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Social defeat in rats as model for depression
S.16 Relevance of animalstress models for psychiatry crease in cortisol level, leads, faster than in normals, to a breakdown of the 5-RT la system. Consequently the anxiety/aggression regulation fails and anxiety/aggression levels rise. Through sustained augmented anxiety/aggression levels, mood regulation gets disturbed and a depression is generated, of which the full name, I propose, is: stressor-precipitated, cortisol-induced, 5-RT related, anxiety/aggression-driven depression, in short: SeCA depression. We predict that the preferential treatment of this subtypeof depression will consist of: direct and selective5-RT 1a agonists and/or: antagonists of cortisol productionor cortisol release. Prevention of this depression type will consists of maintenance treatment with a selective 5-RT1a agonist, in conjunction with attempt to augmentstressor resistance, via psychological interventions. References
Van Praag, H.M. (1992) About thecentrality of mood lowering in mood disorders. Europ. Neuropsychopharm. 2, 393-402. Van Praag, H.M. (1996) Serotonin-related, anxiety/aggression-driven, stressorprecipitated depression. A psychobiological hypothesis. Eur. Psychiatry. II, 57-67. Van Praag, H.M. Faulty cortisol/serotonin interplay Psychopathological and biologicalcharacterisation ofanew, hypothetical depression subtype (SeCA-depression). Psychiatry Research. Submitted.
18.16.021 Social defeat in ratsas model for depression I.M. Koolhaas, P.Meerio, S.P. de Boer,I.H. Strubbe. Dept. of Animal Physiology, P.O. Box 14, 9750AA Haren, TheNetherlands It is well accepted, both from human and from animal studies that loss of environmental control is a major factor in inducing depression. A wide variety of animal models of depression is based on this principle. However, many of these models fail with respect to their face validity because they use stressors which bear little or no relationship to the situations an animal may meet in its everyday life in a natural environment. In the present study social defeat was used as a more natural form of loss of control. Social defeat by a male conspecific induces an acute increase in heart rate, blood pressure and body temperature, strong neuroendocrine responses in plasma catecholamines, corticosterone, prolactin and testosterone (Bohus et al. 1987), as well as changes in central nervous dopaminergic neurotransmission. These responses including the behavioral reaction (flight, immobility) can be considered as part of the classical response to an acute stressor. More important however is the question whether and how such an acute stress response may ultimately induce a depressive state in the animal. Such a question requires a more detailed study of the temporal dynamics of the stress response. Recent studies using more chronic recordings indicate that the various stress parameters have a different time course. Whereas the cardiovascular and catecholaminergic response to an one hour social defeat diminishes within one or two hours after the defeat, the corticosterone response lasts for more than four hours. After an initial rise, plasma testosterone drops below baseline levels and remains at extremely low levels for at least two days. A single social defeat appears to induce a reduction in the circadian variation in body temperature, growth, sexualinterest,open field exploration and food preference(carbohydrate and fat intake) which may last about ten days after the social stress (Koolhaas et al. 1995). There are several reasons to assume that the single social defeat induces a state of depression. First of all, many of these long-term changes can be considered as part of the symptomatology of human depression. Secondly, the behavioral changes induced by the social defeat can be antagonized by standard antidepressive treatments. For example, a one night sleep deprivation normalizes behavior in the subsequent activity period (Meerio et al. 1996). Similar to the effects of sleep deprivation in depressed patients, this effect is only short lasting and disappears after a subsequent night of sleep. A ten days treatment with clomipramine resulted in a lasting normalization of behavior. Pharmacological challenge tests, using an intravenous injection 8OHDPAT (0.05 mglkg) show that the 8-0HDPATinducedcorticosterone responseis reducedtwenty-fourhours afterthe socialdefeat.Similarly, the 8-0HDPAT(0.1 mglkgi.p.)inducedhypothermia responseis significantly reduced after a single social defeat experience. This latter reduction lasts for at least two weeks after the defeat. Such a diminishedcorticosterone and hypothermiaresponsemay be the consequence of a hyposensitivity in
S4-35
the postsynaptic 5-RTla receptor system. Although the data are far from complete, we want to emphasize that social defeat induces changes in a variety of physiological and behavioral parameters each of which may have differentcourse in time, ranging from several hours to several days and weeks. This notion has important theoretical consequences. The different temporal dynamicsof the variousstress parametersimplies that the physiological and behavioral state of the animal shortly after the stressor will be different from the state several days or weeks later. In terms of symptomatology, the syndrome will be different depending on the time of measurement after the uncontrollable stress experience. Moreover, as a consequence of these different states, the vulnerability to subsequent stressorsmay be differentat these points in time after the first stressor as well. This way of reasoning is in line with the literature indicating that the recurrences of affective disordersmay be due to the fact that stressors leaveresidualtraces in the biochemicaland anatomicalsubstrateof affective disorders whichseem to enhance vulnerability. However, much more directanimalexperimental evidenceis necessaryto proof such a sensitization hypothesis. Some studiessupportsuch a sensitization hypothesis.In a studyon the long-termbehavioralconsequences of social defeat,Koolhaas et al (1990)used the behavioral response to a mild environmental stressor as a repeatable challenge test. They observed a progressive increase in immobility behaviorreachinga maximumat three weeks after the defeat. Similar results with the same time course were obtained by Dijken et al (1992) using the same challenge test after a brief session of inescapable footstock. The progressive change observedin these two studies suggests a gradual sensitization to environmental stimuli developingin the course of weeksafter the singlestressexperience. The interpretation of the changesinducedby a single inescapablestress in terms of types of stress-pathology is an important fundamental issue. It is conceivable that in the course of time after the stress experience, the animal may show signs of anxiety disorders, depression or posttraumatic stress disorders. However, rather then extending the discussion on classifications and subdivisions of human affective disorders towards animal models as well, we would like to emphasize that the study of the temporaldynamics of stress responsesand its consequencesmay provide a more fundamental approach of the etiology and symptomatology of stress-related disorders. References
Bohus B,Benus RF, Fokkema DS, Koolhaas JM, Nyakas C, Van Oorttnerssen GA, Prins AlA, De Ruiter AlH, Scheurink AJW,Steffens AB (1987) Neuroendocrine states and behavioral andphysiological stress responses. In: De Kloet ER,Wiegant VM, De Wied D (eds) Progress in Brain Research. 72th edition. Elsevier, Amsterdam, pp 57-70 Dijken HH, Heyden JAMv, Mos J, Tilders FJH (1992) Inescapable footshocks induce progressive and long-lasting behavioural changes in male rats. Physiol Behav 51:787-794 Koolhaas JM, Hermann PM, Kemperman C,Bohus B,Hoofdakker RHvd, Beersma DGM (1990) Single social interaction leading to defeat in male rats induces a gradual, but long lasting behavioral change: a model of depression? Neurosci Res Comm 7: 35-41 Koolhaas JM, Meerlo P, Boer SF(\, Strubbe JH, Bohus B (1995) Social stress in rats: Ananimal model ofdepression? Acta Neuropsychiatrica 7: 9-11 Meerlo P, Overkamp GJF, Benning MA, Koolhaas JM, Hoofdakker RHv (1996) Long term changes in open field behaviour following a single social defeat in rats canbereversed by sleep deprivation. Physiol Behav 60:
I8.16.031 Disruption of circadian rhythms in possible animal models for depression
nw Turek,P.Zee, O. Buxton,O. VanReeth, P.Penev.
Centerfor Circadian Biology & Medicine, Northwestern University, 2153 N. Campus t», Evanston, IL 60208, USA
Disturbances of circadian rhythmicity have been associated with adverse effects on both mental and physical health in humans. Indeed there is now a large amount of evidence to indicate that one of the most common mental illnesses,depression,is associated with abnormalities in circadianrhythms.However, cause and effect relationships between such abnormalities and mood state have not been established. Circadian disturbances in humans can be classifiedunder two general categories. In one categoryare those circadianabnormalities that occur in responseto a conscious human decision to "override" the circadianclock
Van Praag, H.M. (1992) About thecentrality of mood lowering in mood disorders. Europ. Neuropsychopharm. 2, 393-402. Van Praag, H.M. (1996) Serotonin-related, anxiety/aggression-driven, stressorprecipitated depression. A psychobiological hypothesis. Eur. Psychiatry. II, 57-67. Van Praag, H.M. Faulty cortisol/serotonin interplay Psychopathological and biologicalcharacterisation ofanew, hypothetical depression subtype (SeCA-depression). Psychiatry Research. Submitted.
18.16.021 Social defeat in ratsas model for depression I.M. Koolhaas, P.Meerio, S.P. de Boer,I.H. Strubbe. Dept. of Animal Physiology, P.O. Box 14, 9750AA Haren, TheNetherlands It is well accepted, both from human and from animal studies that loss of environmental control is a major factor in inducing depression. A wide variety of animal models of depression is based on this principle. However, many of these models fail with respect to their face validity because they use stressors which bear little or no relationship to the situations an animal may meet in its everyday life in a natural environment. In the present study social defeat was used as a more natural form of loss of control. Social defeat by a male conspecific induces an acute increase in heart rate, blood pressure and body temperature, strong neuroendocrine responses in plasma catecholamines, corticosterone, prolactin and testosterone (Bohus et al. 1987), as well as changes in central nervous dopaminergic neurotransmission. These responses including the behavioral reaction (flight, immobility) can be considered as part of the classical response to an acute stressor. More important however is the question whether and how such an acute stress response may ultimately induce a depressive state in the animal. Such a question requires a more detailed study of the temporal dynamics of the stress response. Recent studies using more chronic recordings indicate that the various stress parameters have a different time course. Whereas the cardiovascular and catecholaminergic response to an one hour social defeat diminishes within one or two hours after the defeat, the corticosterone response lasts for more than four hours. After an initial rise, plasma testosterone drops below baseline levels and remains at extremely low levels for at least two days. A single social defeat appears to induce a reduction in the circadian variation in body temperature, growth, sexualinterest,open field exploration and food preference(carbohydrate and fat intake) which may last about ten days after the social stress (Koolhaas et al. 1995). There are several reasons to assume that the single social defeat induces a state of depression. First of all, many of these long-term changes can be considered as part of the symptomatology of human depression. Secondly, the behavioral changes induced by the social defeat can be antagonized by standard antidepressive treatments. For example, a one night sleep deprivation normalizes behavior in the subsequent activity period (Meerio et al. 1996). Similar to the effects of sleep deprivation in depressed patients, this effect is only short lasting and disappears after a subsequent night of sleep. A ten days treatment with clomipramine resulted in a lasting normalization of behavior. Pharmacological challenge tests, using an intravenous injection 8OHDPAT (0.05 mglkg) show that the 8-0HDPATinducedcorticosterone responseis reducedtwenty-fourhours afterthe socialdefeat.Similarly, the 8-0HDPAT(0.1 mglkgi.p.)inducedhypothermia responseis significantly reduced after a single social defeat experience. This latter reduction lasts for at least two weeks after the defeat. Such a diminishedcorticosterone and hypothermiaresponsemay be the consequence of a hyposensitivity in
S4-35
the postsynaptic 5-RTla receptor system. Although the data are far from complete, we want to emphasize that social defeat induces changes in a variety of physiological and behavioral parameters each of which may have differentcourse in time, ranging from several hours to several days and weeks. This notion has important theoretical consequences. The different temporal dynamicsof the variousstress parametersimplies that the physiological and behavioral state of the animal shortly after the stressor will be different from the state several days or weeks later. In terms of symptomatology, the syndrome will be different depending on the time of measurement after the uncontrollable stress experience. Moreover, as a consequence of these different states, the vulnerability to subsequent stressorsmay be differentat these points in time after the first stressor as well. This way of reasoning is in line with the literature indicating that the recurrences of affective disordersmay be due to the fact that stressors leaveresidualtraces in the biochemicaland anatomicalsubstrateof affective disorders whichseem to enhance vulnerability. However, much more directanimalexperimental evidenceis necessaryto proof such a sensitization hypothesis. Some studiessupportsuch a sensitization hypothesis.In a studyon the long-termbehavioralconsequences of social defeat,Koolhaas et al (1990)used the behavioral response to a mild environmental stressor as a repeatable challenge test. They observed a progressive increase in immobility behaviorreachinga maximumat three weeks after the defeat. Similar results with the same time course were obtained by Dijken et al (1992) using the same challenge test after a brief session of inescapable footstock. The progressive change observedin these two studies suggests a gradual sensitization to environmental stimuli developingin the course of weeksafter the singlestressexperience. The interpretation of the changesinducedby a single inescapablestress in terms of types of stress-pathology is an important fundamental issue. It is conceivable that in the course of time after the stress experience, the animal may show signs of anxiety disorders, depression or posttraumatic stress disorders. However, rather then extending the discussion on classifications and subdivisions of human affective disorders towards animal models as well, we would like to emphasize that the study of the temporaldynamics of stress responsesand its consequencesmay provide a more fundamental approach of the etiology and symptomatology of stress-related disorders. References
Bohus B,Benus RF, Fokkema DS, Koolhaas JM, Nyakas C, Van Oorttnerssen GA, Prins AlA, De Ruiter AlH, Scheurink AJW,Steffens AB (1987) Neuroendocrine states and behavioral andphysiological stress responses. In: De Kloet ER,Wiegant VM, De Wied D (eds) Progress in Brain Research. 72th edition. Elsevier, Amsterdam, pp 57-70 Dijken HH, Heyden JAMv, Mos J, Tilders FJH (1992) Inescapable footshocks induce progressive and long-lasting behavioural changes in male rats. Physiol Behav 51:787-794 Koolhaas JM, Hermann PM, Kemperman C,Bohus B,Hoofdakker RHvd, Beersma DGM (1990) Single social interaction leading to defeat in male rats induces a gradual, but long lasting behavioral change: a model of depression? Neurosci Res Comm 7: 35-41 Koolhaas JM, Meerlo P, Boer SF(\, Strubbe JH, Bohus B (1995) Social stress in rats: Ananimal model ofdepression? Acta Neuropsychiatrica 7: 9-11 Meerlo P, Overkamp GJF, Benning MA, Koolhaas JM, Hoofdakker RHv (1996) Long term changes in open field behaviour following a single social defeat in rats canbereversed by sleep deprivation. Physiol Behav 60:
I8.16.031 Disruption of circadian rhythms in possible animal models for depression
nw Turek,P.Zee, O. Buxton,O. VanReeth, P.Penev.
Centerfor Circadian Biology & Medicine, Northwestern University, 2153 N. Campus t», Evanston, IL 60208, USA
Disturbances of circadian rhythmicity have been associated with adverse effects on both mental and physical health in humans. Indeed there is now a large amount of evidence to indicate that one of the most common mental illnesses,depression,is associated with abnormalities in circadianrhythms.However, cause and effect relationships between such abnormalities and mood state have not been established. Circadian disturbances in humans can be classifiedunder two general categories. In one categoryare those circadianabnormalities that occur in responseto a conscious human decision to "override" the circadianclock