Forced Swim Test Motivation Elevated Plus-Maze 2011-08-15 https://archiv.ub.uni-marburg.de/diss/z2011/0479/cover.png Flint J (2003). Analysis of quantitative trait loci that influence animal behavior. Journal of Neurobiology 54:46-77. Wahlsten D, Metten P, Phillips TJ, Boehm II SL, Burkhart-Kasch S, Dorow J, Doerksen S, Downing C, Fogarty J, Rodd-Henricks K, Hen R, McKinnon CS, Merrill CM, Nolte C, Schalomon M, Schlumbohm JP, Sibert JR, Wenger CD, Dudek BC, Crabbe JC (2003). Different data from different labs: lessons from studies of gene-environment interaction. Journal of Neurobiology 54:283-311. Weintraub D, Newberg AB, Cary MS, Siderowf AD, Moberg PJ, Kleiner-Fisman G, Duda JE, Stern MB, Mozley D, Katz IR (2005). Striatal dopamine transporter imaging correlates with anxiety and depression symptoms in Parkinson's disease. The Journal of Nuclear Medicine 46:227-232. Gosling SD (1998). Personality dimensions in spotted hyenas (Crocuta crocuta). File SE (1990). One-trial tolerance to the anxiolytic effects of chlordiazepoxide in the plus-maze. Psychopharmacology 100:281-282. Andrade MMM, Tomé MF, Santiago ES, Lúcia-Santos A, de Andrade TGCS (2003). Longitudinal study of daily variation of rats' behavior in the elevated plus- maze. Physiology + Behavior 78:125-133. Karl T, Pabst R, von Hörsten S (2003). Behavioral phenotyping of mice in pharmacological and toxicological research. Experimental and Toxicologic Pathology 55:69-83. Liebsch G, Wotjak CT, Landgraf R, Engelmann M (1996). Septal vasopressin modulates anxiety-related behaviour in rats. Neuroscience Letters 217:101-104. Wigger A, Sánchez MM, Mathys KC, Ebner K, Frank E, Liu D, Kresse A, Neumann ID, Holsboer F, Plotsky PM, Landgraf R (2004). Alterations in central neuropeptide expression, release, and receptor binding in rats bred for high anxiety: critical role of vasopressin. Neuropsychopharmacology 29:1-14. Smeets WJAJ, Marín O, González A (2000). Evolution of the basal ganglia: new perspectives through a comparative approach. Journal of Anatomy 196:501-517. Amelang M, Bartussek D, Stemmler G, Hagemann D (2006). Differentielle Psychologie und Persönlichkeitsforschung, 6th ed. Stuttgart: Kohlhammer. Marks IM, Nesse RM (1994). Fear and fitness: an evolutionary analysis of anxiety disorders. Ethology and Sociobiology 15:147-161. Wu SL, Hsu LS, Tu WT, Wang WF, Huang YT, Pawlak CR, Ho YJ (2008). Effects of d-cycloserine on the behavior and ERK activity in the amygdala: Role of individual anxiety levels. Behavioural Brain Research 187:246-253. Jensen J, McIntosh AR, Crawley AP, Mikulis DJ, Remington G, Kapur S (2003) Direct activation of the ventral striatum in anticipation of aversive stimuli. Neuron 40:1251-1257. Deakin JFW, Graeff FG (1991). 5-HT and mechanisms of defence. Journal of Psychopharmacology 5:305-315. Handley SL, McBlane JW (1993). 5-HT drugs in animal models of anxiety. Psychopharmacology 112:13-20. Kõks S, Beljajev S, Koovit I, Abramov U, Bourin M, Vasar E (2001). 8-OH-DPAT, but not deramciclane, antagonizes the anxiogenic-like action of paroxetine in an elevated plus-maze. Psychopharmacology 153:365-372. Silva RCB, Brandão ML (2000). Acute and chronic effects of gepirone and fluoxetine in rats tested in the elevated plus-maze: an ethological analysis. Pharmacology, Biochemistry and Behavior 65:209-216. Ho YJ, Pawlak CR, Guo L, Schwarting RKW (2004). Acute and long-term consequences of single MDMA administration in relation to individual anxiety levels in the rat. Behavioural Brain Research 149:135-144. Gonzalez LE, File SE (1997). A five minute experience in the elevated plus-maze alters the state of benzodiazepine receptor in the dorsal raphe nucleus. The Journal of Neuroscience 17:1505-1511. Enkel T, Gholizadeh D, von Bohlen und Halbach O, Sanchis-Segura C, Hurlemann R, Spanagel R, Gass P, Vollmayr B (2010). Ambiguous-cue interpretation is biased under stress-and depression-like states in rats. Neuropsychopharmacology 35:1008-1015. Depue R, Lenzenweger M (2005). A neurobehavioral dimensional model of personality disturbance. In: M Lenzenweger, J Clarkin (Eds.), Theories of Personality Disorders, 2nd ed. New York: Guilford Press. Treit D (1985). Animal models for the study of anti-anxiety agents: a review. Neuroscience and Biobehavioral Reviews 9:203-222. Barlow DH (2002). Anxiety and its Disorders: The Nature and Treatment of Anxiety and Panic, 2nd ed. New York: Guilford Press. Treit D, Menard J, Royan C (1993). Anxiogenic stimuli in the elevated plus-maze. Pharmacology, Biochemistry and Behavior 44:463-469. Hogg S (1996). A review of the validity and variability of the elevated plus-maze as an animal model of anxiety. Pharmacology, Biochemistry and Behavior 54:21- 30. Ludwig V, Mihov Y, Schwarting RKW (2008). Behavioral and neurochemical consequences of multiple MDMA administrations in the rat: role of individual differences in anxiety-related behavior. Behavioural Brain Research 189:52-64. Schwarting RKW, Pawlak CR (2004). Behavioral neuroscience in the rat: taking the individual into account. Methods and Findings in Experimental and Clinical Pharmacology 26 Suppl 2:17-22. Ueno KI, Togashi H, Mori K, Matsumoto M, Ohashi S, Hoshino A, Fujita T, Saito H, Minami M, Yoshioka M (2002). Behavioural and pharmacological relevance of stroke-prone spontaneously hypertensive rats as an animal model of a developmental disorder. Behavioural Pharmacology 13:1-13. Schwabe K, Klein S, Koch M (2006). Behavioural effects of neonatal lesions of the medial prefrontal cortex and subchronic pubertal treatment with phencyclidine of adult rats. Behavioural Brain Research 168:150-160. Willner P (1991). Behavioural models in psychopharmacology. In: P Willner (Ed.), Behavioural Models in Psychopharmacology: Theoretical, Industrial and Clinical Perspectives, pp 3-18. Cambridge: Cambridge University Press. File SE, Mabbutt PS, Hitchcott P (1990). Characterisation of the phenomenon of "one-trial tolerance" to the anxiolytic effect of chlordiazepoxide in the elevated plus-maze. Psychopharmacology 102:98-101. Letwin NE, Kafkafi N, Benjamini Y, Mayo C, Frank BC, Luu T, Lee NH, Elmer GI (2006). Combined application of behavior genetics and microarray analysis to identify regional expression themes and gene-behaviour associations. The Journal of Neuroscience 26:5277-5287. Dere E, De Souza–Silva MA, Frisch C, Teubner B, Söhl G, Willecke K, Huston JP (2003). Connexin30-deficient mice show increased emotionality and decreased rearing activity in the open–field along with neurochemical changes. European Journal of Neuroscience 18:629-638. 164. van den Heuvel OA, Veltman DJ, Groenewegen HJ, Witter MP, Merkelbach J, Cath DC, van Balkom AJLM, van Oppen P, van Dyck R (2005b). Disorder-specific neuroanatomical correlates of attentional bias in obsessive-compulsive disorder, panic disorder, and hypochondriasis. Archives of General Psychiatry 62:922-933. Steimer T, Driscoll P (2003). Divergent stress responses and coping styles in psychogenetically selected Roman high-(RLA) and low-(RLA) avoidance rats: behavioural, neuroendocrine and developmental aspects. Stress 6:87-100. Garcia AMB, Cardenas FP, Morato S (2005). Effect of different illumination levels on rat behavior in the elevated plus-maze. Physiology + Behavior 85:265-270. Fedotova JO, Hartmann G, Lénárd L, Sapronov NS (2004). Effects of 5-HT 1A receptor agonist and antagonist on anxiety in intact and ovariectomized female rats. Acta Physiologica Hungarica 91:175-184. Ferreira TL, Moreira KM, Ikeda DC, Bueno OFA, Oliveira MGM (2003). Effects of dorsal striatum lesions in tone fear conditioning and contextual fear conditioning. Brain Research 987:17-24. Almeida SS, Garcia RA, de Oliveira LM (1993). Effects of early protein malnutrition and repeated testing upon locomotor and exploratory behaviors in the elevated plus-maze. Physiology + Behavior 54:749-752. Hasuo (1935). Effects of milieu upon character. I. Experiments with young chickens. Japanese Journal of Experimental Psychology 2:109-118. Garbe CM, Kemble ED (1994). Effects of prior agonistic experience on risk assessment and approach behavior evoked by familiar and unfamiliar conspecific odors. Aggressive Behavior 20:143-149. LeDoux JE (2000). Emotion circuits in the brain. Annual Review of Neuroscience 23:155-184. Mathew SJ, Ho S (2006). Etiology and neurobiology of social anxiety disorder. Journal of Clinical Psychiatry 67 Suppl 12:9-13. Tellegen A, Waller NG (1992). Exploring personality through test construction: development of the multidimensional personality questionnaire. Minneapolis, MN: University of Minnesota Press. Unpublished manuscript. File SE (2001). Factors controlling measures of anxiety and responses to novelty in the mouse. Behavioural Brain Research 125:151-157. Schenberg EE, Ferreira TL, Figueredo LZP, Hipólide DC, Nobrega JN, OliveiraMGM (2006). Fear conditioning performance and NMDA receptor subtypes: NR2A differential expression in the striatum. Brain Research Bulletin 69:440-446. Marks IM (1987). Fears, Phobias, and Rituals: Panic, Anxiety, and their Disorders. New York: Oxford University Press. Gosling SD (2001). From mice to men: what can we learn about personality from animal research? Psychological Bulletin 127:45-86. 163. van den Heuvel OA, Veltman DJ, Groenewegen HJ, Cath DC, van Balkom AJLM, van Hartskamp J, Barkhof F, van Dyck R (2005a). Frontal–-dysfunction during planning in obsessive-compulsive disorder. Archives of General Psychiatry 62:301-310. Finn DA, Rutledge-Gorman MT, Crabbe JC (2003). Genetic animal models of anxiety. Neurogenetics 4:109-135. Andrews N, File SE (1993). Handling history of rats modifies behavioural effects of drugs in the elevated plus-maze test of anxiety. European Journal of Pharmacology 235:109-112. Thiel CM, Müller CP, Huston JP, Schwarting RKW (1999). High versus low reactivity to a novel environment: behavioural, pharmacological and neurochemical assessments. Neuroscience 93:243-251. Schneider P, Spanagel R, Schwarting RKW, Pawlak CR (2008). Individual behaviour and relationship between elevated plus-maze and social interaction test in adult rats. Program No. 393. 2008 Abstract Viewer/Itinerary Planner. Kabbaj M, Akil H (2001). Individual differences in novelty-seeking behavior in rats: a c-fos study. Neuroscience 106:535-545. Steimer T, Driscoll P (2005). Inter-individual vs line/strain differences in psychogenetically selected Roman high-(RHA) and low-(RLA) avoidance rats: neuroendocrine and behavioural aspects. Neuroscience + Biobehavioral Reviews 29:99-112. Schneider P, Spanagel R, Pawlak CR (2009). Interleukin-2 affects social interaction behaviour in relation to anxiety-like trait behaviour in the elevated plus- maze in adult Wistar rats. Brain, Behavior, and Immunity 23 Suppl. 1:S19. Schoenbaum G, Setlow B (2003). Lesions of nucleus accumbens disrupt learning about aversive outcomes. The Journal of Neuroscience 23:9833-9841. Horvitz JC (2000). Mesolimbocortical and nigrostriatal dopamine responses to salient non-reward events. Neuroscience 96:651-656. Abramson LY, Seligman MEP (1977). Modeling psychopathology in the laboratory: history and rationale. In: JD Maser, MEP Seligman (Eds.), Psychopathology: Experimental Models, pp 1-26. San Francisco: Freeman. File SE, Andrews N, Wu PY, Zharkovsky A, Zangrossi Jr H (1992). Modification of chlordiazepoxide's behavioural and neurochemical effects by handling and plus- maze experience. European Journal of Pharmacology 218:9-14. Vyas A, Chattarji S (2004). Modulation of different states of anxiety-like behavior by chronic stress. Behavioral Neuroscience 118:1450-1454. London ED, Simon SL, Berman SM, Mandelkern MA, Lichtman AM, Bramen J, Shinn AK, Miotto K, Learn J, Dong Y, Matochik JA, Kurian V, Newton T, Woods R, Rawson R, Ling W (2004). Mood disturbances and regional cerebral metabolic abnormalities in recently abstinent methamphetamine abusers. Archives of General Psychiatry 61:73-84. Lorberbaum JP, Kose S, Johnson MR, Arana GW, Sullivan LK, Hamner MB, Ballenger JC, Lydiard RB, Brodrick PS, Bohning DE, George MS (2004). Neural correlates of speech anticipatory anxiety in generalized social phobia. Neuroreport 15:2701-2705. Graeff FG (1994). Neuroanatomy and neurotransmitter regulation of defensive behaviors and related emotions in animals. Brazilian Journal of Medical and Biological Research 27:811-829. Frussa-Filho R, Ribeiro R de A (2002). One-trial tolerance to the effects of chlordiazepoxide in the elevated plus-maze is not due to acquisition of a phobic avoidance of open arms during initial exposure. Life Sciences 71:519-525. Personality and comorbidity of common psychiatric disorders. British Journal of Psychiatry 186:190-196. Laakso A, Wallius E, Kajander J, Bergman J, Eskola O, Solin O, Ilonen T, Salokangas RKR, Syvälahti E, Hietala J (2003). Personality traits and striatal dopamine synthesis capacity in healthy subjects. American Journal of Psychiatry 160:904-910. PET in generalized anxiety disorder. Biological Psychiatry 29:1181-1199. Almeida SS, Tonkiss J, Galler JR (1996). Prenatal protein malnutrition affects exploratory behavior of female rats in the elevated plus-maze test. Physiology + Behavior 60:675-680. Schwarting RKW, Thiel CM, Müller CP, Huston JP (1998). Relationship between anxiety and serotonin in the ventral striatum. Neuroreport 9:1025-1029. Holmes A, Rodgers RJ (1998). Responses of Swiss-Webster mice to repeated plus-maze experience: further evidence for a qualitative shift in emotional state? Pharmacology, Biochemistry and Behavior 60:473-488. Graeff FG, Guimarães FS, De Andrade TGCS, Deakin JFW (1996). Role of 5-HT in stress, anxiety, and depression. Pharmacology, Biochemistry and Behavior 54:129-141. File SE, Gonzalez LE, Gallant R (1998). Role of the basolateral nucleus of the amygdala in the formation of a phobia. Neuropsychopharmacology 19:397-405. Davis M, Walker D, Lee Y (1997). Roles of the amygdala and bed nucleus of the stria terminalis in fear and anxiety measured with the acoustic startle reflex. Possible relevance to PTSD. Annals of the New York Academy of Sciences 821:305-331. Tollefson GD, Rosenbaum JF (1998). Selective serotonin reuptake inhibitors. In: AF Schatzberg, CB Nemeroff (Eds.), Textbook of Psychopharmacology, pp 219- 237. Washington, DC: American Psychiatric Press, Inc. Stein DJ, Stahl S (2000). Serotonin and anxiety: current models. International Clinical Psychopharmacology 15 Suppl 2:S1-S6. Bauhofer A, Schwarting RKW, Köster M, Schmitt A, Lorenz W, Pawlak CR (2004). Sickness behavior of rats with abdominal sepsis can be improved by antibiotic 34. Dantzer R, O´Connor JC, Freund GG, Johnson RW, Kelley KW (2008). Form inflammation to sickness and depression: when the immune system subjugates the brain. Nature Reviews Neuroscience 9:46-57. Kaesermann HP (1986). Stretched attend posture, a non-social form of ambivalence, is sensitive to a conflict–reducing drug action. Psychopharmacology 89:31-37. Francis RC (1990). Temperament in a fish: a longitudinal study of the development of individual differences in aggression and social rank in the Midas cichlid. Ethology 86:311-325. Hebb DO (1949). Temperament in chimpanzees: I. Method and analyses. The Journal of Comparative and Physiological Psychology 42:192–206. Strelau J (1997). The contribution of Pavlov's typology of CNS properties to personality research. European Psychologist 2:125-138. Gross C, Hen R (2004). The developmental origins of anxiety. Nature Reviews Neuroscience 5:545-552. Yehuda R, Hyman SE (2005). The impact of terrorism on brain, and behavior: what we know and what we need to know. Neuropsychopharmacology 30:1773- 1780. Lathe R (2004). The individuality of mice. Genes, Brain and Behavior 3:317-327. Fernandes C, File SE (1996). The influence of open arm ledges and maze experience in the elevated plus-maze. Pharmacology, Biochemistry and Behavior 54:31-40. Halliday TR (1976). The libidinous newt: an analysis of variations in the sexual behaviour of the male smooth newt, Triturus vulgaris. Animal Behaviour 24:398- 414. Gray JA (1982). The Neuropsychology of Anxiety: An Enquiry into the Functions of the Septo–Hippocampal System, 1st ed. Oxford: Oxford University Press. Woodcock J (2007). The prospects for "personalized medicine" in drug development and drug therapy. Journal of Clinical Pharmacy and Therapeutics 81:164-169. Wichers M, Maes M (2002). The psychoneuroimmuno-pathophysiology of cytokine-induced depression in humans. International Journal of Neuropsychopharmacology 5:375-388. Andreatini R, Vital MABF, Santos GL (2003). The reinstatement of conflict reverses the one-trial tolerance to diazepam on elevated plus-maze. European Neuropsychopharmacology 13 Suppl 4:378-379. File SE, Kenny PJ, Cheeta S (2000). The role of the dorsal hippocampal serotonergic and cholinergic systems in the modulation of anxiety. Pharmacology Biochemistry and Behavior 66: 65-72. Lister RG (1987). The use of a plus-maze to measure anxiety in the mouse. Psychopharmacology 92:180-185. Willner P (1984). The validity of animal models of depression. Psychopharmacology 83:1-16. Karrenbauer BD, Ho YJ, Ludwig V, Löhn J, Spanagel R, Schwarting RKW, Pawlak CR (2009). Time-dependent effects of striatal interleukin-2 on open field behaviour in rats. Journal of Neuroimmunology 208:10-18. Graybiel AM, Rauch SL (2000). Toward a neurobiology of obsessive-compulsive disorder. Neuron 28:343-347. File SE, Zangrossi Jr H, Viana M, Graeff FG (1993). Trial 2 in the elevated plus- maze: a different form of fear? Psychopharmacology 111:491-494. Weiss SM, Wadsworth G, Fletcher A, Dourish CT (1998). Utility of ethological analysis to overcome locomotor confounds in elevated maze models of anxiety. Neuroscience + Biobehavioral Reviews 23:265-271. Willner P (1986). Validation criteria for animal models of human mental disorders: learned helplessness as a paradigm case. Progress in Neuro- Psychopharmacology + Biological Psychiatry 10:677-690. Ho YJ, Eichendorff J, Schwarting RKW (2002). Individual response profiles of male Wistar rats in animal models for anxiety and depression. Behavioural Brain Research 136:1-12. Psychoimmunological effects of dioscorea in ovariectomized rats: role of anxiety level. Annals of General Psychiatry 6:21. Willner P, Mitchell PJ (2002). Animal models of depression: a diathesis/stress approach. In: H D'haenen, JA den Boer, P Willner (Eds.), Biological Psychiatry, pp 703-726. Chichester: Wiley. Andreatini R, Blanchard C, Blanchard R, Brandão ML, Carobrez AP, Griebel G, Guimarães FS, Handley SL, Jenck F, Leite JR, Rodgers J, Schenberg LC, Da Cunha C, Graeff FG (2001). The brain decade in debate: II. Panic or anxiety? From animal models to a neurobiological basis. Brazilian Journal of Medical and Biological Research 34:145-154. Henn FA, Vollmayr B (2005). Stress models of depression: forming genetically vulnerable strains. Neuroscience + Biobehavioral Reviews 29:799-804. Kitabatake Y, Hikida T, Watanabe D, Pastan I, Nakanishi S (2003). Impairment of reward-related learning by cholinergic cell ablation in the striatum. Proceedings of the National Academy of Sciences of the United States of America 100:7965- 7970. Fernández-Teruel A, Escorihuela RM, Gray JA, Aguilar R, Gil L, Giménez-Llort L, Tobeña A, Bhomra A, Nicod A, Mott R, Driscoll P, Dawson GR, Flint J (2002). A quantitative trait locus influencing anxiety in the laboratory rat. Genome Research 12:618-626. Cerebral blood flow in immediate and sustained anxiety. The Journal of Neuroscience 27:6313-6319. Lui S, Huang X, Chen L, Tang H, Zhang T, Li X, Li D, Kuang W, Chan RC, Mechelli A, Sweeney JA, Gong Q (2009). High-field MRI reveals an acute impact on brain function in survivors of the magnitude 8.0 earthquake in China. Proceedings of the National Academy of Sciences of the United States of America 106:15412-15417. Walf AA, Frye CA (2007). The use of the elevated plus maze as an assay of anxiety-related behavior in rodents.Nature Protocols 2:322-328. Schiller D, Levy I, Niv Y, Le Doux JE, Phelps EA (2008). From fear to safety and back: reversal of fear in the human brain. The Journal of Neuroscience 28:11517- 11525. Strack F, Deutsch R (2004). Reflective and impulsive determinants of social behavior. Personality and Social Psychology Review 8:220-247. Depression Interleukin 2 Seit Jahren sind Interaktionen zwischen zentralem Nervensystem und Immunsystem bekannt, welche sich auf Motivation, Emotionen und Verhalten auswirken können. Es wird angenommen, dass Zytokine, Botenstoffe des Immunsystems, motiviertes Verhalten beeinflussen und auf diesem Wege an psychischen Erkrankungen wie Angst und Depression beteiligt sein können. In vorherigen Studien konnte gezeigt werden, dass angstähnliches Verhalten im erhöhten Plus-Labyrinth (elevated plus maze; EPM) bei Ratten mit der Zytokinexpression in verschiedenen Arealen im Gehirn korreliert war - und dass diese Korrelationen zytokin- (Interleukin-2 mRNA) und arealspezifisch (Striatum, frontaler Kortex) waren (Pawlak et al., 2003; Pawlak et al., 2005). Striatal injiziertes Interleukin-2 (IL-2; 1; 10; 25 ng) wirkte sich im Trend biphasisch auf angstähnliches Verhalten im EPM (Pawlak +amp;amp;amp;amp;amp;amp; Schwarting, 2006a). In der ersten vorliegenden Studie (Artikel 1) wurden die Auswirkungen von striatal injiziertem IL-2 (0; 0,1 and 1 ng) auf angstähnliches Verhalten im Offenfeld (OF) untersucht. Die 45minütigen Testungen erfolgten an zwei aufeinanderfolgenden Tagen, während nur vor der ersten Testung IL-2 appliziert wurde. Bei der akuten Testung zeigte sich für die geringste Dosierung (0,1 ng) IL-2 ein nicht signifikanter Anstieg im angstähnlichen Verhalten. Am zweiten Testtag ließ sich für diese Gruppe (0,1 ng) ein signifikant erhöhtes angstähnliches Verhalten gegenüber der höheren Dosis und der Kontrollgruppe beobachten. In einem zweiten Experiment wurde überprüft, ob diese verzögerten Effekte aufgrund eines zeitverzögerten (proaktiven) Wirkungsmechanismus zustande gekommen waren. In diesem Zusammenhang wurden Ratten 24 und 48 Stunden nach der striatalen Injektion von verschiedenen Dosierungen Interleukin-2 (0; 0,01 und 0,1 ng) im OF getestet. An beiden Testungen zeigten sich keine Unterschiede zwischen den Gruppen. Aus diesen Ergebnissen kann geschlussfolgert werden, dass einmalig striatal injiziertes IL-2 (in den verwendeten Dosierungen) emotionsähnliches Verhalten für maximal 24 Stunden beeinflussen kann, und dass eventuell diese Effekte nur in Zusammenhang mit bestimmten Umgebungsreizen (z.B. Offenfeld) zustande kommen, da hier ein proaktiver Wirkungsmechanismus ausgeschlossen werden konnte. Es wird angenommen, dass IL-2 neben den Auswirkungen auf das Verhalten auch neurochemische (z.B. serotonerge oder dopaminerge) Prozesse im Gehirn beeinflusst, die mit Depression und Angst in Verbindung gebracht werden. In Artikel 2 wurden die Auswirkungen von peripher injiziertem IL-2 (2,5 μg/kg) auf die serotonerge (5-HT, 5-Hydroyxtryptophan) und dopaminerge (DA) Neurotransmission in verschiedenen Kortexarealen (präfontal, okzipital, temporal) mittels Mikrodialyse an anästhesierten Ratten untersucht (Exp. 1). Des Weiteren wurde in zwei weiteren Experimenten die Wirkung von IL-2 (0; 1; 2,5; 5 μg/kg, intraperitoneal; i.p.) auf depressivähnliches Verhalten im Forced Swim Test (FST) untersucht. Basierend auf dem in Experiment 1 beobachtetem serotonergen Wirkungsprofil wurden die Tiere in Exp. 2a direkt 5 Minuten (akut) und in Exp. 2b zwei Stunden nach der Injektion (zeitverzögert) getestet. Aufgrund der Vorstudien und des Zusammenhangs zwischen Serotonin und Angst wurde in einem weiteren Experiment (Exp. 3) der potentielle zeitverzögerte Einfluss (zwei Stunden Postinjektion) von IL-2 (0; 1; 2,5; 5 μg/kg, i.p.) auf angstähnliches Verhalten im EPM getestet. In der Mikrodialysestudie zeigte sich, dass systemisch injiziertes IL-2 extrazelluläres Serotonin im präfrontalen (-75%), okzipitalen (-70%) und temporalen (-45%) Kortex reduzierte. Die ersten Effekte zeigten sich 40 Minuten nach der Injektion, erreichten nach ca. 120 Minuten ihr Maximum und blieben über die restliche Testdauer von drei Stunden stabil. Im Gegensatz dazu zeigte sich nur eine allgemeine moderate Reduktion von Dopamin im präfrontalen Kortex, jedoch nicht für bestimmte Zeitpunkte. Diese neurochemischen Effekte werden durch die Ergebnisse der Verhaltensexperimente ergänzt. IL-2 führte bei einer um zwei Stunden verzögerten Testung im FST zu dosisabhängigen Effekten auf depressivähnliches Verhalten mit einem signifikanten Anstieg des Immobilitätsverhaltens in der Gruppe, die mit der niedrigsten Dosierung (1 μg/kg) behandelt wurde. Bei der akuten Testung ließen sich keine Effekte beobachten. Obwohl das EPM einer der am meisten verbreitetesten Tests zur Messung angstähnlichen Verhaltens ist (Artikel 3) und Studien auf eine serotonerge Beteiligung hinweisen, konnten keine zeitverzögerten Effekte von IL-2 auf angstähnliches Verhalten beobachtet werden. Diese Daten verdeutlichen die Potenz von IL-2, neurochemische Prozesse, depressivähnliches und bedingt angstähnliches Verhalten zu beeinflussen, und belegen gleichzeitig, dass dieser Einfluss einem zeitlichen Verlauf folgt, welches möglicherweise auf einen serotonergen Wirkmechanismus hinweist, da die Effekte im gleichen Wirkungszeitfenster auftraten. Psychology Psychologie Microdialysis Emotionen 2011-07-21 Angst It has been known for years that the brain interacts with the immune system and vice versa. Furthermore, it is known that this interaction has an impact on motivation, emotion and behaviour. It is suggested that cytokines, messengers of the immune system, can modulate motivated behaviour and are involved in psychiatric conditions such as anxiety and depression. Previous studies (Pawlak et al., 2003; Pawlak et al., 2005) showed that cytokine expression in specific brain tissues is correlated with anxiety-like behaviour (open arm time) in the elevated plus-maze (EPM) in male Wistar rats, and that this relationship is site- (striatum, frontal cortex) and cytokine-specific (Interleukin-2 mRNA). These studies also found evidence for a biphasic impact of a single striatal IL-2 (1; 10; 25 ng) injection on anxiety-like behaviour in the EPM (Pawlak +amp;amp;amp;amp;amp;amp; Schwarting, 2006a). In the first of the present studies (article 1), rats were tested for anxiety-like effects, acutely and 24 h later (drug free), after a single striatal interleukin-2 injection (0; 0.1 and 1 ng) followed by 45 min open field test. During the acute testing we observed a non-significant increase in anxiety-like behaviour in the group treated with the lowest dose (0.1 ng). On the second test day (24h later), animals treated with the lowest dose showed an increase in anxiety-like behaviour (i.e. reduced centre time) compared to the 1 ng and the control group. Therefore, in a subsequent study we tested for proactive drug mechanisms. Rats were tested in an open field 24 and 48 hours after interleukin-2 (0, 0.01, 0.1 ng) injection. The analyses showed no significant effects for the first (24 h after IL-2 infusion) or for the second exposure (48 h later). Therefore, it was suggested that emotion-related behaviour could be modulated by striatal IL-2 (in the used dosages) over a period of at least 24 h. However, such IL-2 effects can only be observed, if environmental challenges (e.g. open field) immediately follow infusion. In conclusion, proactive drug effects can be excluded for striatal IL-2 effects on emotion-related behaviour. IL-2 is assumed to be one factor which may mediate the behavioural and neurochemical (e.g. serotonergic, dopaminergic) features of depression and anxiety in the brain. The second study (article 2) investigated the impact of systemically injected IL-2 (2.5 μg/kg, i.p.) on serotonergic (5-HT, 5-Hydroxytryptophane) and dopaminergic (DA) neurotransmission in various cortical areas by in-vivo microdialysis in anaesthetised rats (Exp.1). Based on the serotonergic time profile obtained from Exp.1, two further experiments were conducted to test for acute (Exp.2a) and delayed (2 hours post injection, Exp.2b) behavioural effects of systemic IL-2 (0; 1; 2.5; 5.0 μg/kg) on depressive-related behaviour in the Forced Swim Test (FST). Because of the data found in our previous studies and the well known involvement of serotonin in anxiety disorders and anxiety-like behaviour, the effects of systemic IL-2 (0; 1; 2.5; 5.0 μg/kg) were tested in the EPM, 2 hours post injection (Exp.3). The neurochemical results revealed that systemic IL-2 lastingly reduced extracellular 5-HT levels in the medial prefrontal (-75%), occipital (-70%), and temporal (-45%) cortices. The first effects were observed 40 minutes after injection, reached their maximum after circa 120 minutes and remained stable for rest of the experiment, at least 3 hours after IL-2 treatment. In contrast, dopamine was only moderately reduced in the medial prefrontal cortex. The functional relevance of these specific neurochemical changes was supported by subsequent behavioural evaluation since IL-2 had dose-dependent effects on depressive-related behaviour in the FST after delayed testing, with a significant increase in immobility with the lower dose (1 μg/kg). No such effects were observed acutely after injection. Despite the fact that a) the EPM is one of most frequently used tests to measure anxiety-like behaviour (article 3) and b) that anxiety and anxiety-like behaviour are in some way related to serotonin, we found no delayed effects of IL-2 on anxiety-like behaviour in the EPM. In summary, these data show the potency of IL-2 to kinetically influence neurochemical processes and support the hypothesis that IL-2 dose-dependently affects depressive-related and partly anxiety-like behaviour, which may be related to its serotonergic effects in the brain. Tiermodell 2011 Emotion Interleukin 2: Implikationen für Angst und Depression? Ein tierexperimenteller Ansatz Serotonin Philipps-Universität Marburg Publikationsserver der Universitätsbibliothek Marburg Universitätsbibliothek Marburg opus:3852 Fachbereich Psychologie Depression doctoralThesis Zytokine Anxiety urn:nbn:de:hebis:04-z2011-04798 application/pdf Mikrodialyse, HPLC-EC motiviertes Verhalten monograph Corpus striatum ths Prof. Dr. Pawlak Cornelius Pawlak, Cornelius (Prof. Dr.) Forced Swim Test Interleukin 2: Implications for anxiety and depression? An animal model approach Cytokines Psychologie German https://doi.org/10.17192/z2011.0479 2011-08-15 Karrenbauer, Britta Daniela Karrenbauer Britta Daniela Präfrontaler Cortex