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P.2.b.003 Chronic mild stress induces depressive behaviours: role for AMPA receptors and brain-derived neurotrophic factor
P.2.b Affective disorders and antidepressants – Affective disorders (basic) SSRI administration, in both CB1 knockout and wild-type mice. The present results demonstrate that CB1 cannabinoid receptors regulate the emotional responses at a central level, acting on limbic structures and on hypothalamus pituitary adrenal axisaxis. The dysregulation of the cannabinoid activity causes an alteration in this function that is related to the depressive-like phenotype.
P.2.b.003 Chronic mild stress induces depressive behaviours: role for AMPA receptors and brain-derived neurotrophic factor E. Toth ° , R. Gersner, D.E. Dar, I. Akirav, I. Musseri, A. Zangen. Weizmann Institute of Science, Neurobiology, Rehovot, Israel Objective: Exposure to chronic mild stress (CMS) induces anhedonia in adult animals (Willner, 2005), and is associated with the development of depressive neurosis in humans (Anisman, 1997). Several studies suggested that acute stress in young animals induce behavioral abnormalities (Avital, 2005) but the effects of chronic stress on motivational behaviors have not been yet characterized and little is known about the long-term neurochemical effects of CMS in either young or adult animals. Methods: In this study we compared the effect of 4 weeks of chronic mild environmental stressors in young (30 days) versus adult (60 days) male rats on various behaviors. Spontaneous locomotor activity in the home cage, explorative behavior in an open field, the forced swim test, preference for sucrose solutions and the sexual behavior were measured. Expression of AMPA and brainderived neurotrophic factor (BDNF) levels within specific rewardrelated brain regions (prefrontal cortex, anterior and posterior nucleus accumbens, anterior and posterior ventral tegmental area) as well as the dorsal and ventral hippocampus were measured using immunohistochemistry. Results: The present study demonstrated that CMS in adult animals induced anhedonic symptoms, as observed in the sucrose preference (t(14) = 3.275, P = 0.006) and the sexual activity (t(12) = 2.468, P = 0.03), as well as anxiety, as observed in the exploration test (t(29) = 3.362, P < 0.002). On the other hand, CMS in young animals did not induce such behavioral changes. Moreover, home-cage locomotion or swimming activity was not altered by CMS in either young or adult animals. Interestingly, the neurochemical effects of CMS in young animals were different and sometimes opposite from those observe in the adult groups. While exposure of adult animals to CMS caused a decrease in BDNF levels in the dorsal hippocampus (t(10) = 2.715, P = 0.022), the effect of CMS in young animals on BDNF levels was exactly opposite (t(13) = 2.994, P = 0.01). Similarly, BDNF levels in the anterior nucleus accumbens (NAc) were decreased in the adults only (t(12) = 2.32, P = 0.039). In addition, CMS induced a decrease and an increase in GluR1 subunit in the dorsal hippocampus (t(10) = 4.775, P < 0.0001) and the anterior NAc (t(14) = 2.186, P = 0.046), respectively, only in the adults. Both young and adult CMS groups showed a decreased level of GluR1 subunits in the prefrontal cortex (young: t(13) = 2.681, P = 0.019; adult: t(13) = 2.264, P = 0.041), therefore the changes in GluR1 subunits can not account for the anhedonia induce by CMS. Discussion: In conclusion the present results strongly point to a differentiation between young and adult rats after experiencing chronic mild stress. These differences are expressed both in behavioral and site-specific neurochemical alterations associated with depression. One possible explanation for the increase in BDNF levels in the young CMS group is the capability of neuronal
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adaptations in younger ages which allows coping strategies with environmental changes, such as chronic unpredictable stressors. Further research on the link between BDNF, AMPA and their role in the pathophysiology of depression may help in establishing novel therapeutics for the treatment of major depressive disorders. This study have allowed us to gain better insight into the neurochemical basis of depressive behavior and indicate that adolescent depression is different in its pathophysiology and therefore should differ in treatment strategy. References [1] Willner P., 2005, Chronic Mild Stress (CMS) Revisited: Consistency and Behavioural-Neurobiological Concordance in the Effects of CMS, Neuropsychobiology, 52, 90–110. [2] Anisman H., Merali Z., 1997, Chronic stressors and depression: Distinguishing characteristics and individual profiles, Psychopharmacology, 134, 330–332. [3] Avital A., Richter-Levin G., 2005, Exposure to juvenile stress exacerbates the behavioural consequences of exposure to stress in the adult rat, Int J. Neuropsychopharmacol, 8, 163–173.
P.2.b.004 Functional activity of a2 -adrenoceptors in postmortem frontal cortex of depressed suicide victims R. Diez-Alarcia1 ° , E.M. Valdizan2 , J. Gonzalez-Maeso1 , J.A. Garcia-Sevilla3 , A. Pazos2 , J.J. Meana1 . 1 University of the Basque Country, Pharmacology, Leioa, Spain; 2 University of Cantabria, Physiology and Pharmacology, Santander, Spain; 3 University of the Balearic Islands, IUNICS, Mallorca, Spain Abnormalities in the density and functional activity of neurotransmitter receptors that regulate noradrenaline (NA) and serotonin release have been repeatedly reported in brains of suicide victims with mood disorders. Alpha2-adrenoceptors are members of the G protein-coupled receptors family. The binding of the agonist to the receptor induces the activation of G proteins, mainly Gi/Go proteins which mediate, among other events, the inhibition of the adenylyl cyclase enzyme activity. Previous data have shown enhanced alpha2A-adrenoceptor agonist binding sites, and increased sensitivity for the G protein activation (agonist-induced [35S]GTPgammaS binding stimulation) in the frontal cortex of suicide victims with major depression. The titration of the inhibition of cAMP production (adenylyl cyclase activity) induced by an agonist represents another pharmacological approach to evaluate alpha2-adrenoceptor activity in post-mortem human brain. Therefore, inhibition of cAMP production could be altered in the brain of depressed suicide victims. The stimulation of [35S]GTPgammaS binding and the inhibition of cAMP production induced by the alpha2-adrenoceptor agonist UK 14304 (bromoxidine) were evaluated in postmortem prefrontal cortex of depressed suicide victims (n = 12) and matched controls (n = 13). Samples were controlled for sex, age, postmortem delay and storage periods. Concentration-response curves for UK 14304 were performed by non-linear regression analysis to quantitate basal values, the maximal effects (Emax), and the concentrations of the agonist that induce the half-maximal effect (EC50 and IC50 for [35S]GTPgammaS binding and adenylyl cyclase activity, respectively). UK 14304 displayed a higher affinity for the stimulation of [35S]GTPgammaS binding in depressed suicide victims (EC50 = 3.1±2.1 mM) than in controls (EC50 = 15.7±10.3 mM) (p < 0.05, Student’s t test for the log(EC50) values), without
P.2.b.003 Chronic mild stress induces depressive behaviours: role for AMPA receptors and brain-derived neurotrophic factor E. Toth ° , R. Gersner, D.E. Dar, I. Akirav, I. Musseri, A. Zangen. Weizmann Institute of Science, Neurobiology, Rehovot, Israel Objective: Exposure to chronic mild stress (CMS) induces anhedonia in adult animals (Willner, 2005), and is associated with the development of depressive neurosis in humans (Anisman, 1997). Several studies suggested that acute stress in young animals induce behavioral abnormalities (Avital, 2005) but the effects of chronic stress on motivational behaviors have not been yet characterized and little is known about the long-term neurochemical effects of CMS in either young or adult animals. Methods: In this study we compared the effect of 4 weeks of chronic mild environmental stressors in young (30 days) versus adult (60 days) male rats on various behaviors. Spontaneous locomotor activity in the home cage, explorative behavior in an open field, the forced swim test, preference for sucrose solutions and the sexual behavior were measured. Expression of AMPA and brainderived neurotrophic factor (BDNF) levels within specific rewardrelated brain regions (prefrontal cortex, anterior and posterior nucleus accumbens, anterior and posterior ventral tegmental area) as well as the dorsal and ventral hippocampus were measured using immunohistochemistry. Results: The present study demonstrated that CMS in adult animals induced anhedonic symptoms, as observed in the sucrose preference (t(14) = 3.275, P = 0.006) and the sexual activity (t(12) = 2.468, P = 0.03), as well as anxiety, as observed in the exploration test (t(29) = 3.362, P < 0.002). On the other hand, CMS in young animals did not induce such behavioral changes. Moreover, home-cage locomotion or swimming activity was not altered by CMS in either young or adult animals. Interestingly, the neurochemical effects of CMS in young animals were different and sometimes opposite from those observe in the adult groups. While exposure of adult animals to CMS caused a decrease in BDNF levels in the dorsal hippocampus (t(10) = 2.715, P = 0.022), the effect of CMS in young animals on BDNF levels was exactly opposite (t(13) = 2.994, P = 0.01). Similarly, BDNF levels in the anterior nucleus accumbens (NAc) were decreased in the adults only (t(12) = 2.32, P = 0.039). In addition, CMS induced a decrease and an increase in GluR1 subunit in the dorsal hippocampus (t(10) = 4.775, P < 0.0001) and the anterior NAc (t(14) = 2.186, P = 0.046), respectively, only in the adults. Both young and adult CMS groups showed a decreased level of GluR1 subunits in the prefrontal cortex (young: t(13) = 2.681, P = 0.019; adult: t(13) = 2.264, P = 0.041), therefore the changes in GluR1 subunits can not account for the anhedonia induce by CMS. Discussion: In conclusion the present results strongly point to a differentiation between young and adult rats after experiencing chronic mild stress. These differences are expressed both in behavioral and site-specific neurochemical alterations associated with depression. One possible explanation for the increase in BDNF levels in the young CMS group is the capability of neuronal
S303
adaptations in younger ages which allows coping strategies with environmental changes, such as chronic unpredictable stressors. Further research on the link between BDNF, AMPA and their role in the pathophysiology of depression may help in establishing novel therapeutics for the treatment of major depressive disorders. This study have allowed us to gain better insight into the neurochemical basis of depressive behavior and indicate that adolescent depression is different in its pathophysiology and therefore should differ in treatment strategy. References [1] Willner P., 2005, Chronic Mild Stress (CMS) Revisited: Consistency and Behavioural-Neurobiological Concordance in the Effects of CMS, Neuropsychobiology, 52, 90–110. [2] Anisman H., Merali Z., 1997, Chronic stressors and depression: Distinguishing characteristics and individual profiles, Psychopharmacology, 134, 330–332. [3] Avital A., Richter-Levin G., 2005, Exposure to juvenile stress exacerbates the behavioural consequences of exposure to stress in the adult rat, Int J. Neuropsychopharmacol, 8, 163–173.
P.2.b.004 Functional activity of a2 -adrenoceptors in postmortem frontal cortex of depressed suicide victims R. Diez-Alarcia1 ° , E.M. Valdizan2 , J. Gonzalez-Maeso1 , J.A. Garcia-Sevilla3 , A. Pazos2 , J.J. Meana1 . 1 University of the Basque Country, Pharmacology, Leioa, Spain; 2 University of Cantabria, Physiology and Pharmacology, Santander, Spain; 3 University of the Balearic Islands, IUNICS, Mallorca, Spain Abnormalities in the density and functional activity of neurotransmitter receptors that regulate noradrenaline (NA) and serotonin release have been repeatedly reported in brains of suicide victims with mood disorders. Alpha2-adrenoceptors are members of the G protein-coupled receptors family. The binding of the agonist to the receptor induces the activation of G proteins, mainly Gi/Go proteins which mediate, among other events, the inhibition of the adenylyl cyclase enzyme activity. Previous data have shown enhanced alpha2A-adrenoceptor agonist binding sites, and increased sensitivity for the G protein activation (agonist-induced [35S]GTPgammaS binding stimulation) in the frontal cortex of suicide victims with major depression. The titration of the inhibition of cAMP production (adenylyl cyclase activity) induced by an agonist represents another pharmacological approach to evaluate alpha2-adrenoceptor activity in post-mortem human brain. Therefore, inhibition of cAMP production could be altered in the brain of depressed suicide victims. The stimulation of [35S]GTPgammaS binding and the inhibition of cAMP production induced by the alpha2-adrenoceptor agonist UK 14304 (bromoxidine) were evaluated in postmortem prefrontal cortex of depressed suicide victims (n = 12) and matched controls (n = 13). Samples were controlled for sex, age, postmortem delay and storage periods. Concentration-response curves for UK 14304 were performed by non-linear regression analysis to quantitate basal values, the maximal effects (Emax), and the concentrations of the agonist that induce the half-maximal effect (EC50 and IC50 for [35S]GTPgammaS binding and adenylyl cyclase activity, respectively). UK 14304 displayed a higher affinity for the stimulation of [35S]GTPgammaS binding in depressed suicide victims (EC50 = 3.1±2.1 mM) than in controls (EC50 = 15.7±10.3 mM) (p < 0.05, Student’s t test for the log(EC50) values), without