New approaches to antidepressant drug discovery: Beyond monoamines

Nature Reviews Neuroscience

Volumn 7, Issue 2, 2006, Pages 137-151

  Berton, Olivier ^a   Nestler, Eric J ^a  

^a UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALPHA ADRENERGIC RECEPTOR BLOCKING AGENT; ALPHA ADRENERGIC RECEPTOR STIMULATING AGENT; AMFEBUTAMONE; ANTIDEPRESSANT AGENT; ATOMOXETINE; CANNABINOID RECEPTOR AGONIST; CANNABINOID RECEPTOR ANTAGONIST; CITALOPRAM; CORTICOTROPIN RELEASING FACTOR ANTAGONIST; CYTOKINE; DESIPRAMINE; DULOXETINE; FLUOXETINE; GALANIN; HISTONE DEACETYLASE INHIBITOR; IMIPRAMINE; KAPPA OPIATE RECEPTOR ANTAGONIST; LITHIUM; MIRTAZAPINE; MONOAMINE DERIVATIVE; MONOAMINE OXIDASE INHIBITOR; NORADRENALIN UPTAKE INHIBITOR; PHENELZINE; REBOXETINE; SEROTONIN UPTAKE INHIBITOR; TIANEPTINE; TRANYLCYPROMINE; TRICYCLIC ANTIDEPRESSANT AGENT; UNINDEXED DRUG; VENLAFAXINE;

BRAIN DEPTH STIMULATION; BRAIN FUNCTION; BRAIN REGION; CLINICAL EFFECTIVENESS; DEPRESSION; DRUG EFFICACY; DRUG MECHANISM; DRUG SAFETY; ELECTROCONVULSIVE THERAPY; ENZYME ACTIVITY; HUMAN; MAGNETIC STIMULATION; MEDICAL RESEARCH; MOOD DISORDER; NONHUMAN; PRIORITY JOURNAL; PSYCHOTHERAPY; REVIEW; VAGUS NERVE STIMULATION;

ANIMALS; ANTIDEPRESSIVE AGENTS; BIOGENIC MONOAMINES; BRAIN CHEMISTRY; DEPRESSIVE DISORDER; DISEASE MODELS, ANIMAL; HUMANS; HYPOTHALAMO-HYPOPHYSEAL SYSTEM; MODELS, NEUROLOGICAL;

EID: 31444441701     PISSN: 1471003X     EISSN: 14710048     Source Type: Journal    
DOI: 10.1038/nrn1846     Document Type: Review

References (106)

1. Manji, H. K., Drevets, W. C. & Charney, D. S. The cellular neurobiology of depression. Nature Med. 7, 541-547 (2001).
2. Nestler, E. J. et al. Neurobiology of depression. Neuron 34, 13-25 (2002).
3. Gillespie, C. F. & Nemeroff, C. B. Hypercortisolemia and depression. Psychosom. Med. 67 (Suppl.), S26-S28 (2005).
4. Charney, D. S. Psychobiological mechanisms of resilience and vulnerability: implications for successful adaptation to extreme stress. Am. J. Psychiatry 161, 195-216 (2004). A comprehensive review of the many neurotransmitters, neuropeptides and hormones, and their receptors, that have a role in an individual's responses to stress. The author argues that our understanding of depression must include a consideration of resilience (resistance to deleterious effects of stress) as well as vulnerability to such effects.
5. Nestler, E. J. & Carlezon, W. A. Jr. The mesolimbic dopamine reward circuit in depression. Biol. Psychiatry (in the press).
6. Drevets, W. C. Neuroimaging and neuropathological studies of depression: implications for the cognitive-emotional features of mood disorders. Curr. Opin. Neurobiol. 11, 240-249 (2001).
7. Bissette, G. et al. Elevated concentrations of CRF in the locus coeruleus of depressed subjects. Neuropsychopharmacology 28, 1328-1335 (2003).
8. Mayberg, H. S. Positron emission tomography imaging in depression: a neural systems perspective. Neuroimaging Clin. N. Am. 13, 805-815 (2003).
9. Rajkowska, G. Depression: what we can learn from postmortem studies. Neuroscientist 9, 273-284 (2003).
10. Morilak, D. A. & Frazer, A. Antidepressants and brain monoaminergic systems: a dimensional approach to understanding their behavioural effects in depression and anxiety disorders. Int. J. Neuropsychopharmacol. 7, 193-218 (2004). Offers a critical evaluation of monoaminergic mechanisms in antidepressant action.
11. Duman, R. S. Role of neurotrophic factors in the etiology and treatment of mood disorders. Neuromolecular Med. 5, 11-25 (2004). Summarizes the evidence in support of the neurotrophic hypothesis of depression and antidepressant action. In this and other recent reviews, he also discusses several ways to take advantage of this hypothesis for the development of antidepressant agents with novel mechanisms of action, for example, PDE4 inhibitors, and agents directed against neurotrophic signalling proteins.
12. Sapolsky, R. M. Stress hormones: good and bad. Neurobiol. Dis. 7, 540-542 (2000).
13. Pariante, C. M. & Miller, A. H. Glucocorticoid receptors in major depression: relevance to pathophysiology and treatment. Biol. Psychiatry 49, 391-404 (2001).
14. Barden, N. Implication of the hypothalamic-pituitary-adrenal axis in the physiopathology of depression. J. Psychiatry Neurosci. 29, 185-193 (2004).
15. Korte, S. M., Koohaas, J. M., Wingfield, J. C. & McEwen, B. S. The Darwinian concept of stress: benefits of allostasis and costs of allostatic load and the trade-offs in health and disease. Neurosci. Biobehav. Rev. 29, 3-38 (2005). The authors consider an issue at the heart of stress and depression research today, namely, the necessary and beneficial effects of glucocorticoids, and their potential deleterious effects after periods of prolonged and excessive stress.
16. de Kloet, E. R., Joels, M. & Holsboer, F. Stress and the brain: from adaptation to disease. Nature Rev. Neurosci. 6, 463-475 (2005). This review offers an excellent discussion of stress physiology, integrating molecular and behavioural data from animal models to provide a clinical perspective.
17. Dranovsky, A. & Hen, R. Hippocampal neurogenesis: regulation by stress and monoamines. Biol. Psychiatry (in the press).
18. Walker, K. L., Toufexis, D. J. & Davis, M. Role of the bed nucleus of the stria terminalis versus the amygdala in fear, stress, and anxiety. Eur. J. Pharmacol. 163, 199-216 (2003).
19. Pare, D., Quirk, G. J. & LeDoux, J. E. New vistas on amygdala networks in conditioned fear. J. Neurophysiol. 92, 1-9 (2004).
20. 1 receptors in the limbic system is sufficient to suppress the anxiogenic influence of new environments, whereas basal and stress-induced HPA axis activity are unaffected.
21. Charmandari, E., Tsigos, C. & Chrousos, G. Endocrinology of the stress response. Annu. Rev. Physiol. 67, 259-284 (2005).
22. Bale, T. L. & Vale, W. W. CRF and CRF receptors: role in stress responsivity and other behaviors. Annu. Rev. Pharmacol. Toxicol. 44, 525-557 (2004).
23. Li, Y. W. et al. The pharmacology of DMP696 and DMP904, non-peptidergic CRF1 receptor antagonists. CNS Drug Rev. 11, 21-52 (2005). Provides a comprehensive synthesis of animal data available with CRF antagonists in depression-related models.
24. Heinrichs, S. C. & Koob, G. F. Corticotropin-releasing factor in brain: a role in activation, arousal, and affect regulation. J. Pharmacol. Exp. Ther. 311, 427-440 (2004).
25. Zobel, A. W. et al. Effects of the high-affinity corticotropin-releasing hormone receptor 1 antagonist R121919 in major depression: the first 20 patients treated. J. Psychiatry Res. 34, 171-181 (2000).
26. Bosker, F. J. et al. Future antidepressants: what is in the pipeline and what is missing? CNS Drugs 18, 705-732 (2004).
27. Keck, M. E. et al. Reduction of hypothalamic vasopressinergic hyperdrive contributes to clinically relevant behavioral and neuroendocrine effects of chronic paroxetine treatment in a psychopathological rat model. Neuropsychopharmacology 28, 235-243 (2003).
28. Holmes, A. et al. Neuropeptide systems as novel therapeutic targets for depression and anxiety disorders. Trends Pharmacol. Sci. 24, 580-588 (2003).
29. Wersinger, S. R. et al. Vasopressin V1b receptor knockout reduces aggressive behavior in male mice. Mol. Psychiatry 7, 975-984 (2002).
30. Winslow, J. T. & Insel, T. R. Neuroendocrine basis of social recognition. Curr. Opin. Neurobiol. 14, 248-253 (2004).
31. Boyle, M. P. et al. Acquired deficit of forebrain glucocorticoid receptor produces depression-like changes in adrenal axis regulation and behavior. Proc. Natl Acad. Sci. USA 102, 473-478 (2005). The authors used transgenic mice, in which Cre recombinase is expressed under the control of the calcium/calmodulin- dependent protein kinase II promoter, to generate a forebrain-specific knockdown of the glucocorticoid receptor and show the resulting behavioural and neuroendocrine phenotype.
32. Wei, Q. et al. Glucocorticoid receptor overexpression in forebrain: a mouse model of increased emotional liability. Proc. Natl Acad. Sci. USA 101, 11851-11856 (2004). Mice with targeted overexpression of glucocorticoid receptors in the forebrain show enhanced negative affective responses in new or stressful situations and increased responsiveness to monoamine-based antidepressants.
33. Binder, E. B. et al. Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment. Nature Genet. 36, 1319-1325 (2004). This clinical study reports that carriers of a polymorphism in the FKBP5 gene respond faster to antidepressants and have a higher recurrence of depressive episodes than individuals without this polymorphism. FKBP5 encodes a co-chaperone of heat-shock protein 90; the variant causes the glucocorticoid receptor to exhibit a higher affinity for cortisol.
34. Kaufer, D. et al. Restructuring the neuronal stress response with anti-glucocorticoid gene delivery. Nature Neurosci. 7, 947-953 (2004). Shows, by use of viral-mediated gene transfer in rat, that genetic modification of glucocorticoid receptors diminishes the deleterious effects of glucocorticoids both in vitro and in vivo.
35. Akama, K. T. & McEwen, B. S. Gene therapy to bet on: protecting neurons from stress hormones. Trends Pharmacol. Sci. 26, 169-172 (2005).
36. Flores, H. F. et al. Clinical and biological effects of mifepristone treatment for psychotic depression. Neuropharmacology 14 Sep 2005 (doi:10.1038/sj.npp. 1300884). The first report of a double-blind placebo-controlled study showing the efficacy of mifepristone in the treatment of psychotic depression. Alterations in the HPA axis were also observed.
37. Adell, A. et al. Strategies for producing faster acting antidepressants. Drug Discov. Today 10, 578-585 (2005).
38. Jahn, H. et al. Metyrapone as additive treatment in major depression: a double-blind and placebo-controlled trial. Arch. Gen. Psychiatry 61, 1235-1244 (2004).
39. Adell, A. Antidepressant properties of substance P antagonists: relationship to monoaminergic mechanisms? Curr. Drug Targets CNS Neurol. Disord. 3, 113-121 (2004).
40. -/- mice with pharmacological blockade of the substance P (NK1) receptor in assays for antidepressant and anxiolytic drugs. Behav. Pharmacol. 12, 497-508 (2001).
41. Ebner, K., Rupniak, N. M., Saria, A. & Singewald, N. Substance P in the medial amygdala: emotional stress-sensitive release and modulation of anxiety-related behavior in rats. Proc. Natl Acad. Sci. USA 101, 4280-4285 (2004).
42. Kramer, M. S. et al. Distinct mechanism for antidepressant activity by blockade of central substance P receptors. Science 281, 1640-1645 (1998).
43. 1 system and monoaminergic systems in the brain, based on genetic and pharmacological models, as they relate to antidepressant and anxiolytic drug mechanisms.
44. 1 antagonists-serotonin reuptake inhibitors: synthesis and SAR of a new class of potential antidepressants. Bioorg. Med. Chem. Lett. 12, 261-264 (2002).
45. Morcuende, S. et al. Increased neurogenesis and brain-derived neurotrophic factor in neurokinin-1 receptor gene knockout mice. Eur. J. Neurosci. 18, 1828-1836 (2003).
46. Guest, P. C. et al. Mechanisms of action of the antidepressants fluoxetine and the substance P antagonist L-000760735 are associated with altered neurofilaments and synaptic remodeling. Brain Res. 1002, 1-10 (2004).
47. Guiard, B. P. et al. Blockade of substance P (neurokinin 1) receptors enhances extracellular serotonin when combined with a selective serotonin reuptake inhibitor: an in vivo microdialysis study in mice. J. Neurochem. 89, 54-63 (2004).
48. Musazzi, L., Perez, J., Hunt, S. P., Racagni, G. & Popoli, M. Changes in signaling pathways regulating neuroplasticity induced by neurokinin 1 receptor knockout. Eur. J. Neurosci. 21, 1370-1378 (2005).
49. van der Hart, M. G. et al. Chronic psychosocial stress in tree shrews: effect of the substance P (NK1 receptor) antagonist L-760735 and clomipramine on endocrine and behavioral parameters. Psychopharmacology (Berl.) (in the press). Compares the effects of substance P antagonists and tricyclic antidepressants on neuroendocrine and behavioural parameters in a unique primate model of chronic psychosocial stress.
50. Duman, R. S., Heninger, G. R. & Nestler, E. J. A molecular and cellular hypothesis of depression. Arch. Gen. Psychiatry 54, 597-606 (1997).
51. Chen, B. et al. Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication. Biol. Psychiatry 50, 260-265 (2001).
52. Shirayama, Y. et al. Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression. J. Neurosci. 22, 3251-3261 (2002).
53. Monteggia, L. M. et al. Essential role of BDNF in adult hippocampal function. Proc. Natl Acad. Sci. USA 101, 10827-10832 (2004). Used an inducible, cell-targeted knockout system to obtain one of the best demonstrations so far that forebrain BDNF is necessary for antidepressant efficacy in the forced swim test.
54. Eisch, A. J. BDNF in the ventral midbrain-nucleus accumbens pathway: a role in depression. Biol. Psychiatry 54, 994-1005 (2003).
55. Berton, O. et al. Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress. Science (in the press). Chronic social defeat stress causes a long-lasting abnormality in social approach-avoidance behaviour, which is reversed by chronic (but not acute) antidepressant administration. Selective deletion of BDNF in the ventral tegmental area prevents this behavioural abnormality of defeat stress, and induces changes in gene expression in the nucleus accumbens similar to those seen with chronic antidepressant use.
56. Turner, C. A., Akil, A., Watson, S. J. & Evans, S. J. The fibroblast growth factor system and mood disorders. Biol. Psychiatry (in the press). Summarizes recent evidence, much of it from DNA microarray analysis of human brain tissue taken at postmortem, for abnormalities in the FGF system in depression.
57. Simen, B. B., Duman, C. H., Simen, A. A. & Duman, R. S. TNFα signaling in depression and anxiety: behavioral consequences of individual receptor targeting. Biol. Psychiatry (in the press). One of the first studies to characterize depression-like behaviour in animals lacking TNFα. These types of analysis of the large number of mutants available in the cytokine field will help us to clarify the influence of various cytokines and their receptors on depression-like behaviours and antidepressant responses.
58. Chen, A. C., Shirayama, Y., Shin, K. H., Neve, R. L. & Duman, R. S. Expression of the cAMP response element binding protein (CREB) in hippocampus produces an antidepressant effect. Biol. Psychiatry 49, 753-762 (2001).
59. Tully, T., Bourtchouladze, R., Scott, R. & Tallman, J. Targeting the CREB pathway for memory enhancers. Nature Rev. Drug Discov. 2, 267-277 (2003).
60. Mayford, M. & Kandel, E. R. Genetic approaches to memory storage. Trends Genet. 15, 463-470 (1999).
61. Carlezon, W. A. Jr, Duman, R. S. & Nestler, E. J. The many faces of CREB. Trends Pharmacol. Sci. 28, 436-445 (2005).
62. Ramos, B. P. et al. Dysregulation of protein kinase A signaling in the aged prefrontal cortex: new strategy for treating age-related cognitive decline. Neuron 40, 835-845 (2003).
63. Sanacora, G., Rothman, D. L., Mason, G. & Krystal, J. H. Clinical studies implementing glutamate neurotransmission in mood disorders. Ann. NY Acad. Sci. 1003, 292-308 (2003).
64. Paul, I. A. & Skolnick, P. Glutamate and depression: clinical and preclinical studies. Ann. NY Acad. Sci. 1003, 250-272 (2003).
65. Miyamoto, Y. et al. Lower sensitivity to stress and altered monoaminergic neuronal function in mice lacking the NMDA receptor ε4 subunit. J. Neurosci. 22, 2335-2342 (2002).
66. Alt, A., Witkin, J. M. & Bleakman, D. AMPA receptor potentiators as novel antidepressants. Curr. Pharm. Des. 11, 1511-1527 (2005). Discusses the use of positive allosteric modulators of AMPA glutamate receptors as putative antidepressant agents.
67. Swanson, C. J. et al. Metabotropic glutamate receptors as novel targets for anxiety and stress disorders. Nature Rev. Drug Discov. 4, 131-144 (2005).
68. Saito, Y. et al. Molecular characterization of the melanin-concentrating- hormone receptor. Nature 400, 265-269 (1999).
69. Georgescu, D. et al. The neuropeptide MCH controls feeding behavior via a novel hypothalamic-limbic circuit. J. Neurosci. 25, 2933-2940 (2005). Using molecular and pharmacological tools, this provides direct evidence that MCH, acting in the nucleus accumbens, exerts a prodepression-like effect, with antidepressant-like effects exerted by MCH receptor antagonism in this brain region.
70. Borowsky, B. et al. Antidepressant, anxiolytic and anorectic effects of a melanin-concentrating hormone-1 receptor antagonist. Nature Med. 8, 825-830 (2002).
71. Roy, M. et al. Genetic inactivation of melanin-concentrating hormone receptor subtype 1 (MCHR1) in mice exerts anxiolytic-like behavioral effects. Neuropsychopharmcology (in the press). One of several recent reports of the phenotype of MCH receptor-knockout mice. The other articles consider metabolic abnormalities of these knockouts, whereas this study shows a reduction in anxiety-like behaviours. Depression-like behaviour has not yet been reported in MCH receptor-knockouts.
72. Winsky-Sommerer, R. et al. Interaction between the corticotropin- releasing factor system and hypocretins (orexins): a novel circuit mediating stress response. J. Neurosci. 24, 11439-11448 (2004).
73. Takahashi, J. S. Finding new clock components: past and future. J. Biol. Rhythms 19, 339-347 (2004).
74. Reppert, S. M. & Weaver, D. R. Coordination of circadian timing in mammals. Nature 418, 935-941 (2002).
75. McClung, C. et al. Regulation of dopaminergic transmission and cocaine reward by the Clock gene. Proc. Natl Acad. Sci. USA 102, 9377-9381 (2005). Demonstrates that mice lacking functional clock protein show enhanced behavioural responses to cocaine and enhanced firing of ventral tegmental area dopamine neurons. This is one of an increasing number of reports that circadian genes act outside the SCN to regulate complex behaviour.
76. Uz, T. et al. Effect of fluoxetine and cocaine on the expression of clock genes in the mouse hippocampus and striatum. Neuroscience (in the press).
77. McClung, C. A. et al. Disruption of the clock gene in mice induces a manic-like state. Soc. Neurosci. Abstr. 793.20 (2005).
78. Garcia, J. A. et al. Impaired cued and contextual memory in NPAS2-deficient mice. Science 288, 2226-2230 (2000).
79. Dudley, C. A. et al. Altered patterns of sleep and behavioral adaptability in NPAS2-deficient mice. Science 301, 379-383 (2003). This and related studies by the same authors document a role for NPAS2, a clock-like transcription factor, in circadian variations in feeding, sleeping and other complex behaviours. These effects of NPAS2 are independent of the SCN and apparently mediated via forebrain regions.
80. Manji, H. K. et al. Enhancing neuronal plasticity and cellular resilience to develop novel, improved therapeutics for difficult-to-treat depression. Biol. Psychiatry 53, 707-742 (2003).
81. Li, X., Bijur, G. N. & Jope, R. S. Glycogen synthase kinase-3β, mood stabilizers, and neuroprotection. Bipolar Disord. 4, 137-144 (2002).
82. Markou, A. (ed.) Animal models of depression and antidepressant activity. Neurosci. Biobehav. Rev. 29, 501-909 (2005). A recent issue of Neuroscience and Biobehavioral Reviews that is devoted entirely to animal models of depression. It includes numerous outstanding and up-to-date reviews of diverse behavioural paradigms used to study depression-like behaviour and antidepressant action in animals.
83. Nestler, E. J. et al. Preclinical models: status of basic research in depression. Biol. Psychiatry 52, 503-528 (2002).
84. Mayberg, H. S. et al. Deep brain stimulation for treatment-resistant depression. Neuron 45, 651-660 (2005). This study of six patients with severe depression showed that most experienced some benefit on deep brain stimulation of a region of cingulate cortex, which showed abnormal functioning in brain imaging investigations of these patients.
85. Sapolsky, R. Gene therapy for psychiatric disorders. Am. J. Psychiatry 1 60, 208-220 (2003).
86. Diagnostic Statistical Manual of Mental Disorders (American Psychiatric Press, Washington, DC, 2000).
87. Mague, S. D. et al. Antidepressant-like effects of κ-opioid receptor antagonists in the forced swim test in rats. J. Pharmacol. Exp. Ther. 305, 323-330 (2003).
88. McLaughlin, J. P., Marton-Popovici, M. & Chavkin, C. κ opioid receptor antagonism and prodynorphin gene disruption block stress-induced behavioral responses. J. Neurosci. 23, 5674-5683 (2003). References 87 and 88 were two of the first to demonstrate antidepressant-like effects of κ opioid antagonists after systemic administration.
89. Shippenberg, T. S. & Rea, W. Sensitization to the behavioral effects of cocaine: modulation by dynorphin and κ-opioid receptor agonists. Pharmacol. Biochem. Behav. 57, 449-455 (1997).
90. Viveros, M. P., Marco, E. M. & File, S. E. Endocannabinoid system and stress and anxiety responses. Pharmacol. Biochem. Behav. 81, 331-342 (2005).
91. Haller, J. et al. CB1 cannabinoid receptors mediate anxiolytic effects: convergent genetic and pharmacological evidence with CB1-specific agents. Behav. Pharmacol. 15, 299-304 (2004).
92. Kathuria, S. et al. Modulation of anxiety through blockade of anandamide hydrolysis. Nature Med. 9, 76-81 (2003). Shows that genetic ablation of one of the enzymes that degrade the endogenous cannabinoid ligand anandamide exerts anxiolytic-like effects in rodents.
93. 1 antagonist rimonabant, now in clinical trials for obesity, on emotional behaviour relevant to anxiety- and depression-like symptoms.
94. 1 receptor.
95. Dunn, A. J., Swiergiel, A. H. & de Beaurepaire, R. Cytokines as mediators of depression: What can we learn from animal studies? Neurosci. Biobehav. Rev. 29, 891-909 (2005). Provides an excellent review of the actions of cytokines in the brain and their possible relevance to depression and antidepressant treatments.
96. Castanon, N., Medina, C., Mormede, C. & Dantzer, R. Chronic administration of tianeptine balances lipopolysaccharide-induced expression of cytokines in the spleen and hypothalamus of rats. Psychoneuroendocrinology 29, 778-790 (2004).
97. Strle, K. et al. Interleukin-10 in the brain. Crit. Rev. Immunol. 21, 427-449 (2001).
98. Barden, N. et al. Antidepressant action of agomelatine (S 20098) in a transgenic mouse model. Prog. Neuropsychopharmacol. Biol. Psychiatry 29, 908-916 (2005).
99. Holmes, A. et al. Phenotypic assessment of galanin overexpressing and galanin receptor R1 knockout mice in the tail suspension test for depression-related behavior. Psychopharmacology 178, 276-285 (2005).
100. Levenson, J. M. & Sweatt, J. D. Epigenetic mechanisms in memory formation. Nature Rev. Neurosci. 6, 108-118 (2005). An excellent review of an evolving literature that demonstrates the influence of chromatin remodelling on synaptic plasticity and learning and memory.
101. +/- mice: a model for the cognitive deficit in Rubinstein-Taybi syndrome and its amelioration. Neuron 42, 947-959 (2004).
102. Tsankova, N. M., Kumar, A. & Nestler, E. J. Histone modifications at gene promoter regions in rat hippocampus after acute and chronic electroconvulsive seizures. J. Neurosci. 24, 5603-5610 (2004).
103. Kumar, A. et al. Chromatin remodeling is a key mechanism underlying cocaine-induced plasticity in striatum. Neuron 48, 303-314 (2005).
104. Tsankova, N. M., Berton, O. & Nestler, E. J. Stable changes in histone modifications at the BDNF gene in hippocampus in depression and antidepressant action: possible role for HDAC5. Soc. Neurosci. Abstr. 638. 13 (2005).
105. Weaver, I. C. et al. Epigenetic programming by maternal behavior. Nature Neurosci. 7, 847-854 (2004). The authors demonstrate that early maternal separation causes hypermethylation of the glucocorticoid receptor gene, which underlies several behavioural and neuroendocrine abnormalities seen in the animals that survive to adulthood.
106. Tomasz Matys, T. et al. Tissue plasminogen activator promotes the effects of corticotropin-releasing factor on the amygdala and anxiety-like behavior. Proc. Natl Acad. Sci. USA 101, 16345-16350 (2004).