12. Calton JL,Kang MH,Wilson WA,Moore SD(2000).NMDA-Receptor-dependent synaptic activation of voltage-dependent calcium channels in basolateral amygdala.J Neurophysiol,83,685-692.
  13. Carroll BJ(1982).The dexamethasone suppression test for melancholia.Br J Psychiatry,140,292-304.
  14. Cattarelli M,Demael A(1986).Basal plasma corticosterone level after bilateral selective lesions of the olfactory pathways in the rat.Experientia,42,169-171.
  15. Cheng AT,Chen TH,Chen CC,Jenkins R(2000).Psychosocial and psychiatric risk factors for suicide.Case-control psychological autopsy study. Br J Psychiatry,177,360-365.
  16. Chong MY,Tsang HY,Chen CS(2001).Community study of depression in old age in Taiwan: prevalence, life events and socio-demographic correlates.Br J Psychiatry,178,29-35.
  17. Collins GG(1984).Amino acid transmitter candidates in various regions of the primary olfactory cortex following bulbectomy.Brain Res,296,145-147.
  18. Collins GG(1979).Effect of chronic bulbectomy on the depth distribution of amino acid transmitter candidates in rat olfactory cortex.Brain Res,171,552-555.
  19. Collins GG(1982).Some effects of excitatory amino acid receptor antagonists on synaptic transmission in the rat olfactory cortex slice.Brain Res,244,311-318.
  20. Cotman CW,Monaghan DT,Ottersen OP,Storm-Mathisen J(1987).Anatomical organization of excitatory amino acid receptors and their pathways.Trends Neurosci,10,273-279.
  21. Crawley JN,Evers JR,Paul SM(1992).Polyamines inhibit N-methyl-D-aspartate antagonist-induced darting behavior in the rat prefrontal cortex.Brain Res,586,6-11.
  22. Davis M(1992).The role of the amygdala in fear and anxiety.Annu Rev Neurosci,15,353-375.
  23. Davis M,Rainnie D,Cassell M(1994).Neurotransmission in the rat amygdala related to fear and anxiety.Trends Neurosci,17,208-214.
  24. DeOlmos J,Alheid GF,Beltramino CA,Paxinos G (ed.)(1985).The Rat Nervous System.New York:Acadamic Press.
  25. Drevets WC(2001).Neuroimaging and neuropathological studies of depression: implications for the cognitive-emotional features of mood disorders.Cuff Opin Neurobiol,11,240-249.
  26. Duman RS(2002).Synaptic plasticity and mood disorders.Mol Psychiatry,7,29-34.
  27. Fagg GE,Foster AC(1983).Amino acid neurotransmitters and their pathways in the mammalian central nervous system.Neuroscience,9,701-719.
  28. Garcia Y,Ibarra C,Jaffe EH(1995).NMDA and non-NMDA receptor-mediated release of [3H]GABA from granule cell dendrites of rat olfactory bulb.J Neurochem,64,662-669.
  29. Gerfen CR,Wilson CJ,Swanson LW (eds.),Bjorklund A (eds.),Hokfelt T, (eds.)(1996).Handbook of Chemical Neuroanatomy.Elsevier:
  30. Glavin GB,Pare WP,Sandbak T,Bakke HK,Munson R(1994).Restraint stress in biomedical research: an update.Neurosci Biobehav Rev,18,223-249.
  31. Godfrey DA,Ross CD,Carter JA,Lowry OH,Matschinsky FM(1980).Effect of intervening lesions on amino acid distributions in rat olfactory cortex and olfactory bulb.J Histochem Cytochem,28,1157-1169.
  32. Harkin A,Kelly JP,Leonard BE(2003).A review of the relevance and validity of olfactory bulbectomy as a model of depression.Clin Neurosci Res,3,253-262.
  33. Heresco-Levy U,Javitt DC(1998).The role of N-methyl-D-aspartate (NMDA) receptor-mediated neurotransmission in the pathophysiology and therapeutics of psychiatric syndromes: Eur Neurop-sychopharmacol,8,141-152.
  34. Ho YJ,Chang YC,Liu TM,Tai MY,Wong CS,Tsai YF(2000).Striatal glutamate release during novelty exposure-induced hyperactivity in olfactory but-bectomized rats.Neurosci Lett,287,117-120.
  35. Ho YJ,Chen KH,Tai MY,Tsai YF(2004).MK-801 suppresses muricidal behavior but not locomotion in olfactory bulbectomized rats: involvement of NMDA receptors.Pharmacol Biochem Behav,77,641-646.
  36. Ho YJ,Liu T,Tai M(2001).Effects of olfactory bulbectomy on NMDA receptor density in the rat brain.Brain Res,900,214-218.
  37. Hsuchou H,Ho YJ,Shui HA,Tai MY,Chen KH,Tsai YF(2002).Effects of incisor-cutting on muricidal behavior induced by olfactory bulbectomy in rats.Physiol Behav,76,669-675.
  38. Huang YY,Martin KC,Kandel ER(2000).Both protein kinase A and mitogen-activated protein kinase are required in the amygdala for the macromolecular synthesis-dependent late phase of long-term potentiation.J Neurosci,20,6317-6325.
  39. Hwu HG,Yeh EK,Chang LY(1989).Prevalence of psychiatric disorders in Taiwan defined by the Chinese Diagnostic Interview Schedule.Acta Psychiatr Scand,79,136-147.
  40. Izquierdo I,Bianchin M,Silva MB(1993).CNQX infused into rat hippocampus or amygdala disrupts the expression of memory of two different tasks.Behav Neural Biol,59,1-4.
  41. Izquierdo I,da Cunha C,Rosat R,Jerusalinsky D,Ferreira MB,Medina JH(1992).Neurotransmitter receptors involved in post-training memory processing by the amygdala, medial septum, and hippocampus of the rat.Behav Neural Biol,58,16-26.
  42. Izquierdo I,Medina JH(1997).Memory formation: the sequence of biochemical events in the hippocampus and its connection to activity in other brain structures.Neurobiol Learn Mem,68,285-316.
  43. Jackson ME,Moghaddam B(2001).Amygdala regulation of nucleus accumbens dopamine output is governed by the prefrontal cortex.J Neurosci,21,676-681.
  44. Jones SM,Johnson KM(1989).Effects of amygdaloid kindling on NMDA receptor function and regulation.Exp Neurol,106,52-60.
  45. Karli P,Vergnes M(1965).Role des differentes compos-antes du complexe nucleair amygdalieu dans la facilitation de aggressivite interspecifique du rat.CR Seances Soc Biol Fil,159,754.
  46. Kelly JP,Leonard BE(1999).An investigation of the antidepressant properties of lofepramine and its desmethylated metabolites in the forced swim and olfactory bulbectomized rat models of depression.Eur Neuropsychopharmacol,9,101-105.
  47. Kelly JP,Wrynn AS,Leonard BE(1997).The olfactory bulbectomized rat as a model of depression: an update.Pharmacol Ther,74,299-316.
  48. Kim M,Campeau S,Falls WA,Davis M(1993).Infusion of the non-NMDA receptor antagonist CNQX into the amygdala blocks the expression of fear-potentiated startle.Behav Neural Biol,59,5-8.
  49. Kita H,Kitai ST(1990).Amygdaloid projections to the frontal cortex and the striatum in the rat.J Comp Neurol,298,40-49.
  50. Krystal JH,D''Souza DC,Petrakis IL(1999).NMDA agonists and antagonists as probes of glutamatergic dysfunction and pharmacotherapies in neuropsychiatric disorders.Harv Rev Psychiatry,7,125-143.
  51. Kuipers SD,Trentani A,Den Boer JA,Ter Horst GJ(2003).Molecular correlates of impaired prefrontal plasticity in response to chronic stress.J Neurochem,85,1312-1323.
  52. Lane RD,Reiman EM,Bradley MM(1997).Neuroanatomical correlates of pleasant and unpleasant emotion.Neuropsychologia,35,1437-1444.
  53. Leonard BE,Tuite M(1981).Anatomical, physiological, and behavioral aspects of olfactory bulbectomy in the rat.Int Rev Neurobiol,22,251-286.
  54. Liang KC,Hon W,Davis M(1994).Pre- and posttraining infusion of N-methyl-D-aspartate receptor antagonists into the amygdala impair memory in an inhibitory avoidance task.Behav Neurosci,108,241-253.
  55. Liang KC,Lin MH,Tyan YM(1993).Involvement of amygdala N-methyl-D-aspartate receptors in long-term retention of an inhibitory avoidance response in rats.Chinese J. Physiol,36,47.
  56. Lin CH,Lee CC,Gean PW(2003).Involvement of a calcineurin cascade in amygdala depotentiation and quenching of fear memory.Mol Pharmacol,63,44-52.
  57. Louilot A,Besson C(2000).Specificity of amygdalostriatal interactions in the involvement of mesencephalic dopaminergic neurons in affective perception.Neuroscience,96,73-82.
  58. Lowell E,White JR(1965).Olfactory bulb projections of the rat.Anat Rec,152,465-480.
  59. Lowy MT,Gault L,Yamamoto BK(1993).Adrenalectomy attenuates stress-induced elevations in extracellular glutamate concentrations in the hippocampus.J Neurochem,61,1957-1960.
  60. Lu RB,Ko HC,Lin YT,Shen LJ(1991).Platelet 5-HT in depression: a preliminary study.Clin Psychiatry,5,29-35.
  61. Mar A,Spreekmeester E,Rochford J(2000).Antidepressants preferentially enhance habituation to novelty in the olfactory bulbectomized rat.Psychopharmacology (Berl),150,52-60.
  62. Mar A,Spreekmeester E,Rochford J(2002).Fluoxetine-induced increases in open-field habituation in the olfactory bulbectomized rat depend on test aversiveness but not on anxiety.Pharmacol Biochem Behav,73,703-712.
  63. McDonald AJ(1996).Glutamate and aspartate immuno-reactive neurons of the rat basolateral amygdala: colocalization of excitatory amino acids and projections to the limbic circuit.J Comp Neurol,365,367-379.
  64. McDonald AJ(1992).Projection neurons of the basolateral amygdala: a correlative Golgi and retrograde tract tracing study.Brain Res Bull,28,179-185.
  65. McDonald AJ,Aggleton JP (Ed.)(1992).The Amygdala: Neurobiological Aspects of Emotion Memory and Memory Dysfunction.New York:Wiley-Liss.
  66. McGaugh JL(2000).Memory--a century of consolidation.Science,287,248-251.
  67. McKernan MG,Shinnick-Gallagher P(1997).Fear conditioning induces a lasting potentiation of synaptic currents in vitro.Nature,390,607-611.
  68. McNish KA,Davis M(1997).Olfactory bulbectomy enhances sensitization of the acoustic startle reflex produced by acute or repeated stress.Behav Neurosci,111,80-91.
  69. Mesches MH,Bianchin M,McGaugh JL(1996).The effects of intra-amygdala infusion of the AMPA receptor antagonist CNQX on retention performance following aversive training.Neurobiol Learn Mem,66,324-340.
  70. Moghaddam B(1993).Stress preferentially increases extraneuronal levels of excitatory amino acids in the prefrontal cortex: comparison to hippocampus and basal ganglia.J Neurochem,60,1650-1657.
  71. Nakanishi H,Ukai K,Nakagawa T,Watanabe S,Kamata O,Yamamoto K(1990).Enhancement of NMDA receptor-mediated synaptic potential evoked in rat medial-amygdala neuron following olfactory bulbectomy.Brain Res,532,69-75.
  72. Nemeroff CB(1994).Evolutionary trends in the pharma-cotherapeutic management of depression.J Clin Psychiatry,55,3-15.
  73. Norrholm SD,Ouimet CC(2001).Altered dendritic spine density in animal models of depression and in response to antidepressant treatment.Synapse,42,151-163.
  74. Nowak G(1996).Calcium antagonists in the olfactory bulbectomy animal model of depression: effect on the cortical NMDA receptor complex.Pol J Pharmacol,48,137-143.
  75. Nowak G,Ordway GA,Paul IA(1995).Alterations in the N-methyl-D-aspartate (NMDA) receptor complex in the frontal cortex of suicide victims.Brain Res,675,157-164.
  76. O''Neill B,Leonard BE(1990).Abnormal zymosan-induced neutrophil chemiluminescence as a marker of depression.J Affect Disord,19,265-272.
  77. Papp M,Moryl E(1994).Antidepressant activity of noncompetitive and competitive NMDA receptor antagonists in a chronic mild stress model of depression.Eur J Pharmacol,263,1-7.
  78. Paul IA,Layer RT,Skolnick P,Nowak G(1993).Adaptation of the NMDA receptor in rat cortex following chronic electroconvulsive shock or imipramine.Eur J Pharmacol,247,305-311.
  79. Pause BM,Krauel K(2000).Chemosensory event-related potentials (CSERP) as a key to the psychology of odors.Int Psychophysiol,36,105-122.
  80. Paykel E(1992).Hank book of affective disorders.New York:Guilford Press.
  81. Redmond AM,Kelly JP,Leonard BE(1997).Behavioural and neurochemical effects of dizocilpine in the olfactory bulbectomized rat model of depression.Pharmacol Biochem Behav,58,355-359.
  82. Reid IC,Stewart CA(2001).How antidepressants work: new perspectives on the pathophysiology of depressive disorder.Br J Psychiatry,178,299-303.
  83. Richelson E(2001).Pharmacology of antidepressants.Mayo Clin Proc,76,511-527.
  84. Roberson ED,English JD,Sweatt JD(1996).A biochemist's view of long-term potentiation.Learn Mem,3,1-24.
  85. Robichaud M,Beauchemin V,Lavoie N,Dennis T,Debonnel G(2001).Effects of bilateral olfactory bulbectomy on N-methyl-D-aspartate receptor function: autoradiographic and behavioral studies in the rat.Synapse,42,95-103.
  86. Sajdyk TJ,Schober DA,Gehiert DR,Shekhar A(1999).Role of corticotropin-releasing factor and urocortin within the basolateral amygdala of rats in anxiety and panic responses.Behav Brain Res,100,207-215.
  87. Sajdyk TJ,Shekhar A(1997).Excitatory amino acid receptor antagonists block the cardiovascular and anxiety responses elicited by gamma-aminobuty-ric acidA receptor blockade in the basolateral am ygdala of rats.J Pharmacol Exp Ther,283,969-977.
  88. Saulskaya N,Marsden CA(1995).Extracellular glutamate in the nucleus accumbens during a conditioned emotional response in the rat.Brain Res,698,114-120.
  89. Sesack SR,Deutch AY,Roth RH,Bunney BS(1989).Topographical organization of the efferent projections of the medial prefrontal cortex in the rat: an anterograde tract-tracing study with Phaseolus vulgaris leucoagglutinin.J Comp Neurol,290,213-242.
  90. Shibata S,Suwandi D,Yamamoto T,Ueki S(1982).Effects of medial amygdaloid lesions on the initiation and the maintenance of muricide in olfactory bulbectomized rats.Physiol Behav,29,939-941.
  91. Shibata S,Watanabe S(1994).Facilitatory effect of olfactory bulbectomy on 2-deoxyglucose uptake in rat amygdala slices.Brain Res,665,147-150.
  92. Shors TJ,Pickett J,Wood G,Paczynski M(1999).Acute stress persistently enhances estrogen levels in the female rat.Stress,3,163-171.
  93. Smith WJ,Stewart J,Pfaus JG(1997).Tail pinch induces fos immunoreactivity within several regions of the male rat brain: effects of age.Physiol Behav,61,717-723.
  94. Song C,Leonard BE(1993).effect of thymopeptides on the behavior and some immunological responses in the olfactory bulbectomized rat.Med Sci Res,20,929-930.
  95. Song C,Leonard BE(1994).Serotonin reuptake inhibitors reverse the impairments in behavior, neurotransmitter and immune functions in the olfactory bulbectomized rat.Hum Psychopharmacol,9,135-146.
  96. Song C,Leonard BE(1995).The effects of olfactory bulbectomy in rat, alone or in combination with anti-depressants and endogenous factors, on immune function.Hum Psychopharmacol,10,7-18.
  97. Steiner JE,Lidar-Lifschitz D,Perl E(1993).Taste and odor: reactivity in depressive disorders, a multidisciplinary approach.Percept Mot Skills,77,1331-1346.
  98. Stock HS,Hand GA,Ford K,Wilson MA(2001).Changes in defensive behaviors following olfactory bulbectomy in male and female rats.Brain Res,903,242-246.
  99. Straughan DW,Legge KF(1965).The pharmacology of amygdaloid neurones.J Pharm Pharmacol,17,675-677.
  100. Trullas R,Skolnick P(1990).Functional antagonists at the NMDA receptor complex exhibit antidepressant actions.Eur J Pharmacol,185,1-10.
  101. Van de Kar LD,Blair ML(1999).Forebrain pathways mediating stress-induced hormone secretion.Front Neuroendocrinol,20,1-48.
  102. van Riezen H,Leonard BE(1990).Effects of psychotropic drugs on the behavior and neurochemistry of olfactory bulbectomized rats.Pharmacol Ther,47,21-34.
  103. van Riezen H,Schnieden H,Wren A(1976).Behavioural changes following olfactory bulbectomy in rats: a possible model for the detection of antidepressant drugs [proceedings].Br J Pharmacol,57,426-427.
  104. van Rijzingen IM,Gispen WH,Spruijt BM(1995).Olfactory bulbectomy temporarily impairs Morris maze performance: an ACTH(4-9) analog accel-lerates return of function.Physiol Behav,58,147-152.
  105. Vergnes M,Karli P(1963).Declenchement du comportenent d'agression interspecifique Rat-Souris par ablation bilaterale des bulbes olfactifs: action de l'hydroxyzine sur cette aggressivite provoquee.CR Seances Soc Biol Fil,157
  106. Watanabe S,Fukuda T,Ueko S(1980).Changes in electroencephalogram of the rat following olfactory bulbectomy.Tohoku J Exp Med,130,41-48.
  107. Weinstock M,Poltyrev T,Schorer-Apelbaum D,Men D,McCarty R(1998).Effect of prenatal stress on plasma corticosterone and catecholamines in response to footshock in rats.Physiol Behav,64,439-444.
  108. Wheeler D,Boutelle MG,Fillenz M(1995).The role of N-methyl-D-aspartate receptors in the regulation of physiologically released dopamine.Neuroscience,65,767-774.
  109. Woodruff GN,Foster AC,Gill R,Kemp JA,Wong EH,Iversen LL(1987).The interaction between MK-801 and receptors for N-methyl-D-aspartate: functional consequences.Neuropharmacology,26,903-909.
  110. Wrynn AS,Mac Sweeney CP,Franconi F(2000).An in-vivo magnetic resonance imaging study of the olfactory bulbectomized rat model of depression.Brain Res,879,193-199.
  111. Wrynn AS,Sebens JB,Koch T,Leonard BE,Korf J(2000).Prolonged c-Jun expression in the basolateral amygdala following bulbectomy: possible implications for antidepressant activity and time of onset.Brain Res Mol Brain Res,76,7-17.
  112. Zald DH,Pardo JV(1997).Emotion, olfaction, and the human amygdala: amygdala activation during aversive olfactory stimulation.Proc Natl Acad Sci USA,94,4119-4124.
  113. 何應瑞(2002)。博士論文(博士論文)。國立台灣大學生理學研究所。
  114. 胡海國、林信男(1995)。生物精神醫學。台北市:健康文化事業有限公司。
  115. 陸汝斌、柯慧貞(1993)。憂鬱症在生物化學上的異質性。中華精神醫學,7,3-9。
  116. 楊斯年、陸汝斌(1996)。憂鬱症。醫學繼續教育,6,433-440。
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