The key question is what aspects of serotonin function are most involved. Preclinical studies of transgenic mice have provided important clues to the answers to this question. The behavioral

phenotype of serotonin (5-hydroxytrytamine) 5-HT1A knockout mice includes increases in anxiety-like behaviors.92,93 These behaviors are mediated by postsynaptic 5-HT1A receptors in the hippocampus, amygdala, and cortex.94 A finding of potential clinical relevance is that embryonic and early postnatal shutdown of 5-HT1A Inhibitors,research,lifescience,medical receptor expression produces an anxiety phenotype that cannot be rescued with restoration of 5-HT1A receptors. In contrast, when 5-HT1A receptor expression is reduced in adulthood and then reinstated, the anxiety phenotype is no longer present.94 These results indicate that altered function of 5-HT1A receptors early Inhibitors,research,lifescience,medical in life may produce long-term abnormalities in the regulation of anxiety behaviors. A possible mechanism related to this observation is early life stress increases CRH and Cortisol levels, which in turn downregulate 5-HT1A receptors resulting in lower threshold for anxiogenic stressful Inhibitors,research,lifescience,medical life events. Alternatively, 5-HT1A receptors may be decreased on a genetic basis. Consistent with at least a partial genetic diathesis is the finding that the density of 5-HT1A receptor is reduced in depressed

patients when depressed as well as in remission.95 Examination of 5-HT1A receptor density in patients with anxiety disorders while ill and in remission is now indicated. Drugs with full agonist effects at the postsynaptic 5-HT1A receptor may be effective anxiolytic medications in children, adolescents, and adults with

anxiety disorders. There is also evidence that the serotonin transporter Inhibitors,research,lifescience,medical (5-HTT) plays a role in the vulnerability to anxiety disorders. Transgenic mice with a 5-HTT knockout exhibit an excessive Inhibitors,research,lifescience,medical anxiety phenotype.96 These mice also do not show the expected behavioral changes following treatment with selective serotonin transporter inhibitor antidepressant drugs.97 A very exciting recent report found that human subjects with a specific polymorphism of the 5-HTT gene (allele) are particularly vulnerable to depression following the experience of adverse isothipendyl life events.98 Similar gene-environment investigations are needed in patients with anxiety disorders. Benzodiazepine Exposure to inescapable small molecule library screening stressors produce decreases in benzodiazepine receptor binding in the cortex, with some studies showing a decrease in the hippocampus.99 Neuroimaging studies reveal reduced cortical and subcortical benzodiazepine receptor binding in patients with PTSD and PD.101-103 The findings could be related to a downregulation of benzodiazepine receptor binding following exposure to the stress. Further assessment of benzodiazepine receptors in other anxiety disorders, such as GAD and SAD, is needed.