憂鬱症為現今社會普遍發生且嚴重的一種心理精神疾病，儘管憂鬱症的課題已經被相當程度的重視，並且也有許多相關的研究探討，然而截至目前為止，對於憂鬱症的治療效果仍普遍不理想。例如藥物的起始作用慢、藥效作用低且在經歷長期投藥的情況下常引起體內藥物毒性的產生與累積。因此，研究出一個更有效的治療策略來加速藥效產生並延長藥效的持續作用是現今相當重要的課題。在此實驗中，我們擬建立出更快速且有效的憂鬱症治療的策略及方法。在建立動物的憂鬱模式中，我們利用了小鼠坐骨神經損傷模型所引起的慢性疼痛進而產生類憂鬱的行為表現，並以體重下降、絕望行為以及令動物體愉悅的事物偏好程度下降來作為分析的指標，來檢測合併治療方法的可行性。在以腹腔注射的方式投予三環抗鬱藥imipramine及同時將其飼養於豐富優渥的環境之下，觀察使用此等方法是否能更有效的改善小鼠的類憂鬱行為。在尾巴懸吊試驗及糖水偏好試驗的研究中我們發現合併使用imipramine及豐富優渥環境飼養的條件下，可以較快速及持久地改善其類憂鬱之行為。此外，我們也發現坐骨神經損傷之小鼠其腹面海馬迴CA1區域和大腦前額皮質區的錐狀神經細胞元的型態會發生改變，並且在合併使用imipramine及豐富優渥環境的處理，雖然無法完全修正神經元的型態，但仍具有明顯減緩神經元型態改變的情形。接著再利用即時定量聚合酵素連鎖反應測量海馬迴CA1區域和大腦前額皮質區域腦衍生神經滋長因子、血管內皮生長因子以及白細胞介素-1β之mRNA的表現量時，我們發現合併使用imipramine及豐富優渥環境飼養籠具有快速的增加腦衍生神經滋長因子、血管內皮生長因子之mRNA的作用，但不改變白細胞介素-1β之mRNA的表現。在以VEGF受體二型剔除的基因轉殖小鼠作為研究的模式下，我們則發現VEGF受體第二型剔除的基因轉殖小鼠對於合併使用imipramine及豐富優渥環境飼養籠的處理所產生的抗憂鬱行為表現效果明顯的較野生型小鼠效果差。總結以上實驗結果，我們認為合併使用imipramine及豐富優渥環境飼養籠可以產生較快速並長久的抗憂鬱效果。此等策略可能在未來可以做為治療憂鬱症的一個重要參考。

Depression is one of the most common and most serious mental health problems facing people today. Despite years of research and efforts to develop effective treatments, currently available medications have significant limitations, most notably low response rate, time lag for treatment response and high toxicity. Therefore, developing a rapid onset of action and more effective treatment strategies are urgently needed.
We used a combinational therapy of an enriched environment (EE) and a tricyclic antidepressant imipramine for relieving depressive-like behaviors induced by neuropathic pain in a mouse model of spared nerve injury (SNI).
As compared with sham-operated animals, SNI mice exhibited mechanical allodynia and displayed an increased depressive-like behavior, as revealed by a loss of body weight, a decrease in sucrose preference, and an increase in immobility time during the tail suspension test. SNI mice also exhibited a significant decrease in the number of dendritic spines in hippocampal CA1 and medial prefrontal cortex pyramidal neurons. We also found the morphology of the pyramidal neurons in hippocampal CA1 and medial prefrontal cortex changed. Measured the BDNF、VEGF and IL-1β mRNA in hippocampal CA1 and medial prefrontal cortex, SNI mice also exhibited a decreased level in mRNA. A subchronic (4 days) combination of an EE and imipramine treatment produced robust and rapid antidepressant-like responses compared with single treatment. Mice treated by a subchronic (4 days) combination of an EE and imipramine decreased depressive-like behavior in the behavioral tests. These antidepressant effects are accompanied by a reversal of dendritic and synaptic reorganization brought about by SNI. The levels of BDNF and VEGF mRNA in hippocampal CA1 and medial prefrontal cortex were also elevated by the combinational treatment. We also used heterozygous Flk-1 knockout mice to confirm the specific role of VEGF signaling in the effect of combinational treatment.
These results support that combinational therapy is more effective in providing antidepressant effects than a single treatment. These findings may highlight a novel strategy of combining multiple molecular targets to rescue depressive-like symptoms.

Alexia E. Metz1, Hau-Jie Yau, Maria Virginia Centeno, A. Vania Apkarian, and Marco Martina (2009) Morphological and functional reorganization of rat medial prefrontal cortex in neuropathic pain. PNAS 106:2423–2428.

Anup G, Pillai, Danielle de Jong, Sofia Kanatsou, Harm Krugers, Alana Knapman, Jan-Michael Heinzmann, Florian Holsboer, Rainer Landgraf, Marian Joëls, Chadi Touma (2012) dendritic morphology of hippocampal and amygdalar neurons in adolescent mice is resilient to genetic differences in stress reactivity. PLoS One. 7:e38971.

Apkarian AV, Sosa Y, Krauss BR, Thomas PS, Fredrickson BE, Levy RE, Harden RN, Chialvo DR (2004) Chronic pain patients are impaired on an emotional decision-making task. Pain 108:129-136.

Autry AE, Adachi M, Nosyreva E, Na ES, Los MF, Cheng PF, Kavalali ET, Monteggia LM (2011) NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature 475:91-95.

Barlow DH. (2005) Abnormal psychology: An integrative approach (5th ed.).

Benoit Petit-Demouliere, Franck Chenu, Michel Bourin (2005) Forced swimming test in mice: a review of antidepressant activity Psychopharmacology 177:245–255.

Bindu B, Alladi PA, Mansooralikhan BM, Srikumar BN, Raju TR, Kutty BM (2007) Short term exposure to an enriched environment enhances dendritic branching but not brain-derived neurotrophic factor expression in the hippocampus of rats with ventral subicular lesions. Neuroscience 144:412-423.

Blier P (2001) Pharmacology of rapid-onset antidepressant treatment strategies. J Clin Psychiatry 62 Suppl 15:12-17.

Blier P (2001) Possible neurobiological mechanisms underlying faster onset of antidepressant action. J Clin Psychiatry 62 Suppl 4:7-11.

Blum R, Kafitz KW, Konnerth A (2002) Neurotrophin-evoked depolarization requires the sodium channel NaV1.9 Nature 419:687-693.

Bremner JD, Narayan M, Anderson ER, Staib LH, Miller HL, Charney DS (2000) Hippocampal Volume Reduction in Major Depression. Am J Psychiatry 157:115-118.

Brown CE, Wong C, Murphy TH (2008) Rapid morphologic plasticity of peri-infarct dendritic spines after focal ischemic stroke. Stroke. 39:1286-1291.

Bruce S. McEwen (2006) Physiology and Neurobiology of Stress and Adaptation: Central Role of the Brain. Physiol Rev 87:873-904.

Carlo A. Porro, Patrizia Baraldi, Giuseppe Pagnoni, Marco Serafini, Patrizia Facchin, Marta Maieron, Paolo Nichelli (2002) Does Anticipation of Pain Affect Cortical Nociceptive Systems? J Neurosci 22:3206-3214.

Castrén E, Rantamäki T (2010) The role of BDNF and its receptors in depression and antidepressant drug action: Reactivation of developmental plasticity. Dev Neurobiol 70:289-297.

Ceretta LB, Réus GZ, Stringari RB, Ribeiro KF, Zappellini G, Aguiar BW, Pfaffenseller B, Lersh C, Kapczinski F, Quevedo J (2012) Imipramine treatment reverses depressive-like behavior in alloxan-diabetic rats. Diabetes Metab Res Rev 28:139-144.

Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL (1994) Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 53:55-63.

Chiuan-Shiou Chiou, Chiung-Chun Huang, Ying-Ching Liang, Yu-Chuan Tsai, Kuei-Sen Hsu (2012) Impairment of long-term depression in the anterior cingulate cortex of mice with bone cancer pain. Pain 153:2097–2108.

Colla M, Kronenberg G, Deuschle M, Meichel K, Hagen T, Bohrer M, Heuser I (2007) Hippocampal volume reduction and HPA-system activity in major depression. J Psychiatr Res 41:553-560.

Cross-national comparisons of the prevalences and correlates of mental disorders. WHO International Consortium in Psychiatric Epidemiology

Cryan JF, Mombereau C, Vassout A (2005) The tail suspension test as a model for assessing antidepressant activity: review of pharmacological and genetic studies in mice. Neurosci Biobehav Rev 29:571-625.

Decosterd I, Woolf CJ (2000) Spared nerve injury: an animal model of persistent peripheral neuropathic pain. Pain 87:149-158.

Delgado PL (2000) Depression: the case for a monoamine deficiency. J Clin Psychiatry 61 Suppl 6:7-11.

Duman RS (2004) Depression: a case of neuronal life and death? Biol Psychiatry 56:140-145.

Eero Castrén, Vootele Võikar, Tomi Rantamäki (2007) Role of neurotrophic factors in depression. Transl Neurosci 7:18-21.

Elhwuegi AS (2004) Central monoamines and their role in major depression. Prog Neuropsychopharmacol Biol Psychiatry 28:435-451.

Feighner JP (1999) Mechanism of action of antidepressant medications.
J Clin Psychiatry 60 Suppl 4:4-11.

Forbes NF, Stewart CA, Matthews K, Reid IC (1996) Chronic mild stress and sucrose consumption: validity as a model of depression. Physiol Behav 60:1481-1484.

G J Norman, K Karelina, N Zhang, J C Walton, J S Morris and A C DeVries (2010) Stress and IL-1β contribute to the development of depressive-like behavior following peripheral nerve injury. Molecular Psychiatry 15:404–414.

Hasler G, Drevets WC, Manji HK, Charney DS (2004) Discovering endophenotypes for major depression. Neuropsychopharmacology 29:1765-1781.

Hattori S, Hashimoto R, Miyakawa T, Yamanaka H, Maeno H, Wada K, Kunugi H (2007) Enriched environments influence depression-related behavior in adult mice and the survival of newborn cells in their hippocampi. Behav Brain Res 180:69-76.

Heldt SA, Stanek L, Chhatwal JP, Ressler KJ (2007) Hippocampus-specific deletion of BDNF in adult mice impairs spatial memory and extinction of aversive memories Mol Psychiatry 12:656-670.

Huang YF, Yang CH, Huang CC, Hsu KS (2012) Vascular endothelial growth factor-dependent spinogenesis underlies antidepressant-like effects of enriched environment. J Biol Chem 287:40938-40955.

Isao Kitayama, Takatoshi Yaga, Tetsuro Kayahara, Katsuma Nakano, Sumio Murase, Masato Otani, Junichi Nomura (1997) Long-Term Stress Degenerates, But Imipramine Regenerates, Noradrenergic Axons in the Rat Cerebral Cortex. Biological Psychiatry 42:687–696.

Itoh T, Tokumura M, Abe K (2004) Effects of rolipram, a phosphodiesterase 4 inhibitor, in combination with imipramine on depressivebehavior, CRE-binding activity and BDNF level in learned helplessness rats. Eur J Pharmacol. 498:135-142.

John F. Cryan, Cedric Mombereau, Annick Vassout (2005) The tail suspension test as a model for assessing antidepressant activity: Review of pharmacological and genetic studies in mice. Animal Models of Depression and Antidepressant Activity 29:571-625.

K.G. Rasmussen, T.A. Rummans (2002) Electroconvulsive therapy in the management of chronic pain Curr. Pain Headache Rep 6:17–22.

Lêda S.B. Garcia a, Clarissa M. Comima, Samira S. Valvassoria, Gislaine Z. Réus a, Luciana M. Barbosa a, Ana Cristina Andreazza b, Laura Stertz b, Gabriel R. Fries b, Elaine Cristina Gavioli a, Flavio Kapczinski b, João Quevedo (2008) Acute administration of ketamine induces antidepressant-like effects in the forced swimming test and increases BDNF levels in the rat hippocampus. Progress in Neuro-Psychopharmacology and Biological Psychiatry 32:140-144.

Liston C, Miller MM, Goldwater DS, Radley JJ, Rocher AB, Hof PR, Morrison JH, McEwen BS (2006) Stress-induced alterations in prefrontal cortical dendritic morphology predict selective impairments in perceptual attentional set-shifting. J Neurosci 26:7870-7874.

Llorens-Martín MV, Rueda N, Martínez-Cué C, Torres-Alemán I, Flórez J, Trejo JL (2007) Both increases in immature dentate neuron number and decreases of immobility time in the forced swim test occurred in parallel after environmental enrichment of mice. Neuroscience 147:631-638.

Lyons WE, Mamounas LA, Ricaurte GA, Coppola V, Reid SW, Bora SH, Wihler C, Koliatsos VE, Tessarollo L (1999) Brain-derived neurotrophic factor-deficient mice develop aggressiveness and hyperphagia in conjunction with brain serotonergic abnormalities. Proc Natl Acad Sci U S A 96:15239-15244.

Maletic V, Raison CL (2009) Neurobiology of depression,, fibromyalgia and neuropathic pain. Front Biosci 14:5291-5338.

Malykhin N. V., Carter R., Seres P., Coupland N. J (2010) Structural changes in the hippocampus in major depressive disorder. Contributions of disease and treatment. J. Psychiatry Neurosci 35:337–343.

Marchetti C, Tafi E, Middei S, Rubinacci MA, Restivo L, Ammassari-Teule M, Marie H (2010) Synaptic adaptations of CA1 pyramidal neurons induced by a highly effective combinational antidepressant therapy. Biol Psychiatry 67:146-154.

Mariusz Papp, Paul Willner, and Richard Muscat (1991) An animal model of anhedonia: attenuation of sucrose consumption and place preference conditioning by chronic unpredictable mild stress. Psychopharmacology 104:255-259.

Monteggia LM, Barrot M, Powell CM, Berton O, Galanis V, Gemelli T, Meuth S, Nagy A, Greene RW, Nestler EJ (2004) Essential role of brain-derived neurotrophic factor in adult hippocampal function Proc Natl Acad Sci U S A 101:10827-10832.

Murer MG, Yan Q, Raisman-Vozari R (2001) Brain-derived neurotrophic factor in the control human brain, and in Alzheimer's disease and Parkinson's disease. Prog Neurobiol 63:71-124.

Neil Carlson (2005) Foundations of Physiological Psychology, 6th ed. P.108

Nowacka MM, Obuchowicz E (2012) Vascular endothelial growth factor (VEGF) and its role in the central nervous system: a new element in the neurotrophic hypothesis of antidepressant drug action. Neuropeptides 46:1-10.

Nutt DJ (2008) Relationship of neurotransmitters to the symptoms of major depressive disorder". Journal of Clinical Psychiatry 69 Suppl E1: 4–7.

Pittenger C., Duman R. S (2008) Stress, depression, and neuroplasticity. A convergence of mechanisms. Neuropsychopharmacology 33:88–109.

Richner M, Bjerrum OJ, Nykjaer A, Vaegter CB (2011) The spared nerve injury (SNI) model of induced mechanical allodynia in mice. J Vis Exp 54:57-66.

Ronald S. Duman, Lisa M. Monteggia (2006) A Neurotrophic Model for Stress-Related Mood Disorders. Biol Psychiatry 15:1116-1127.

Shimizu E, Hashimoto K, Okamura N, Koike K, Komatsu N, Kumakiri C, Nakazato M, Watanabe H, Shinoda N, Okada S, Iyo M (2003) Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants. Biol Psychiatry 54:70-75.

S Jha, B Dong, and K Sakata (2011) Enriched environment treatment reverses depression-like behavior and restores reduced hippocampal neurogenesis and protein levels of brain-derived neurotrophic factor in mice lacking its expression through promoter IV. Transl Psychiatry 1:40.

Smith MA, Makino S, Kvetnansky R, Post RM (1995) Stress and glucocorticoids affect the expression of brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus. J Neurosci 15:1768-1777.

Sousa N., Lukoyanov N. V., Madeira M. D., Almeida O. F., Paula-Barbosa M. M (2000) Reorganization of the morphology of hippocampal neurites and synapses after stress-induced damage correlates with behavioral improvement.Neuroscience 97:253–266.

Stahl SM (1998) Basic psychopharmacology of antidepressants, part 1: Antidepressants have seven distinct mechanisms of action. J Clin Psychiatry Suppl 4:5-14.

Steru L., Chermat R., Thierry B., Simon P (1985) The tail suspension test: a new method for screening antidepressants in mice. Psychopharmacology 85:367–370.

Strekalova T, Spanagel R, Bartsch D, Henn FA, Gass P (2004) Stress-induced anhedonia in mice is associated with deficits in forced swimming and exploration. Neuropsychopharmacology 29:2007-2017.
Susan C. Cook, Cara L. Wellman (2004) Chronic stress alters dendritic morphology in rat medial prefrontal cortex. Journal of Neurobiology 60:236-248.

Vanderkooy JD, Kennedy SH, Bagby RM (2002) Antidepressant side effects in depression patients treated in a naturalistic setting: a study of bupropion, moclobemide, paroxetine, sertraline, and venlafaxine. Canadian Journal of Psychiatry. Revue Canadienne de Psychiatrie 47: 174-180.

Veena J, Srikumar BN, Mahati K, Bhagya V, Raju TR, Shankaranarayana Rao BS (2009) Enriched environment restores hippocampal cell proliferation and ameliorates cognitive deficits in chronically stressed rats J Neurosci Res 87:831-843.

Viikki M, Anttila S, Kampman O, Illi A, Huuhka M, Setälä-Soikkeli E, Mononen N, Lehtimäki T, Leinonen E (2010) Vascular endothelial growth factor (VEGF) polymorphism is associated with treatment resistant depression. Neurosci Lett 477:105-108.

Wang J, Goffer Y, Xu D, Tukey DS, Shamir DB, Eberle SE, Zou AH, Blanck TJ, Ziff EB (2011) A single subanesthetic dose of ketamine relieves depression-like behaviors induced by neuropathic pain in rats. Anesthesiology 115:812-821.

Warner-Schmidt JL, Duman RS (2007) VEGF is an essential mediator of the neurogenic and behavioral actions of antidepressants. Proc Natl Acad Sci U S A 104:4647-4652.

Warner-Schmidt JL, Duman RS (2008) VEGF as a potential target for therapeutic intervention in depression. Curr Opin Pharmacol 8:14-19.

Wei Wang, Dalong Sun, Bin Pan, Christopher J Roberts, Xinglai Sun, Cecilia J Hillard, Qing-song Liu (2010) Deficiency in Endocannabinoid Signaling in the Nucleus Accumbens Induced by Chronic Unpredictable Stress. Neuropsychopharmacology 35:2249–2261.

Wright RL, Conrad CD (2008) Enriched environment prevents chronic stress-induced spatial learning and memory deficits. Behav. Brain Res 187:41-47.