[en] Depression is extremely harmful to modern society. Despite its complex spectrum of symptoms, previous studies have mostly focused on the monaminergic system in search of pharmacological targets. However, other neurotransmitter systems have also been linked to the pathophysiology of depression. In this study, we provide evidence for a role of the cholinergic system in depressive-like behavior of female mice. We evaluated mice knockdown for the vesicular acetylcholine transporter (VAChT KD mice), which have been previously shown to exhibit reduced cholinergic transmission. Animals were subjected to the tail suspension and marble burying tests, classical paradigms to assess depressive-like behaviors and to screen for novel antidepressant drugs. In addition, brain levels of serotonin and dopamine were measured by high performance liquid chromatography. We found that female homozygous VAChT KD mice spent less time immobile during tail suspension and buried less marbles, indicating a less depressive phenotype. These differences in behavior were reverted by central, but not peripheral, acetylcholinesterase inhibition. Moreover, female homozygous VAChT KD mice exhibited higher levels of dopamine and serotonin in the striatum, and increased dopamine in the hippocampus. Our study thus shows a connection between depressive-like behaviors and the cholinergic system, and that the latter interacts with the monoaminergic system.
Disciplines :
Life sciences: Multidisciplinary, general & others
Bremner, J.D., Narayan, M., Anderson, E.R., Staib, L.H., Miller, H.L., Charney, D.S., Hippocampal volume reduction in major depression. Am. J. Psychiatry 157 (2000), 115–118, 10.1176/ajp.157.1.115.
Murray, C.J., Lopez, A.D., Alternative projections of mortality and disability by cause 1990–2020: global burden of disease study. Lancet 349 (1997), 1498–1504.
Barchas, J.D., Altemus, M., Monoamine Hypotheses of Mood Disorders. 1999 (Accessed 29 October 2015) http://www.ncbi.nlm.nih.gov/books/NBK28257/.
Quesseveur, G., Gardier, A.M., Guiard, B.P., The monoaminergic tripartite synapse: a putative target for currently available antidepressant drugs. Curr. Drug Targets 14 (2013), 1277–1294.
Perez-Caballero, L., Perez-Egea, R., Romero-Grimaldi, C., Puigdemont, D., Molet, J., Caso, J.R., Mico, J.A., Perez, V., Leza, J.C., Berrocoso, E., Early responses to deep brain stimulation in depression are modulated by anti-inflammatory drugs. Mol. Psychiatry 19 (2014), 607–614.
Nemeroff, C.B., The burden of severe depression: a review of diagnostic challenges and treatment alternatives. J. Psychiatry Res. 41 (2007), 189–206.
Dupuy, J.M., Ostacher, M.J., Huffman, J., Perlis, R.H., Nierenberg, A.A., A critical review of pharmacotherapy for major depressive disorder. Int. J. Neuropsychopharmacol. 14 (2011), 1417–1431.
Vieta, E., Colom, F., Therapeutic options in treatment-resistant depression. Ann. Med. 43 (2011), 512–530.
Gershon, S., Shaw, F.H., Psychiatric sequelae of chronic exposure to organophosphorus insecticides. Lancet 277 (1961), 1371–1374.
Furey, M.L., Drevets, W.C., Antidepressant efficacy of the antimuscarinic drug scopolamine: a randomized placebo-controlled clinical trial. Arch. Gen. Psychiatry 63 (2006), 1121–1129.
Saricicek, A., Esterlis, I., Maloney, K.H., Mineur, Y.S., Ruf, B.M., Muralidharan, A., Chen, J.I., Cosgrove, K.P., Kerestes, R., Ghose, S., Tamminga, C.A., Pittman, B., Bois, F., Tamagnan, G., Seibyl, J., Picciotto, M.R., Staley, J.K., Bhagwagar, Z., Persistent β2*-nicotinic acetylcholinergic receptor dysfunction in major depressive disorder. Am. J. Psychiatry 169 (2012), 851–859, 10.1176/appi.ajp.2012.11101546.
Mineur, Y.S., Obayemi, A., Wigestrand, M.B., Fote, G.M., Calarco, C.A., Li, A.M., Picciotto, M.R., Cholinergic signaling in the hippocampus regulates social stress resilience and anxiety-and depression-like behavior. Proc. Natl. Acad. Sci. 110 (2013), 3573–3578.
Chau, D.T., Rada, P.V., Kim, K., Kosloff, R.A., Hoebel, B.G., Fluoxetine alleviates behavioral depression while decreasing acetylcholine release in the nucleus accumbens shell. Neuropsychopharmacology 36 (2011), 1729–1737.
Piccinelli, M., Wilkinson, G., Gender differences in depression. Br. J. Psychiatry. 177 (2000), 486–492, 10.1192/bjp.177.6.486.
Steel, Z., Marnane, C., Iranpour, C., Chey, T., Jackson, J.W., Patel, V., Silove, D., The global prevalence of common mental disorders: a systematic review and meta-analysis 1980–2013. Int. J. Epidemiol. 43 (2014), 476–493, 10.1093/ije/dyu038.
Furey, M.L., Khanna, A., Hoffman, E.M., Drevets, W.C., Scopolamine produces larger antidepressant and antianxiety effects in women than in men. Neuropsychopharmacology 35 (2010), 2479–2488, 10.1038/npp.2010.131.
Prado, V.F., Martins-Silva, C., de Castro, B.M., Lima, R.F., Barros, D.M., Amaral, E., Ramsey, A.J., Sotnikova, T.D., Ramirez, M.R., Kim, H.-G., others, Mice deficient for the vesicular acetylcholine transporter are myasthenic and have deficits in object and social recognition. Neuron 51 (2006), 601–612.
Steru, L., Chermat, R., Thierry, B., Simon, P., The tail suspension test: a new method for screening antidepressants in mice. Psychopharmacology (Berl.) 85 (1985), 367–370.
Cryan, J.F., Mombereau, C., Vassout, A., The tail suspension test as a model for assessing antidepressant activity: review of pharmacological and genetic studies in mice. Neurosci. Biobehav. Rev. 29 (2005), 571–625.
Ichimaru, Y., Egawa, T., Sawa, A., 5-HT1A-receptor subtype mediates the effect of fluvoxamine a selective serotonin reuptake inhibitor, on marble-burying behavior in mice. Jpn. J. Pharmacol. 68 (1995), 65–70.
Nicolas, L.B., Kolb, Y., Prinssen, E.P., A combined marble burying–locomotor activity test in mice: a practical screening test with sensitivity to different classes of anxiolytics and antidepressants. Eur. J. Pharmacol. 547 (2006), 106–115.
Palucha, A., Pilc, A., Metabotropic glutamate receptor ligands as possible anxiolytic and antidepressant drugs. Pharmacol. Ther. 115 (2007), 116–147.
Handley, S.L., others, Evaluation of marble-burying behavior as a model of anxiety. Pharmacol. Biochem. Behav. 38 (1991), 63–67.
Thomas, A., Burant, A., Bui, N., Graham, D., Yuva-Paylor, L.A., Paylor, R., Marble burying reflects a repetitive and perseverative behavior more than novelty-induced anxiety. Psychopharmacology (Berl.). 204 (2009), 361–373.
Gusmão, I.D., Monteiro, B.M., Cornélio, G.O., Fonseca, C.S., Moraes, M.F., Pereira, G.S., Odor-enriched environment rescues long-term social memory, but does not improve olfaction in social isolated adult mice. Behav. Brain Res. 228 (2012), 440–446.
Walsh, R.N., Cummins, R.A., The open-field test: a critical review. Psychol. Bull., 83, 1976, 482.
Prut, L., Belzung, C., The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: a review. Eur. J. Pharmacol. 463 (2003), 3–33.
Samuels, B.A., Hen, R., Novelty-suppressed feeding in the mouse, mood anxiety relat: phenotypes mice charact. Using Behav. Tests 2 (2011), 107–112.
Abercrombie, E.D., Keefe, K.A., DiFrischia, D.S., Zigmond, M.J., Differential effect of stress on In vivo dopamine release in striatum, nucleus accumbens, and medial frontal cortex. J. Neurochem. 52 (1989), 1655–1658, 10.1111/j.1471-4159.1989. tb09224. x.
Enrico, P., Bouma, M., de Vries, J.B., Westerink, B.H.C., The role of afferents to the ventral tegmental area in the handling stress-induced increase in the release of dopamine in the medial prefrontal cortex: a dual-probe microdialysis study in the rat brain. Brain Res. 779 (1998), 205–213, 10.1016/S0006-8993(97)01132-3.
Kaufer, D., Friedman, A., Seidman, S., Soreq, H., Acute stress facilitates long-lasting changes in cholinergic gene expression. Nature 393 (1998), 373–377.
Bradford, M.M., A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem. 72 (1976), 248–254.
Lima, F.B., Szawka, R.E., Anselmo-Franci, J.A., Franci, C.R., Pargyline effect on luteinizing hormone secretion throughout the rat estrous cycle: correlation with serotonin, catecholamines and nitric oxide in the medial preoptic area. Brain Res. 1142 (2007), 37–45.
Lookingland, K.J., Jarry, H.D., Moore, K.E., The metabolism of dopamine in the median eminence reflects the activity of tuberoinfundibular neurons. Brain Res. 419 (1987), 303–310.
Rabelo, P.C.R., Almeida, T.F., Guimarães, J.B., Barcellos, L.A.M., Cordeiro, L.M.S., Moraes, M.M., Coimbra, C.C., Szawka, R.E., Soares, D.D., Intrinsic exercise capacity is related to differential monoaminergic activity in the rat forebrain. Brain Res. Bull. 112 (2015), 7–13.
Fibiger, H.C., The organization and some projections of cholinergic neurons of the mammalian forebrain. Brain Res. Rev. 4 (1982), 327–388.
Alexander, J.L., Dennerstein, L., Kotz, K., Richardson, G., Women, anxiety and mood: a review of nomenclature, comorbidity and epidemiology. Expert Rev. Neurother. 7 (2007), S45–S58, 10.1586/14737175.7.11s.S45.
Seeman, M.V., Psychopathology in women and men: focus on female hormones. Am. J. Psychiatry, 1997 (Accessed 4 June 2016) http://ajp.psychiatryonline.org//pdf/10.1176/ajp.154.12.1641.
Sakae, D.Y., Marti, F., Lecca, S., Vorspan, F., Martín-García, E., Morel, L.J., Henrion, A., Gutiérrez-Cuesta, J., Besnard, A., Heck, N., Herzog, E., Bolte, S., Prado, V.F., Prado, M. a. M., Bellivier, F., Eap, C.B., Crettol, S., Vanhoutte, P., Caboche, J., Gratton, A., Moquin, L., Giros, B., Maldonado, R., Daumas, S., Mameli, M., Jamain, S., El Mestikawy, S., The absence of VGLUT3 predisposes to cocaine abuse by increasing dopamine and glutamate signaling in the nucleus accumbens. Mol. Psychiatry 20 (2015), 1448–1459, 10.1038/mp.2015.104.
Guzman, M.S., De Jaeger, X., Raulic, S., Souza, I.A., Li, A.X., Schmid, S., Menon, R.S., Gainetdinov, R.R., Caron, M.G., Bartha, R., others Elimination of the vesicular acetylcholine transporter in the striatum reveals regulation of behaviour by cholinergic-glutamatergic co-transmission. PLoS-Biol, 9, 2011, 2327.
Aosaki, T., Miura, M., Suzuki, T., Nishimura, K., Masuda, M., Acetylcholine–dopamine balance hypothesis in the striatum: an update. Geriatr. Gerontol. Int. 10 (2010), S148–S157.
Kalueff, A.V., Fox, M.A., Gallagher, P.S., Murphy, D.L., Hypolocomotion, anxiety and serotonin syndrome-like behavior contribute to the complex phenotype of serotonin transporter knockout mice. Genes Brain Behav. 6 (2007), 389–400.
Janowsky, D., Davis, J., El-Yousef, M.K., Sekerke, H.J., A cholinergic-adrenergic hypothesis of mania and depression. Lancet 300 (1972), 632–635.
A.P. Association, Diagnostic and Statistical Manual of Mental Disorders (DSM). 1994, Am. Psychiatr. Assoc., Wash. DC, 143–147.
Mineur, Y.S., Picciotto, M.R., Nicotine receptors and depression: revisiting and revising the cholinergic hypothesis. Trends Pharmacol. Sci. 31 (2010), 580–586.
Vakalopoulos, C., A cholinergic hypothesis of the unconscious in affective disorders. Front. Neurosci., 7, 2013, 10.3389/fnins.2013.00220.