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Christina Dalla , PhD Assistant Professor in Psychopharmacology

Animal models of depression: how about females?. Christina Dalla , PhD Assistant Professor in Psychopharmacology. Dep. of Pharmacology, Medical School, University of Athens, Greece cdalla@med.uoa.gr. Sex differences in neuropsychiatry. *. *. *. *. *. ECNP/ECB report 2010.

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Christina Dalla , PhD Assistant Professor in Psychopharmacology

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  1. Animal models of depression: how about females? Christina Dalla, PhD Assistant Professor in Psychopharmacology Dep. of Pharmacology, Medical School, University of Athens, Greece cdalla@med.uoa.gr

  2. Sex differences in neuropsychiatry * * * * * ECNP/ECB report 2010

  3. Sex differences in psychopharmacology of depression Conflicting human data… • Men respond better to imipramine, while women respond better to sertraline (Kornstein et al 2000). • Women have a better response to the SSRI citalopram than men(Young et al 2009, STAR*D study). • Womenare usually exposed to higher levels of antidepressants than men (Kokras, Dalla et al, 2011). • 1993: NIH Revitalization Act to increase representation of women in clinical trials.

  4. Mostly male animals are used in basic research Animal studies Human studies A. K. Beerya, I. Zucker. “Sex bias in neuroscience and biomedical research” Neuros. and Biobeh. Rev. 35, 2011, 565–572

  5. Animal models/tests of depressionenvironmental changes, genetic, selective breeding, lesions, pharmacological Forced swim test Chronic mild stress Flinders sensitive line rats Learned helplessness model Olfactory bulbectomy Social defeat/ instability Predator odor exposure Maternal separation Knockout mice (e.g. 5-HTT, BDNF) C. Dallaet al, Basic & Clin. Pharm. and Toxicol, 2010, Mar;106(3):226-33

  6. Sex differences in behavioral indices and underlying neurobiology are present in all models of depression. This depends on the parameters that we study and on basal differences between males and females. In many cases, antidepressant treatment masks basal sex differences. C. Dalla et al, Current topics in Behavioral Neurosciences, 8, 98-113, 2010

  7. Sex differences in models of depression… • In contrast to males, females do not express learned helplessness in a shuttle-box (Dalla et al, Neuropsychopharmacology, 2008). • Chronic mild stress • Chronic mild stress dopaminergic activity only in the prefrontal cortex of females (Dalla et al, Physiology & Behavior, 2008). 5-HIAA/5-HT only in the female hippocampus (Dalla et al, Neuroscience 2004). CMS ♂ ♀ 5-HT1A mRNA levels only in the male hippocampus (Pitychoutis, Dalla, et al, Neuroscience 2012)

  8. Chronic mild stress induces anhedonia, a symptom of depression in both sexes Sucrose preferenceis a trickier index in females… Dalla C. et al, Neuroscience 2005

  9. Chronic mild stress enhances corticosterone levels and reduces serotonergic activity only in the hippocampus of females Corticosterone in serum 5-HIAA/5-HT in the hippocampus Dalla C. et al, Neuroscience, 2005

  10. Forced swim test (FST) Video by VassilisKafetzopoulos, Department of Pharmacology, Athens University Medical School

  11. Kinoscope: a newly-developed program for behavioral scoring • For manual scoring, registration and analysis of behavior • Behavioral data are stored in a local database • Freely available to the academic community • Email: kinoscope@codemax.gr or go to: http://www.med.uoa.gr/pharmacology/en Dept. of Pharmacology, D. Baltas, & C. Dalla, in preparation

  12. Sex differences in the forced swim test… FST ♂ • Forced swim test 5-HIAA/5-HT only in the female hippocampus (Drossopoulou, Dalla, et al, Neuroscience 2004). • Forced swim test DOPAC/DA and HVA/DA only in the male prefrontal cortex and hippocampus (Dalla, et al, Physiology & Behavior 2008). • Sex differences in antidepressant response in Flinders Sensitive Line (Kokras, Dalla, et al, J. of Psychopharmacology, 2009 ) ♀ FST Test FST Pretest 24h

  13. Females show higher immobility levels than males… Sex differences in FST are not dependent on sex differences in basal corticosterone levels Kokras N., Dalla C., et al, Neuropharmacology, 62, 436-455, 2012

  14. FST: in which phase of the estrous cycle? Diestrus I and II Proestrus Estrus

  15. Antidepressant effects during normal estrogen fluctuation Sertraline i.p., 3 inj. 10mg/kg or 40 mg/kg or vehicle FST Pretest FST Test Adult male and female Wistar rats Vaginal smears 19 h 4h 1h Males Females proestrous Females estrous Females diestrous I Females diestrus II Males Females estrus Females diestrus I Females diestrous II Females proestrus 15 groups

  16. Results Immobility The antidepressant effect is less evident in the transition from diestrus II to proestrus. Swimming ? ?

  17. Uterus weight correlates with swimming duration only in vehicle-treated females RESULTS Correlation .. because SSRI treatment masks the estrogen-swimming correlation

  18. Behavior in FST correlates with serotonergic activity in the prefrontal cortex… Mikail, Dalla et al Physiology & Behavior, 2012

  19. Prefrontal cortex- Hippocampus communication Breakdown Hippocampus is directly connected to the prefrontal cortex The reverse connection relies mainly on a relay thalamus nucleus, the nucleus reuniens

  20. Experimental design FST test FST pretest Adult male and female Wistar rats Vaginal smears diestrus I diestrus II 19h 4h 1h 1 week Sacrifice Lesion evaluation Reuniens lesion or sham operation (NMDA or vehicle infusion) 3 i.p. sertraline 10mg/kg injections or vehicle (SSRI antidepressant treatment)

  21. 150 Sham - Vehicle Sham - Sertraline Lesion - Vehicle 100 Lesion - Sertraline duration (s) 50 0 Males Females Depressive-behavior is decreased when the hippocampus-PFC circuit is disrupted IMMOBILITY * * * * * * * * * * * * Sertraline has no effect in lesionedmales V. Kafetzopoulos& C. Dalla, in preparation

  22. Conclusions Baseline • Depression research should be sex-aware. New and current models need careful validation in females. • Forced swim test and chronic mild stress can be appropriate for females. • Optimal behavioral indices for each sex need to be determined. • In the forced swim test it is preferable to use females in thediestrousphasesof the estrous cycle. • Treatment-sensitive behavioral indices are not always the same in males and females. • Treatment response depends on the sex-differentiated baseline. • Sex differences in phenotype following antidepressant treatment are masked. Treatment

  23. Research group Dr. N. Kokras, V. Kafetzopoulos, D. Papassava, T. Mavridis, N. Pastromas, E. Tzouveka, C. Dioli, M. Koronaiou, A. Vassalou Em. Prof. Z. Papadopoulou-Daifoti Dr. P. Pitychoutis • Collaborators • Ass. Prof. K. Antoniou, Ioannina, Greece • Dr. Charlotte Cornil and Prof. Jacques Balthazart, Liege, Belgium • Prof. N. Sousa and Dr. I. Sotiropoulos, ICVS, Portugal • Dr. Osborne F. X. Almeida, Max Planck Institute of Psychiatry, Germany • Prof. A. Gravanis and Dr. I. Charalabopoulos, Crete, Greece Thank you cdalla@med.uoa.gr

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