The proposed research has the following specific goals: (1) to assess, at the clinical level, noradrenergic (NA), benzodiazepine-gammaminobutyric acid receptor (BZ-GABA), and serotonergic (5-HT) function in healthy subjects and patients with Agoraphobia and Panic Attacks (APA) to determine whether there is a dysfunction of these systems in APA. (2) Examination of the antipanic efficacy of lorazepam and [buspirone] compared to placebo and imipramine in a double blind treatment protocol. The effectiveness of these treatments will be analyzed in relation to pretreatment clinical variables, especially the severity of depression and agoraphobia, the frequency of panic attacks and the neurobiological profile. Particular attention will be directed toward the time course of treatment efficacy and the spectrum of symptoms affected. (3) Investigation of the mechanism of action of drugs effective in the treatment of APA. This will be done by determination of the effects of lorazepam, [buspirone], imipramine and placebo on NA, BZ-GABA and 5-HT function over whether such effects are related to treatment response. Norepinephrine turnover will be measured by determination of plasma free 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) levels. The effects of the alpha-2 adrenergic autoreceptor antagonist, yohimbine, on MHPG, cortisol, ACTH, behavior, cardiovascular function, and somatic symptoms will be used as an index of NA function. BZ-GABA receptor function will be assessed by determining the biochemical, behavioral and autonomic effects of pentylenetetrazol, a competitive antagonist of [3H]-diazepam binding. Serotonergic function will be determined by measuring ability of tryptophan, a 5-HT precursor, to increase prolactin levels and alter mood. These studies should provide data relevant to the evidence that increased NA function occurs in some forms of human anxiety and some antipanic drugs reduce NA activity. It will evaluate hypothesis, generated from preclinical investigations, that BZ-GABA and 5-HT dysfunction are also related to anxiety development and treatment. The information obtained from these studies may be important for the identification and development of more specific and efficacious treatment for patients with anxiety disorders.
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