This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Social phobia is a common mental disorder (lifetime prevalence 2.4-13.3%) characterized by a marked and persistent fear of one or more social or performance situations in which a person is exposed to unfamiliar people or to possible scrutiny by others. Both basic science and clinical findings provide evidence for a role of the endogenous opioid system in social phobia. Naloxone, a non-specific opioid receptor antagonist, causes the release of cortisol by antagonizing the tonic opioid inhibitory activity on the CRF releasing neurons of the PVN. Assessment of the cortisol response to naloxone thus provides an estimate of the degree of endogenous opioid system activity at the PVN. This procedure has been utilized in studies of alcoholism, post-traumatic stress disorder, major depression and obsessive compulsive disorder, but has not been evaluated to date in social phobia patients. A genetic component to social phobia is supported by a number of twin studies and familial heritability studies, yet linkage analysis has found no effect of the serotonin transporter, serotonin 2 receptor, dopamine transporter, dopamine 2, 3, and 4 receptor genes. Opioid system genes have not been assessed in social phobia patients. One such gene, OPRM1, has been implicated in differential cortisol response to naloxone The study will employ a placebo-controlled, balanced, within-subject design involving two test days over a 3-7 day period. Fifty subjects (25 subjects with DSM-IV social phobia and 25 age- and sex-matched control subjects) will undergo the pharmacological challenge procedures and genotyping for the Asn40Asp -opioid receptor polymorphism. On each test day subjects will receive either naloxone or placebo, in random order, separated by at least 3 days. Self-report measures, vital signs (including blood pressure, pulse, and temperature), and serum cortisol and ACTH samples will be obtained at -15 minutes, at baseline, and at 15, 30, 45, 60, 75, and 90 minutes following the infusion. The results of this study will illuminate components of the underlying pathophysiology of social phobia, and contribute to the potential development of future pharmacologic treatments based on the endogenous opioid system.
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