Anxiety Disorders: Barad M

Davis M, Barad M, Otto M, Southwick S. · Department of Psychiatry, Emory University, Atlanta, GA, USA. · J Trauma Stress. · Pubmed #17075906 No free full text.

Abstract: Given the ever-increasing sources of trauma both nationally and globally, it is imperative to develop new and better treatments for anxiety disorders such as posttraumatic stress disorder (PTSD). This review is a collection of presentations that seek to do just that, either by using pharmacotherapy to try to prevent or erase the formation of traumatic fear memories, or to enhance exposure-based cognitive-behavioral therapy using pharmacological agents that have been effective in enhanced extinction of fear in rodents.

Barad M. · Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, UCLA, 635 Charles Young Drive South, Los Angeles, CA 90095, USA. · Curr Opin Neurobiol. · Pubmed #16260129 No free full text.

Abstract: Fear extinction, the reduction of fear by repeated exposure to the object of fear, is a crucial paradigm of inhibitory learning and the acknowledged preclinical model for behavior therapy of human anxiety. Recent insights have clarified roles for infralimbic prefrontal cortex, hippocampus and periaqueductal gray in extinction learning, while maintaining a central role for the basolateral amygdaloid nucleus in the acquisition and storage of this learning. Simultaneously, molecular insights have implicated several neurotransmitter and second messenger systems in extinction learning, and revealed that extinction is surprisingly easy to improve, yielding the promise of a novel approach to improved psychiatric treatments for a variety of human anxiety disorders.

Bredy TW, Barad M. · Semel Institute for Neuroscience and Human Behavior, UCLA, Los Angeles, California 90095, USA. · Learn Mem. · Pubmed #18174372 links to  free full text

Abstract: Histone modifications contribute to the epigenetic regulation of gene expression, a process now recognized to be important for the consolidation of long-term memory. Valproic acid (VPA), used for many years as an anticonvulsant and a mood stabilizer, has effects on learning and memory and enhances the extinction of conditioned fear through its function as a histone deacetylase inhibitor (HDAC). Here we report that VPA enhances long-term memory for both acquisition and extinction of cued-fear. Interestingly, VPA enhances extinction, but also enhances renewal of the original conditioned fear when tested in a within-subjects design. This effect appears to be related to a reconsolidation-like process since a single CS reminder in the presence of VPA can enhance long-term memory for the original fear in the context in which fear conditioning takes place. We also show that by modifying the intertrial interval during extinction training, VPA can strengthen reconsolidation of the original fear memory or enhance long-term memory for extinction such that it becomes independent of context. These findings have important implications for the use of HDAC inhibitors as adjuncts to behavior therapy in the treatment of phobia and related anxiety disorders.

Bredy TW, Wu H, Crego C, Zellhoefer J, Sun YE, Barad M. · Department of Psychiatry and Biobehavioral Sciences, Brain Research Institute, Semel Institute for Neuroscience and Human Behavior, Los Angeles, California 90095, USA. · Learn Mem. · Pubmed #17522015 links to  free full text

Abstract: Extinction of conditioned fear is an important model both of inhibitory learning and of behavior therapy for human anxiety disorders. Like other forms of learning, extinction learning is long-lasting and depends on regulated gene expression. Epigenetic mechanisms make an important contribution to persistent changes in gene expression; therefore, in these studies, we have investigated whether epigenetic regulation of gene expression contributes to fear extinction. Since brain-derived neurotrophic factor (BDNF) is crucial for synaptic plasticity and for the maintenance of long-term memory, we examined histone modifications around two BDNF gene promoters after extinction of cued fear, as potential targets of learning-induced epigenetic regulation of gene expression. Valproic acid (VPA), used for some time as an anticonvulsant and a mood stabilizer, modulates the expression of BDNF, and is a histone deacetylase (HDAC) inhibitor. Here, we report that extinction of conditioned fear is accompanied by a significant increase in histone H4 acetylation around the BDNF P4 gene promoter and increases in BDNF exon I and IV mRNA expression in prefrontal cortex, that VPA enhances long-term memory for extinction because of its HDAC inhibitor effects, and that VPA potentiates the effect of weak extinction training on histone H4 acetylation around both the BDNF P1 and P4 gene promoters and on BDNF exon IV mRNA expression. These results suggest a relationship between histone H4 modification, epigenetic regulation of BDNF gene expression, and long-term memory for extinction of conditioned fear. In addition, they suggest that HDAC inhibitors may become a useful pharmacological adjunct to psychotherapy for human anxiety disorders.

Ponnusamy R, Nissim HA, Barad M. · Department of Psychiatry and Biobehavioral Sciences, Neuropsychiatric Institute and Brain Research Institute, University of California, Los Angeles, CA 90095, USA. · Learn Mem. · Pubmed #16077018 links to  free full text

Abstract: Extinction of conditioned fear in animals is the explicit model of behavior therapy for human anxiety disorders, including panic disorder, obsessive-compulsive disorder, and post-traumatic stress disorder. Based on previous data indicating that fear extinction in rats is blocked by quinpirole, an agonist of dopamine D2 receptors, we hypothesized that blockade of D2 receptors might facilitate extinction in mice, while agonists should block extinction, as they do in rats. One day after fear conditioning mice with three pairings of a white noise conditional stimulus (CS) with moderate footshock, we injected the D2 antagonist, sulpiride, the D2 agonist, quinpirole, or vehicle, just before repeated CS presentations to generate extinction. We assayed fear by measuring behavioral freezing during extinction presentations and then drug-free during CS presentations 1 d later. We found that sulpiride injections before extinction training facilitated extinction memory 24 h later, while quinpirole partially blocked extinction memory compared with vehicle-injected controls. Notably, sulpiride treatment yielded significant extinction after spaced CS presentations, which yield no extinction at all in vehicle-treated mice. These findings suggest that dopamine D2-mediated signaling contributes physiological inhibition of extinction, and that D2 antagonists may be useful adjuncts to behavior therapy of human anxiety disorders.