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John F. Sheridan - One of the best experts on this subject based on the ideXlab platform.
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Ropivacaine and Bupivacaine prevent increased pain sensitivity without altering neuroimmune activation following repeated Social defeat stress.
Brain behavior and immunity, 2017Co-Authors: Caroline M. Sawicki, John F. Sheridan, January K. Kim, Michael D. Weber, B.l. Jarrett, Jonathan P. Godbout, Michelle L. HumeidanAbstract:Abstract Objective Mounting evidence indicates that stress influences the experience of pain. Exposure to psychoSocial stress disrupts bi-directional communication pathways between the central nervous system and peripheral immune system, and can exacerbate the frequency and severity of pain experienced by stressed subjects. Repeated Social defeat (RSD) is a murine model of psychoSocial stress that recapitulates the immune and Behavioral responses to stress observed in humans, including activation of stress-reactive neurocircuitry and increased pro-inflammatory cytokine production. It is unclear, however, how these stress-induced neuroimmune responses contribute to increased pain sensitivity in mice exposed to RSD. Here we used a technique of regional analgesia with local anesthetics in mice to block the development of mechanical allodynia during RSD. We next investigated the degree to which pain blockade altered stress-induced neuroimmune activation and depressive-like Behavior. Methods Following development of a mouse model of regional analgesia with discrete sensory blockade over the dorsal-caudal aspect of the spine, C57BL/6 mice were divided into experimental groups and treated with Ropivacaine (0.08%), Liposomal Bupivacaine (0.08%), or Vehicle (0.9% NaCl) prior to exposure to stress. This specific region was selected for analgesia because it is the most frequent location for aggression-associated pain due to biting during RSD. Mechanical allodynia was assessed 12 h after the first, third, and sixth day of RSD after resolution of the sensory blockade. In a separate experiment, Social Avoidance Behavior was determined after the sixth day of RSD. Blood, bone marrow, brain, and spinal cord were collected for immunological analyses after the last day of RSD in both experiments following Behavioral assessments. Results RSD increased mechanical allodynia in an exposure-dependent manner that persisted for at least one week following cessation of the stressor. Mice treated with either Ropivacaine or Liposomal Bupivacaine did not develop mechanical allodynia following exposure to stress, but did develop Social Avoidance Behavior. Neither drug affected stress-induced activation of monocytes in the bone marrow, blood, or brain. Neuroinflammatory responses developed in all treatment groups, as evidenced by elevated IL-1β mRNA levels in the brain and spinal cord after RSD. Conclusions In this study, psychoSocial stress was associated with increased pain sensitivity in mice. Development of mechanical allodynia with RSD was blocked by regional analgesia with local anesthetics, Ropivacaine or Liposomal Bupivacaine. Despite blocking mechanical allodynia, these anesthetic interventions did not prevent neuroimmune activation or Social Avoidance associated with RSD. These data suggest that stress-induced neuroinflammatory changes are not associated with increased sensitivity to pain following RSD. Thus, blocking peripheral nociception was effective in inhibiting enhanced pain signaling without altering stress-induced immune or Behavioral responses.
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Antidepressant imipramine diminishes stress-induced inflammation in the periphery and central nervous system and related anxiety- and depressive- like Behaviors.
Brain behavior and immunity, 2016Co-Authors: Karol Ramirez, John F. SheridanAbstract:In order to relieve anxiety and depression accompanying stress, physicians resort to tricyclic antidepressants, such as imipramine. We had previously shown that imipramine reversed stress-induced Social Avoidance Behavior, and down-regulated microglial activation 24days after stress cessation. To further characterize the effects of imipramine on stress induced neuroimmune dysregulation and associated changes in Behavior, the aims of this study were to determine if imipramine 1) ameliorated stress-induced inflammation in the periphery and central nervous system, and 2) prevented stress related anxiety- and depressive-like Behaviors. C57BL/6 mice were treated with imipramine (15mg/kg) in their drinking water, and exposed to repeated Social defeat (RSD). Imipramine attenuated stress-induced corticosterone and IL-6 responses in plasma. Imipramine decreased the percentage of monocytes and granulocytes in the bone marrow and circulation. However, imipramine did not prevent splenomegaly, stress-related increased percentage of granulocytes in this organ, and the production of pro-inflammatory cytokines in the spleen, following RSD. Moreover, imipramine abrogated the accumulation of macrophages in the brain in mice exposed to RSD. Imipramine blocked neuroinflammatory signaling and prevented stress-related anxiety- and depressive-like Behaviors. These data support the notion that pharmacomodulation of the monoaminergic system, besides exerting anxiolytic and antidepressant effects, may have therapeutic effects as a neuroimmunomodulator during stress.
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Neuroinflammatory Dynamics Underlie Memory Impairments after Repeated Social Defeat
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2016Co-Authors: Daniel B. Mckim, John F. Sheridan, Anzela Niraula, A.j. Tarr, Eric S. Wohleb, Jonathan P. GodboutAbstract:Repeated Social defeat (RSD) is a murine stressor that recapitulates key physiological, immunological, and Behavioral alterations observed in humans exposed to chronic psychoSocial stress. PsychoSocial stress promotes prolonged Behavioral adaptations that are associated with neuroinflammatory signaling and impaired neuroplasticity. Here, we show that RSD promoted hippocampal neuroinflammatory activation that was characterized by proinflammatory gene expression and by microglia activation and monocyte trafficking that was particularly pronounced within the caudal extent of the hippocampus. Because the hippocampus is a key area involved in neuroplasticity, Behavior, and cognition, we hypothesize that stress-induced neuroinflammation impairs hippocampal neurogenesis and promotes cognitive and affective Behavioral deficits. We show here that RSD caused transient impairments in spatial memory recall that resolved within 28 d. In assessment of neurogenesis, the number of proliferating neural progenitor cells (NPCs) and the number of young, developing neurons were not affected initially after RSD. Nonetheless, the neuronal differentiation of NPCs that proliferated during RSD was significantly impaired when examined 10 and 28 d later. In addition, Social Avoidance, a measure of depressive-like Behavior associated with caudal hippocampal circuitry, persisted 28 d after RSD. Treatment with minocycline during RSD prevented both microglia activation and monocyte recruitment. Inhibition of this neuroinflammatory activation in turn prevented impairments in spatial memory after RSD but did not prevent deficits in neurogenesis nor did it prevent the persistence of Social Avoidance Behavior. These findings show that neuroinflammatory activation after psychoSocial stress impairs spatial memory performance independent of deficits in neurogenesis and Social Avoidance. SIGNIFICANCE STATEMENT Repeated exposure to stress alters the homeostatic environment of the brain, giving rise to various cognitive and mood disorders that impair everyday functioning and overall quality of life. The brain, previously thought of as an immune-privileged organ, is now known to communicate extensively with the peripheral immune system. This brain–body communication plays a significant role in various stress-induced inflammatory conditions, also characterized by psychological impairments. Findings from this study implicate neuroimmune activation rather than impaired neurogenesis in stress-induced cognitive deficits. This idea opens up possibilities for novel immune interventions in the treatment of cognitive and mood disturbances, while also adding to the complexity surrounding the functional implications of adult neurogenesis.
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GABAergic modulation with classical benzodiazepines prevent stress-induced neuro-immune dysregulation and Behavioral alterations.
Brain behavior and immunity, 2015Co-Authors: Karol Ramirez, Anzela Niraula, John F. SheridanAbstract:Abstract Objective PsychoSocial stress is associated with altered immunity, anxiety, and depression. Repeated Social defeat (RSD), a model of Social stress, triggers egress of inflammatory myeloid progenitor cells (MPCs; CD11b + /Ly6C hi ) that traffic to the brain, promoting anxiety-like Behavior. In parallel, RSD enhances neuroinflammatory signaling and long-lasting Social avoidant Behavior. Lorazepam and clonazepam are routinely prescribed anxiolytics that act by enhancing GABAergic activity in the brain. Besides binding to the central benzodiazepine binding site (CBBS) in the central nervous system (CNS), lorazepam binds to the translocator protein (TSPO) with high affinity causing immunomodulation. Clonazepam targets the CBBS and has low affinity for the TSPO. Here the aims were to determine if lorazepam and clonazepam would: (1) prevent stress-induced peripheral and central inflammatory responses, and (2) block anxiety and Social Avoidance Behavior in mice subjected to RSD. Methods C57/BL6 mice were divided into experimental groups, and treated with either lorazepam (0.10 mg/kg), clonazepam (0.25 mg/kg) or vehicle (0.9% NaCl). Behavioral data and tissues were collected the morning after the last cycle of RSD. Results Lorazepam and clonazepam were effective in attenuating mRNA expression of CRH in the hypothalamus and corticosterone in plasma in mice subjected to RSD. Both drugs blocked stress-induced levels of IL-6 in plasma. Lorazepam and clonazepam had different effects on stress-induced enhancement of myelopoiesis and inhibited trafficking of monocytes and granulocytes in circulation. Furthermore, lorazepam, but not clonazepam, inhibited splenomegaly and the production of pro-inflammatory cytokines in the spleen following RSD. Additionally, lorazepam and clonazepam, blocked stress-induced accumulation of macrophages (CD11b + /CD45 high ) in the CNS. In a similar manner, both lorazepam and clonazepam prevented neuroinflammatory signaling and reversed anxiety-like and depressive-like Behavior in mice exposed to RSD. Conclusion These data support the notion that lorazepam and clonazepam, aside from exerting anxiolytic and antidepressant effects, may have therapeutic potential as neuroimmunomodulators during psychoSocial stress. The reversal of RSD-induced Behavioral outcomes may be due to the enhancement of GABAergic neurotransmission, or some other off-target effect. The peripheral actions of lorazepam, but not clonazepam, seem to be mediated by TSPO activation.
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Imipramine attenuates neuroinflammatory signaling and reverses stress-induced Social Avoidance.
Brain behavior and immunity, 2015Co-Authors: Karol Ramirez, D.t. Shea, Daniel B. Mckim, Brenda F. Reader, John F. SheridanAbstract:PsychoSocial stress is associated with altered immunity, anxiety and depression. Previously we showed that repeated Social defeat (RSD) promoted microglia activation and Social Avoidance Behavior that persisted for 24 days after cessation of RSD. The aim of the present study was to determine if imipramine (a tricyclic antidepressant) would reverse RSD-induced Social Avoidance and ameliorate neuroinflammatory responses. To test this, C57BL/6 mice were divided into treatment groups. One group from RSD and controls received daily injections of imipramine for 24 days, following 6 cycles of RSD. Two other groups were treated with saline. RSD mice spent significantly less time in the interaction zone when an aggressor was present in the cage. Administration of imipramine reversed Social Avoidance Behavior, significantly increasing the interaction time, so that it was similar to that of control mice. Moreover, 24 days of imipramine treatment in RSD mice significantly decreased stress-induced mRNA levels for IL-6 in brain microglia. Following ex vivo LPS stimulation, microglia from mice exposed to RSD, had higher mRNA expression of IL-6, TNF-α, and IL-1β, and this was reversed by imipramine treatment. In a second experiment, imipramine was added to drinking water confirming the reversal of Social avoidant Behavior and decrease in mRNA expression of IL-6 in microglia. These data suggest that the antidepressant imipramine may exert its effect, in part, by down-regulating microglial activation.
Bauke Buwalda - One of the best experts on this subject based on the ideXlab platform.
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Repeated Social stress leads to contrasting patterns of structural plasticity in the amygdala and hippocampus
Behavioural brain research, 2018Co-Authors: Deepika Patel, Shobha Anilkumar, Sumantra Chattarji, Bauke BuwaldaAbstract:Previous studies have demonstrated that repeated immobilization and restraint stress cause contrasting patterns of dendritic reorganization as well as alterations in spine density in amygdalar and hippocampal neurons. Whether Social and ethologically relevant stressors can induce similar patterns of morphological plasticity remains largely unexplored. Hence, we assessed the effects of repeated Social defeat stress on neuronal morphology in basolateral amygdala (BLA), hippocampal CA1 and infralimbic medial prefrontal cortex (mPFC). Male Wistar rats experienced Social defeat stress on 5 consecutive days during confrontation in the resident-intruder paradigm with larger and aggressive Wild-type Groningen rats. This resulted in clear Social Avoidance Behavior one day after the last confrontation. To assess the morphological consequences of repeated Social defeat, 2 weeks after the last defeat, animals were sacrificed and brains were stained using a Golgi-Cox procedure. Morphometric analyses revealed that, compared to controls, defeated Wistar rats showed apical dendritic decrease in spine density on CA1 but not BLA. Sholl analysis demonstrated a significant dendritic atrophy of CA1 basal dendrites in defeated animals. In contrast, basal dendrites of BLA pyramidal neurons exhibited enhanced dendritic arborization in defeated animals. Social stress failed to induce lasting structural changes in mPFC neurons. Our findings demonstrate for the first time that Social defeat stress elicits divergent patterns of structural plasticity in the hippocampus versus amygdala, similar to what has previously been reported with repeated physical stressors. Therefore, brain region specific variations may be a universal feature of stress-induced plasticity that is shared by both physical and Social stressors.
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Repeated Social stress in rats leads to contrasting patterns of structural plasticity in the amygdala and hippocampus
European Neuropsychopharmacology, 2017Co-Authors: Deepika Patel, Sumantra Chattarji, Bauke BuwaldaAbstract:Previous studies have demonstrated that repeated immobilization and restraint stress cause contrasting patterns of dendritic reorganization as well as alterations in spine density in amygdalar and hippocampal neurons. Whether Social and ethologically relevant stressors can induce similar patterns of morphological plasticity remains largely unexplored. Hence, we assessed the effects of repeated Social defeat stress on neuronal morphology in basolateral amygdala (BLA), hippocampal CA1 and infralimbic medial prefrontal cortex (mPFC). Male Wistar rats experienced Social defeat stress on 5 consecutive days during confrontation in the resident-intruder paradigm with larger and aggressive Wild-type Groningen rats. This resulted in clear Social Avoidance Behavior one day after the last confrontation. To assess the morphological consequences of repeated Social defeat, 2 weeks after the last defeat, animals were sacrificed and brains were stained using a Golgi-Cox procedure. Morphometric analyses revealed that, compared to controls, defeated Wistar rats showed apical dendritic decrease in spine density on CA1 but not BLA. Sholl analysis demonstrated a significant dendritic atrophy of CA1 basal dendrites in defeated animals. In contrast, basal dendrites of BLA pyramidal neurons exhibited enhanced dendritic arborization in defeated animals. Social stress failed to induce lasting structural changes in mPFC neurons. Our findings demonstrate for the first time that Social defeat stress elicits divergent patterns of structural plasticity in the hippocampus versus amygdala, similar to what has previously been reported with repeated physical stressors. Therefore, brain region specific variations may be a universal feature of stress-induced plasticity that is shared by both physical and Social stressors.
Joseph S. Stephan - One of the best experts on this subject based on the ideXlab platform.
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Methionine mediates resilience to chronic Social defeat stress by epigenetic regulation of NMDA receptor subunit expression
Psychopharmacology, 2020Co-Authors: Maria Bilen, Pascal Ibrahim, Nour Barmo, Edwina Abou Haidar, Nabil Karnib, Lauretta El Hayek, Mohamad Khalifeh, Vanessa Jabre, Rouba Houbeika, Joseph S. StephanAbstract:Rationale Previous studies suggested that methionine (Met) levels are decreased in depressed patients. However, whether the decrease in this amino acid is important for phenotypic Behaviors associated with depression has not been deciphered. Objective The response of individuals to chronic stress is variable, with some individuals developing depression and others becoming resilient to stress. In this study, our objective was to examine the effect of Met on susceptibility to stress. Methods Male C57BL/6J mice were subjected to daily defeat sessions by a CD1 aggressor, for 10 days. On day 11, the Behavior of mice was assessed using Social interaction and open-field tests. Mice received Met 4 h before each defeat session. Epigenetic targets were assessed either through real-rime RTPCR or through Western Blots. Results Met did not modulate anxiety-like Behaviors, but rather promoted resilience to chronic stress, rescued Social Avoidance Behaviors and reversed the increase in the cortical expression levels of N-methyl- d -aspartate receptor (NMDAR) subunits. Activating NMDAR activity abolished the ability of Met to promote resilience to stress and to rescue Social Avoidance Behavior, whereas inhibiting NMDAR did not show any synergistic or additive protective effects. Indeed, Met increased the cortical levels of the histone methyltransferase SETDB1, and in turn, the levels of the repressive histone H3 lysine (K9) trimethylation (me3). Conclusions Our data indicate that Met rescues susceptibility to stress by inactivating cortical NMDAR activity through an epigenetic mechanism involving histone methylation.
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Methionine mediates resilience to chronic Social defeat stress by epigenetic regulation of NMDA receptor subunit expression.
Psychopharmacology, 2020Co-Authors: Maria Bilen, Pascal Ibrahim, Nour Barmo, Nabil Karnib, Mohamad Khalifeh, Vanessa Jabre, Rouba Houbeika, Edwina Abou Haidar, Lauretta El Hayek, Joseph S. StephanAbstract:Previous studies suggested that methionine (Met) levels are decreased in depressed patients. However, whether the decrease in this amino acid is important for phenotypic Behaviors associated with depression has not been deciphered. The response of individuals to chronic stress is variable, with some individuals developing depression and others becoming resilient to stress. In this study, our objective was to examine the effect of Met on susceptibility to stress. Male C57BL/6J mice were subjected to daily defeat sessions by a CD1 aggressor, for 10 days. On day 11, the Behavior of mice was assessed using Social interaction and open-field tests. Mice received Met 4 h before each defeat session. Epigenetic targets were assessed either through real-rime RTPCR or through Western Blots. Met did not modulate anxiety-like Behaviors, but rather promoted resilience to chronic stress, rescued Social Avoidance Behaviors and reversed the increase in the cortical expression levels of N-methyl-d-aspartate receptor (NMDAR) subunits. Activating NMDAR activity abolished the ability of Met to promote resilience to stress and to rescue Social Avoidance Behavior, whereas inhibiting NMDAR did not show any synergistic or additive protective effects. Indeed, Met increased the cortical levels of the histone methyltransferase SETDB1, and in turn, the levels of the repressive histone H3 lysine (K9) trimethylation (me3). Our data indicate that Met rescues susceptibility to stress by inactivating cortical NMDAR activity through an epigenetic mechanism involving histone methylation.
Lan Xiao - One of the best experts on this subject based on the ideXlab platform.
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quetiapine modulates histone methylation status in oligodendroglia and rescues adolescent Behavioral alterations of Socially isolated mice
Frontiers in Psychiatry, 2020Co-Authors: Xianjun Chen, Hao Liu, Jingli Gan, Xiaorui Wang, Xuejun Liang, Lan XiaoAbstract:Epigenetic alterations and impaired oligodendroglial myelination in the prefrontal cortex have been shown to correlate with Behavioral and cognitive dysfunctions in Social deprivation. Our previous study demonstrated that quetiapine, an atypical antipsychotic, could promote oligodendroglial differentiation and myelination. However, whether and how quetiapine could be beneficial in modulating aberrant epigenetic alterations in oligodendroglial cells and relieving Behavioral alterations from Social isolation is unknown. In this study, quetiapine was orally administered in adolescent mice undergoing mild stress of Social isolation. We firstly confirmed that Social isolation during a novel adolescent period could impair sociability, but not locomotive Behaviors in mice. Moreover, quetiapine alleviated myelin deficits, and increased levels of histone methylation (H3K9me3) in mature oligodendroglia in the prefrontal cortex of Socially isolated mice. Strikingly, quetiapine treatment significantly increased locomotive activity, and successfully reversed Social Avoidance Behavior of the Socially isolated mice. Taken together, our data suggest that quetiapine may rescue Behavioral changes from Social isolation through modulating epigenetic status toward the beneficial direction for oligodendroglial maturation, providing new insights into the pharmacological mechanism of quetiapine for mental illnesses.
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F197. PROMOTING MYELIN REPAIR RESCUES MICE FROM SCHIZOPHRENIA-LIKE Behavior INDUCED BY Social ISOLATION
Schizophrenia Bulletin, 2018Co-Authors: Lan XiaoAbstract:AbstractBackgroundAlthough pathological and genetic evidence suggest that oligodendrocyte (OL) or myelin deficits are associated with schizophrenia, the contribution of OL/myelin deficits to its etiology has not been clearly dissected, because OL/myelin abnormalities may be a concomitant phenomenon during the pathogenesis of schizophrenia.MethodsUsing olig2 ablation specifically in OLs (olig2 CKO) mice, we detected myelin development status and animal Behaviors under normal condition or subjected to Social isolation. We also examined the therapeutic effect of FDA-approved compounds, like quetiapine (an APD) or clemastine (a histamine antagonist) on animal Behaviors.ResultsOur results demonstrated that deleting of olig2 leaded to impaired development of OLs and myelin deficit from postnatal day14 (P14) to P56, preferentially in cerebral cortex, and these young adult Olig2 KO mice showed anxiety-like Behavior, motor skill learning deficit and cognitive deficit. Moreover, Olig2 CKO mice exhibited earlier Social Avoidance Behavior than the WT littermates under prolonged Social isolation, indicating that myelin deficit may enhance risk of schizophrenia upon environmental stress attacking. Interestingly, enhancing oligodendrocyte generation and myelin repair by quetiapine or clemastine successfully reversed the above phenotype.DiscussionTaking together, promoting myelin repair may present a new therapeutic strategy against schizophrenia.
Karol Ramirez - One of the best experts on this subject based on the ideXlab platform.
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Antidepressant imipramine diminishes stress-induced inflammation in the periphery and central nervous system and related anxiety- and depressive- like Behaviors.
Brain behavior and immunity, 2016Co-Authors: Karol Ramirez, John F. SheridanAbstract:In order to relieve anxiety and depression accompanying stress, physicians resort to tricyclic antidepressants, such as imipramine. We had previously shown that imipramine reversed stress-induced Social Avoidance Behavior, and down-regulated microglial activation 24days after stress cessation. To further characterize the effects of imipramine on stress induced neuroimmune dysregulation and associated changes in Behavior, the aims of this study were to determine if imipramine 1) ameliorated stress-induced inflammation in the periphery and central nervous system, and 2) prevented stress related anxiety- and depressive-like Behaviors. C57BL/6 mice were treated with imipramine (15mg/kg) in their drinking water, and exposed to repeated Social defeat (RSD). Imipramine attenuated stress-induced corticosterone and IL-6 responses in plasma. Imipramine decreased the percentage of monocytes and granulocytes in the bone marrow and circulation. However, imipramine did not prevent splenomegaly, stress-related increased percentage of granulocytes in this organ, and the production of pro-inflammatory cytokines in the spleen, following RSD. Moreover, imipramine abrogated the accumulation of macrophages in the brain in mice exposed to RSD. Imipramine blocked neuroinflammatory signaling and prevented stress-related anxiety- and depressive-like Behaviors. These data support the notion that pharmacomodulation of the monoaminergic system, besides exerting anxiolytic and antidepressant effects, may have therapeutic effects as a neuroimmunomodulator during stress.
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GABAergic modulation with classical benzodiazepines prevent stress-induced neuro-immune dysregulation and Behavioral alterations.
Brain behavior and immunity, 2015Co-Authors: Karol Ramirez, Anzela Niraula, John F. SheridanAbstract:Abstract Objective PsychoSocial stress is associated with altered immunity, anxiety, and depression. Repeated Social defeat (RSD), a model of Social stress, triggers egress of inflammatory myeloid progenitor cells (MPCs; CD11b + /Ly6C hi ) that traffic to the brain, promoting anxiety-like Behavior. In parallel, RSD enhances neuroinflammatory signaling and long-lasting Social avoidant Behavior. Lorazepam and clonazepam are routinely prescribed anxiolytics that act by enhancing GABAergic activity in the brain. Besides binding to the central benzodiazepine binding site (CBBS) in the central nervous system (CNS), lorazepam binds to the translocator protein (TSPO) with high affinity causing immunomodulation. Clonazepam targets the CBBS and has low affinity for the TSPO. Here the aims were to determine if lorazepam and clonazepam would: (1) prevent stress-induced peripheral and central inflammatory responses, and (2) block anxiety and Social Avoidance Behavior in mice subjected to RSD. Methods C57/BL6 mice were divided into experimental groups, and treated with either lorazepam (0.10 mg/kg), clonazepam (0.25 mg/kg) or vehicle (0.9% NaCl). Behavioral data and tissues were collected the morning after the last cycle of RSD. Results Lorazepam and clonazepam were effective in attenuating mRNA expression of CRH in the hypothalamus and corticosterone in plasma in mice subjected to RSD. Both drugs blocked stress-induced levels of IL-6 in plasma. Lorazepam and clonazepam had different effects on stress-induced enhancement of myelopoiesis and inhibited trafficking of monocytes and granulocytes in circulation. Furthermore, lorazepam, but not clonazepam, inhibited splenomegaly and the production of pro-inflammatory cytokines in the spleen following RSD. Additionally, lorazepam and clonazepam, blocked stress-induced accumulation of macrophages (CD11b + /CD45 high ) in the CNS. In a similar manner, both lorazepam and clonazepam prevented neuroinflammatory signaling and reversed anxiety-like and depressive-like Behavior in mice exposed to RSD. Conclusion These data support the notion that lorazepam and clonazepam, aside from exerting anxiolytic and antidepressant effects, may have therapeutic potential as neuroimmunomodulators during psychoSocial stress. The reversal of RSD-induced Behavioral outcomes may be due to the enhancement of GABAergic neurotransmission, or some other off-target effect. The peripheral actions of lorazepam, but not clonazepam, seem to be mediated by TSPO activation.
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Imipramine attenuates neuroinflammatory signaling and reverses stress-induced Social Avoidance.
Brain behavior and immunity, 2015Co-Authors: Karol Ramirez, D.t. Shea, Daniel B. Mckim, Brenda F. Reader, John F. SheridanAbstract:PsychoSocial stress is associated with altered immunity, anxiety and depression. Previously we showed that repeated Social defeat (RSD) promoted microglia activation and Social Avoidance Behavior that persisted for 24 days after cessation of RSD. The aim of the present study was to determine if imipramine (a tricyclic antidepressant) would reverse RSD-induced Social Avoidance and ameliorate neuroinflammatory responses. To test this, C57BL/6 mice were divided into treatment groups. One group from RSD and controls received daily injections of imipramine for 24 days, following 6 cycles of RSD. Two other groups were treated with saline. RSD mice spent significantly less time in the interaction zone when an aggressor was present in the cage. Administration of imipramine reversed Social Avoidance Behavior, significantly increasing the interaction time, so that it was similar to that of control mice. Moreover, 24 days of imipramine treatment in RSD mice significantly decreased stress-induced mRNA levels for IL-6 in brain microglia. Following ex vivo LPS stimulation, microglia from mice exposed to RSD, had higher mRNA expression of IL-6, TNF-α, and IL-1β, and this was reversed by imipramine treatment. In a second experiment, imipramine was added to drinking water confirming the reversal of Social avoidant Behavior and decrease in mRNA expression of IL-6 in microglia. These data suggest that the antidepressant imipramine may exert its effect, in part, by down-regulating microglial activation.
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117. Imipramine attenuates neuroinflammation and reverses stress-induced Social Avoidance
Brain Behavior and Immunity, 2014Co-Authors: Karol Ramirez, D.t. Shea, Daniel B. Mckim, Brenda F. Reader, J.c. Avalon, J.p. Godbout, John F. SheridanAbstract:PsychoSocial stress is associated with altered immunity and mood disorders. We previously showed that repeated Social defeat (RSD) promotes long-lasting microglial activation associated with Social Avoidance Behavior, which is maintained for at least 24 days after cessation of RSD. Here our aims were to determine if Imipramine (tricyclic antidepressant) would reverse RSD-induced Social Avoidance and ameliorate neuroinflammatory responses. CB57/BL6 mice were divided into treatment groups. One group from RSD and controls received daily injections of Imipramine for 24 days, after 6 cycles of RSD. Two other groups were treated with saline. RSD mice spent significantly less time in the interaction zone when an aggressor was introduced into the cage. Administration of Imipramine reversed Social Avoidance Behavior, significantly increasing the interaction time, so that it was similar to that of nondefeated mice. Moreover, 24 days of Imipramine treatment in RSD mice significantly decreased stress-induced mRNA levels of IL-6 in microglia. Following ex-vivo LPS stimulation, microglia from mice exposed to RSD, produced higher levels of IL-6, TNF-α, and IL-1B, and this was reversed by Imipramine. In a second experiment, Imipramine was added to drinking water confirming reversal of Social avoidant Behavior and decrease in mRNA expression of IL-6 in microglia. These data demonstrate that antidepressants may exert their effects in part by down-regulating neuroinflammation. This research was supported by NIH/NIMH R01 MH097243-02 and R01 MH093473-03.