114 Similarly, the expression of neurotrophic and their receptors, thought to underlie rapid changes in dendritic and synaptic architecture, is impaired by stress and enhanced under many learning conditions.115 Interference with neurogenesis or neurotrophic Bioactive Compound Library screening factor production in the hippocampus prevents the behavioral effects of antidepressants to improve fearful responses in experimental animals.116 Medications and CBT may therefore ameliorate maladaptive structural and neurochemical responses

by increasing the resilience of stress circuitry to impairments in neuronal and synaptic proliferation, thus allowing greater Inhibitors,research,lifescience,medical synaptic connectivity, adaptability, and preserved function.107 This notion is supported by experimental findings of SSRI-induced trophic changes in several neuronal elements, including promoting neurotrophin expression and neurogenesis in brain regions relevant to anxiety disorders.117 Inhibitors,research,lifescience,medical SSRIs have been shown to block the impairing effect of Inhibitors,research,lifescience,medical stress on hippocampal neurogenesis and induce both improved

behavioral responses and elevations in multiple synaptic remodeling proteins.118 Furthermore, chronic, but not acute, administration of SSRIs increase the expression of neurotrophic factors,115 suggesting that the delay in clinical response to SSRIs may reflect the time course of neurogenesis or other changes in neuronal excitability.11 Several other antianxiety medications, including SNRIs, have Inhibitors,research,lifescience,medical been found to normalize behavior, and also restore neurotrophin levels, in experimental animals. After repeated restraint

stress to rats, venlafaxine accelerated restoration of neurotrophin levels and hippocampal neurogenesis.120 Inhibitors,research,lifescience,medical Duloxetine was also shown to increase local neurotrophin transcription at synapses, enhancing plasticity, and this effect was only seen after chronic administration.121 Several of the mediators known to affect anxiety responsivity, including both stressful experiences and therapeutic medications, are further thought to operate through epigenetic mechanisms involving found changes in the regulation of chromatin arrangements by histone proteins.122, 123 Similar neurotrophic effects in animals, mediated by histone acetylation, are seen following environmental enrichment treatments, with improved plasticity and learning, even in mice with history of severe stress or neurodegeneration.124-126 As neurogenesis is limited to circumscribed brain regions after early brain development, and SSRIs have been shown to induce synaptic remodeling and behavioral improvements even when neurogenesis is prevented,127 it is unlikely that one plasticity mechanism is solely responsible for the improvements related to pharmacotherapy for anxiety and mood disorders.