What's Love Got to do with it: Role of oxytocin in trauma, attachment and resilience.

Oxytocin (OT) is a neurohypophysial hormone and neuropeptide produced by the hypothalamus and released by the pituitary gland. It has multiple physiological roles including stimulation of parturition and lactation, and promotion of pro-adaptive social behaviors necessary for mammalian survival. OT interacts with one receptor subtype: the OT receptor (OTR) which, upon stimulation, triggers different intracellular signal transduction cascades to mediate its physiological actions. Preclinical studies show that OT regulates social behaviors such as pair bonding, recognition and social interaction. It also coordinates the activation of the hypothalamic-pituitary-adrenal (HPA) axis and the release of corticotrophin-releasing hormone. Further evidence suggests that OT plays an important role in regulating caloric intake and metabolism, and in maintaining electrolyte and cardiovascular homeostasis. OT is also involved in attenuating the neurophysiological and neurochemical effects of trauma on the brain and body by facilitating both physical attachment such as wound healing, and psychological/social attachment, thereby increasing resilience to subsequent traumatic events. Clinical trials have reported that intranasal administration of OT provides therapeutic benefits for patients diagnosed with traumatic stress-related diseases such as major depressive disorders and post-traumatic stress disorder. OT's therapeutic benefits may result from context-dependent interactions with key neural pathways (social, cognitive, and reward), neurotransmitters (dopamine, norepinephrine, serotonin, and endogenous opioids), and biomarkers (adrenocorticotropic hormone, cortisol, and dehydroepiandrosterone sulfate), that lead to a decrease in stress -associated behaviors, and facilitate post-traumatic growth, ultimately leading to increased resilience, through improved social cohesion and attachment. OT induced-augmentation of physical and cognitive resilience may play a significant role in both the prevention of, and improved clinical outcomes for, traumatic stress-related disorders following either acute or enduring traumatic experiences.

High-risk psychotropic medications for US children with trauma sequelae.

Children exposed to trauma are predisposed to develop a number of mental health syndromes. They are prone to under-treatment with effective psychosocial interventions and over-treatment with high-risk psychotropic medications, especially polypharmacy and the use of antipsychotics for unapproved conditions. We review the evidence for psychosocial and pharmacological treatments for mental health problems associated with high exposure to childhood trauma - identifying those in foster care as an index group - and the frequency of high-risk pharmacological practices. We describe current efforts to reduce over-treatment of children with high-risk psychotropic medications and propose further recommendations to protect and provide effective care for these vulnerable children.

The Big Role of Small RNAs in Anxiety and Stress-Related Disorders.

In the study of complex, heterogeneous disorders, such as anxiety and stress-related disorders, epigenetic factors provide an additional level of heritable complexity. MicroRNAs (miRNAs) are a class of small, noncoding RNAs that function as epigenetic modulators of gene expression by binding to target messenger RNAs (mRNAs) and subsequently blocking translation or accelerating their degradation. In light of their abundance in the central nervous system (CNS) and their involvement in synaptic plasticity and neuronal differentiation, miRNAs represent an exciting frontier to be explored in the etiology and treatment of anxiety and stress-related disorders. This chapter will present a thorough review of miRNAs, their functions, and mRNA targets in the CNS, focusing on their role in anxiety and stress-related disorders as described by studies performed in animals and human subjects.

The Emerging Role of Metabotropic Glutamate Receptors in the Pathophysiology of Chronic Stress-Related Disorders.

Chronic stress-related psychiatric conditions such as anxiety, depression, and alcohol abuse are an enormous public health concern. The etiology of these pathologies is complex, with psychosocial stressors being among the most frequently discussed risk factors. The brain glutamatergic neurotransmitter system has often been found involved in behaviors and pathophysiologies resulting from acute stress and fear. Despite this, relatively little is known about the role of glutamatergic system components in chronic psychosocial stress, neither in rodents nor in humans. Recently, drug discovery efforts at the metabotropic receptor subtypes of the glutamatergic system (mGlu1-8 receptors) led to the identification of pharmacological tools with emerging potential in psychiatric conditions. But again, the contribution of individual mGlu subtypes to the manifestation of physiological, molecular, and behavioral consequences of chronic psychosocial stress remains still largely unaddressed. The current review will describe animal models typically used to analyze acute and particularly chronic stress conditions, including models of psychosocial stress, and there we will discuss the emerging roles for mGlu receptor subtypes. Indeed, accumulating evidence indicates relevance and potential therapeutic usefulness of mGlu2/3 ligands and mGlu5 receptor antagonists in chronic stress-related disorders. In addition, a role for further mechanisms, e.g. mGlu7-selective compounds, is beginning to emerge. These mechanisms are important to be analyzed in chronic psychosocial stress paradigms, e.g. in the chronic subordinate colony housing (CSC) model. We summarize the early results and discuss necessary future investigations, especially for mGlu5 and mGlu7 receptor blockers, which might serve to suggest improved therapeutic strategies to treat stress-related disorders.

D-Cycloserine acts via increasing the GluN1 protein expressions in the frontal cortex and decreases the avoidance and risk assessment behaviors in a rat traumatic stress model.

D-cycloserine (DCS), an FDA approved anti-tuberculosis drug has extensively been studied for its cognitive enhancer effects in psychiatric disorders. DCS may enhance the effects of fear extinction trainings in animals during exposure therapy and hence we investigated the effects of DCS on distinct behavioral parameters in a predator odor stress model and tested the optimal duration for repeated daily administrations of the agent. Cat fur odor blocks were used to produce stress and avoidance and risk assessment behavioral parameters were used where DCS or saline were used as treatments in adjunct to extinction trainings. We observed that DCS facilitated extinction training by providing further extinction of avoidance responses, risk assessment behaviors and increased the contact with the cue in a setting where DCS was administered before extinction trainings for 3 days without producing a significant tolerance. In amygdala and hippocampus, GluN1 protein expressions decreased 72h after the fear conditioning in the traumatic stress group suggesting a possible down-regulation of NMDARs. We observed that extinction learning increased GluN1 proteins both in the amygdaloid complex and the dorsal hippocampus of the rats receiving extinction training or extinction training with DCS. Our findings also indicate that DCS with extinction training increased GluN1 protein levels in the frontal cortex. We may suggest that action of DCS relies on enhancement of the consolidation of fear extinction in the frontal cortex.

Effects of acute cortisol administration on perceptual priming of trauma-related material.

Intrusive memories are a hallmark symptom of posttraumatic stress disorder (PTSD). They reflect excessive and uncontrolled retrieval of the traumatic memory. Acute elevations of cortisol are known to impair the retrieval of already stored memory information. Thus, continuous cortisol administration might help in reducing intrusive memories in PTSD. Strong perceptual priming for neutral stimuli associated with a "traumatic" context has been shown to be one important learning mechanism that leads to intrusive memories. However, the memory modulating effects of cortisol have only been shown for explicit declarative memory processes. Thus, in our double blind, placebo controlled study we aimed to investigate whether cortisol influences perceptual priming of neutral stimuli that appeared in a "traumatic" context. Two groups of healthy volunteers (N = 160) watched either neutral or "traumatic" picture stories on a computer screen. Neutral objects were presented in between the pictures. Memory for these neutral objects was tested after 24 hours with a perceptual priming task and an explicit memory task. Prior to memory testing half of the participants in each group received 25 mg of cortisol, the other half received placebo. In the placebo group participants in the "traumatic" stories condition showed more perceptual priming for the neutral objects than participants in the neutral stories condition, indicating a strong perceptual priming effect for neutral stimuli presented in a "traumatic" context. In the cortisol group this effect was not present: Participants in the neutral stories and participants in the "traumatic" stories condition in the cortisol group showed comparable priming effects for the neutral objects. Our findings show that cortisol inhibits perceptual priming for neutral stimuli that appeared in a "traumatic" context. These findings indicate that cortisol influences PTSD-relevant memory processes and thus further support the idea that administration of cortisol might be an effective treatment strategy in reducing intrusive reexperiencing.

Fingolimod, ¿un fármaco para olvidar? / No disponible

No disponible

Cyclooxygenase-2 blockade inhibits accumulation and function of myeloid-derived suppressor cells and restores T cell response after traumatic stress.

Myeloid-derived suppressor cells (MDSCs) play a crucial role in T cell dysfunction, which is related to poor outcome in patients with severe trauma. Cyclooxygenase-2 (Cox-2) contributes to immune disorder in trauma and infection via production of prostaglandin E2. However, the role of Cox-2 in the accumulation and function of MDSCs after traumatic stress has not been fully elucidated. In the present study, we treated murine trauma model with NS398, a selective Cox-2 inhibitor. Then the percentages of CD11b+/Gr-1+ cells, proliferation and apoptosis of CD4+ T cells were determined. Arginase activity and arginase-1 (Arg-1) protein expression of splenic CD11b+/Gr-1+ cells, and delayed-type hypersensitivity (DTH) response were analyzed. The results showed that Cox-2 blockade significantly decreased the percentages of CD11b+/Gr-1+ cells in the spleen and bone marrow 48 and 72 h after traumatic stress. NS398 inhibited arginase activity and down-regulated the Arg-1 expression of splenic CD11b+/Gr-1+ cells. Moreover, NS398 could promote proliferation and inhibit apoptosis of CD4+ T cells. It also restored DTH response of traumatic mice. Taken together, our data revealed that Cox-2 might play a pivotal role in the accumulation and function of MDSC after traumatic stress.

An open-label study of guanfacine extended release for traumatic stress related symptoms in children and adolescents.

OBJECTIVE: The purpose of this open-label pilot study was to investigate the effectiveness and tolerability of guanfacine extended release (GXR) 1-4 mg given in the evening, on the symptoms of traumatic stress (reexperiencing, avoidance, overarousal), generalized anxiety, and functional impairment in children and adolescents with a history of traumatic stress with or without posttraumatic stress disorder (PTSD). As many of our sample had associated attention-deficit/hyperactivity disorder (ADHD) symptoms, we also assessed whether the presence of traumatic stress symptoms impaired the effectiveness of GXR in the treatment of comorbid ADHD symptoms. METHODS: Participants were 19 children and adolescents 6-18 years of age, with current traumatic stress symptoms. In an 8 week open-label design, each patient's scores on parent-, child-, and clinician-reported symptom rating scales assessing traumatic stress symptoms, generalized anxiety, ADHD symptoms, functional impairment, and global symptom severity and improvement (n=17) were evaluated off and on GXR using χ(2) goodness-of-fit tests, paired t tests, and repeated measures analyses of variance (ANOVAs). To examine patterns of change in outcome measures across treatment, MPlus software was used to conduct linear growth curves modeled with individual-varying times of observation (i.e., random slopes). RESULTS: Using an average GXR daily dose of 1.19 mg±0.35 mg and an average weight-adjusted daily dose of 0.03 mg/kg±0.01 mg/kg, significant differences were found on all symptom severity measures. Parent reported UCLA Reaction Index scores assessing cluster B (reexperiencing), C (avoidant), and D (overarousal) symptoms significantly improved. In the presence of PTSD symptoms, children with ADHD experienced significantly improved ADHD symptom scores, suggesting that comorbidity does not attenuate an ADHD symptom response to GXR therapy. Medication was generally well tolerated. CONCLUSIONS: Within the limits of an open-label, hypothesis-generating pilot study, our results suggest that the α2A-adrenoceptor agonist GXR may have therapeutic effects in the treatment of PTSD symptoms in traumatically stressed children and adolescents. The effective dose may be lower than that found for ADHD. Our pilot study supports the need for further controlled research on the effects of GXR and other α2A-adrenoceptor agonists in pediatric disorders of traumatic stress.

Epigenetic regulation of RAC1 induces synaptic remodeling in stress disorders and depression.

Depression induces structural and functional synaptic plasticity in brain reward circuits, although the mechanisms promoting these changes and their relevance to behavioral outcomes are unknown. Transcriptional profiling of the nucleus accumbens (NAc) for Rho GTPase-related genes, which are known regulators of synaptic structure, revealed a sustained reduction in RAS-related C3 botulinum toxin substrate 1 (Rac1) expression after chronic social defeat stress. This was associated with a repressive chromatin state surrounding the proximal promoter of Rac1. Inhibition of class 1 histone deacetylases (HDACs) with MS-275 rescued both the decrease in Rac1 transcription after social defeat stress and depression-related behavior, such as social avoidance. We found a similar repressive chromatin state surrounding the RAC1 promoter in the NAc of subjects with depression, which corresponded with reduced RAC1 transcription. Viral-mediated reduction of Rac1 expression or inhibition of Rac1 activity in the NAc increases social defeat-induced social avoidance and anhedonia in mice. Chronic social defeat stress induces the formation of stubby excitatory spines through a Rac1-dependent mechanism involving the redistribution of synaptic cofilin, an actin-severing protein downstream of Rac1. Overexpression of constitutively active Rac1 in the NAc of mice after chronic social defeat stress reverses depression-related behaviors and prunes stubby spines. Taken together, our data identify epigenetic regulation of RAC1 in the NAc as a disease mechanism in depression and reveal a functional role for Rac1 in rodents in regulating stress-related behaviors.

Influence and interaction of genetic polymorphisms in the serotonin system and life stress on antidepressant drug response.

Variation in genes implicated in serotonin neurotransmission may interact with environmental factors to influence antidepressant response. We aimed to determine how a range of polymorphisms in serotonergic genes determine this response to treatment and how they interact with childhood trauma and recent life stress in a Chinese sample. In total, 14 single nucleotide polymorphisms (SNPs) in coding regions of 10 serotonergic genes (HTR1A, HTR1B, HTR1D, HTR2A, HTR3A, HTR3C, HTR3D, HTR3E, HTR5A and TPH2) were genotyped in 308 Chinese Han patients with major depressive disorder. Response to 6 weeks' antidepressant treatment was determined by change in the 17-item Hamilton Depression Rating Scale (HDRS-17) score, and previous stressful events were evaluated by the Life Events Scale (LES) and Childhood Trauma Questionnaire-Short Form (CTQ-SF). Two 5-HT1B receptor SNPs (rs6296 and rs6298) and one tryptophan hydroxylase2 (rs7305115) SNP were significantly associated with antidepressant response in this Chinese sample, as was a haplotype in TPH2 (rs7305115 and rs4290270). A gene-gene interaction on antidepressant response was found between SNPs in HTR1B, HTR3A and HTR5A in female subjects. The HTR1B SNPs demonstrated interaction with recent stress, while that for TPH2 interacted with childhood trauma to influence antidepressant response.

Intraperitoneal injection of neuropeptide Y (NPY) alters neurotrophin rat hypothalamic levels: Implications for NPY potential role in stress-related disorders.

Neuropeptide Y (NPY) is a 36-amino acid peptide which exerts several regulatory actions within peripheral and central nervous systems. Among NPY actions preclinical and clinical data have suggested that the anxiolytic and antidepressant actions of NPY may be related to its antagonist action on the hypothalamic-pituitary-adrenal (HPA) axis. The neurotrophins brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) are proteins involved in the growth, survival and function of neurons. In addition to this, a possible role of neurotrophins, particularly BDNF, in HPA axis hyperactivation has been proposed. To characterize the effect of NPY on the production of neurotrophins in the hypothalamus we exposed young adult rats to NPY intraperitoneal administration for three consecutive days and then evaluated BDNF and NGF synthesis in this brain region. We found that NPY treatment decreased BDNF and increased NGF production in the hypothalamus. Given the role of neurotrophins in the hypothalamus, these findings, although preliminary, provide evidence for a role of NPY as inhibitor of HPA axis and support the idea that NPY might be involved in pathologies characterized by HPA axis dysfunctions.

Impact of concurrent naturalistic pharmacotherapy on psychotherapy of complicated grief.

Complicated grief (CG) is a debilitating syndrome that can be reliably identified, but there is a paucity of research examining treatment of CG. A targeted psychotherapy for complicated grief (CGT) was recently shown to be efficacious [Shear, K., Frank, E., Houck, P.R., Reynolds, C.F., 3rd, 2005. Treatment of complicated grief: a randomized controlled trial. Journal of the American Medical Association 293, 2601-2608]. We provide a detailed examination of the association of naturalistic pharmacotherapy use with treatment response and study completion in the psychotherapy study. Patients on an antidepressant medication were more likely to complete a full course of CGT (91% vs. 58% completed), while antidepressant use had no effect on completion rates for the comparator, interpersonal psychotherapy (70% vs. 77%). Our naturalistic data underscore the need for prospective, randomized controlled studies of CG pharmacotherapy and psychotherapy alone and in combination.

Therapeutic effects of glyprolines (PGP, GP, and PG) in rats with stress-induced behavioral disorders.

Experiments on male outbred albino rats showed that stress (10-min swimming) increased anxiety and inhibited orientation and exploratory activities. Poststress (15 min after the end of swimming) intranasal administration of peptides Pro-Gly-Pro and Gly-Pro in a dose of 3.7 micromol/kg prevented stress-induced behavioral disorders. This effect persisted for 3 h.

An overview of SSR149415, a selective nonpeptide vasopressin V(1b) receptor antagonist for the treatment of stress-related disorders.

Vasopressin (AVP) and corticotropin-releasing factor (CRF) are key mediators in the organism's neuro-adaptive response to stress. Through pituitary and central vasopressin V(1b) receptors, AVP participates in the control of the hypothalamic-pituitary-adrenal axis (HPA) and is involved in various emotional processes. SSR149415 is the first selective, orally active vasopressin V(1b) receptor antagonist yet described. It is a competitive antagonist with nanomolar affinity for animal and human V(1b) receptors and displays a highly selective profile with regard to a large number of receptors or enzymes. In vitro, SSR149415 potently antagonizes functional cellular events associated with V(1b) receptor activation by AVP, such as intracellular Ca(2+) increase or proliferation in various cell systems. Pharmacological studies, performed by measuring ACTH secretion induced by various stimulants such as hormones (AVP or AVP + CRF) or physical stress (restraint or forced swimming stress and dehydration) in conscious rats or mice, confirm the antagonist profile of SSR149415 and its efficacy in normalizing ACTH secretion in vivo. SSR149415 is active by the oral route, at doses from 3 mg/kg, it potentiates CRF effect and displays a long-lasting oral effect in the different models. At 10 mg/kg p.o. its duration of action is longer than 4 h. This molecule also decreases anxiety and exerts marked antidepressant-like activity in several predictive animal models. The anxiolytic effects of SSR149415 have been demonstrated in various Generalized Anxiety Disorders (GAD) models (four-plate, punished drinking, elevated plus-maze, light dark, mouse defense test battery, fear-potentiated startle and social interaction tests). It is as effective as the benzodiazepine diazepam in the acute stress exposure test. SSR149415 has similar efficacy to the reference antidepressant drug, fluoxetine, in acute (forced-swimming) and chronic (chronic mild stress and subordination stress) situations in rodents. SSR149415 also reduces offensive aggression in the resident-intruder model in mice and hamsters. Depending on the model, the minimal effective doses are in the range of 1-10 mg/kg i.p. or 3-10 mg/kg p.o. SSR149415 is devoid of adverse effects on motor activity, sedation, memory or cognitive functions and produces no tachyphylaxis when administered repeatedly. It is well-tolerated in animals and humans and exhibits an adequate ADME profile. Thus, SSR149415 is a new dual anxiolytic/antidepressant compound, which appears to be free of the known side effects of classical anxiolytic/antidepressant drugs. Clinical trials are in progress, they will hopefully demonstrate its therapeutical potential for treating stress-related disorders.

Metabotropic glutamate receptors as novel targets for anxiety and stress disorders.

Anxiety and stress disorders are the most commonly occurring of all mental illnesses, and current treatments are less than satisfactory. So, the discovery of novel approaches to treat anxiety disorders remains an important area of neuroscience research. Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system, and G-protein-coupled metabotropic glutamate (mGlu) receptors function to regulate excitability via pre- and postsynaptic mechanisms. Various mGlu receptor subtypes, including group I (mGlu(1) and mGlu(5)), group II (mGlu(2) and mGlu(3)), and group III (mGlu(4), mGlu(7) and mGlu(8)) receptors, specifically modulate excitability within crucial brain structures involved in anxiety states. In addition, agonists for group II (mGlu(2/3)) receptors and antagonists for group I (in particular mGlu(5)) receptors have shown activity in animal and/or human conditions of fear, anxiety or stress. These studies indicate that metabotropic glutamate receptors are interesting new targets to treat anxiety disorders in humans.

Highlights from the Fifth International Meeting on Metabotropic Glutamate Receptors, held September 18-23, 2005, in Taormina, Sicily, Italy. Metabotropic glutamate receptors as therapeutic targets.

The study of metabotropic glutamate receptors (mGluRs) is one of the fastest growing areas of neuropharmacology. The Fifth International Meeting on Metabotropic Glutamate Receptors, held September 18-23, 2005, in Taormina, Sicily, Italy, encompassed more than 80 oral presentations and 70 poster presentations. The role of mGluRs in various physiological and pathological conditions, such as learning and memory, modulation of sensory inputs, control of movement, schizophrenia, anxiety, seizures, addiction to drugs, neurodegeneration and developmental regulation of synaptic circuits, was discussed.

Behavioral, adrenal, and sympathetic responses to long-term administration of an oral corticotropin-releasing hormone receptor antagonist in a primate stress paradigm.

CRH is a main regulator of the stress response. This neuropeptide and its specific receptors, CRHR-1 and CRHR-2, are disseminated throughout the central nervous system. There is a significant interspecies difference in the distribution of CRHR within the central nervous system. CRH-R1 antagonists may attenuate stress-related behavior in rats without compromising adrenal function, but few studies have addressed the same question in higher mammals. Antalarmin (AA) is a specific CRHR-1 antagonist suitable for oral administration. Social separation is a potent stressor for rhesus monkeys. Therefore, we sought to investigate the hormonal responses to chronic administration of AA using a primate stress model. Eight preadolescent (4-6 kg) male rhesus monkeys received AA (20 mg/kg.d) or placebo (PBO) orally. All animals were on a regular day/light cycle and were fed with standard monkey chow daily. The study (114 d) was comprised of the following consecutive phases: adaptation, baseline, separation (stress), recovery, and cross-over. During social separation, solid panels separated the individuals. Cerebrospinal fluid (CSF) and femoral venous blood samples were obtained once a week on the fourth day of separation under ketamine anesthesia. Serum samples were also obtained 1 and 2 h after separation. CSF samples were assayed for CRH, AA, norepinephrine (NE) and epinephrine (EPI). Plasma was assayed for ACTH, cortisol, NE, and EPI. AA was detected in the plasma of each monkey while they were taking the active drug and in none of the animals on PBO. Among the behaviors assessed, environmental exploration, a behavior inhibited by stress, was increased during AA administration. However, AA at this dose did not affect other anxiety-related behavioral end points, including self-directed behavior, vocalization, or locomotion. We also observed that: 1) ACTH decreased between adaptation and baseline, indicating that the animals had adjusted to the novel environment; 2) ACTH and cortisol increased significantly after social separation, indicating that social separation was an adequate model for acute stress; 3) NE and EPI increased significantly during acute stress in the AA and PBO groups (P < 0.005, NE; P < 0.001, EPI); 4) after chronic stress, by d 4 of separation, ACTH levels were no longer significantly different from baseline, and NE and EPI remained slightly elevated when compared with baseline (P < 0.05, NE; P < 0.01, EPI); and 5) all the animals remained healthy and gained the expected weight during the study. In summary, oral chronic administration of a specific CRH-R1 antagonist to rhesus monkeys does not blunt the sympathoadrenal response to stress while increasing environmental exploration, a behavior that is normally suppressed during stressful events. Taken together, these findings suggest that CRHR-1 antagonists may be a valid treatment for stress-related disorders.