There considerable preclinical data demonstrating an important role for the brain noradrenergic (NE) and serotonergic (5-HT) neurotransmitter systems in the expression of fear in animals. These systems also appear to be involved in the pathophysiology of human anxiety, since panic disorder (PD) patients have a marked behavioral (anxiety), physiologic and biochemical response to the alpha 2 adrenergic antagonist yohimbine implicating NE dysregulation in PD, and panic patients improve clinically following chronic administration of medications which influence 5-HT function, like the serotonin reuptake inhibitors. There is a large amount of data describing the intimate anatomic and functional relationships between the NE and 5-HT systems in laboratory animals, but there is little data on the interaction of these two systems in humans. We have recently demonstrated an increase in the anxiogenic effects of yohimbine in healthy human subjects who have ingested an amino acid drink that depletes plasma tryptophan by over 80%. This suggests that an acute impairment of 5-HT function increases the symptomatic response to increased NE activity. We will test the hypothesis that rapid reduction of brain serotonin levels will markedly increase the symptomatic response to the alpha 2 adrenergic antagonist, yohimbine, in PD patients. In order to evaluate this prediction we propose first to study the behavioral effects of tryptophan (TRP) depletion alone in a group of PD patients, since the effects of TRP depletion have not been systematically evaluated in these patients. Then we will examine the behavioral response of a separate group of PD patients to a combined challenge with TRP depletion followed by intravenous yohimbine 0.2 mg/kg. If there is not a marked change in symptomatic response to this dose of yohimbine, we will repeat the combined challenge using a dose of 0.3 mg/kg yohimbine. The knowledge acquired could contribute to a deeper understanding of the pathophysiology of PD and the therapeutic mechanisms of action of successful antipanic treatments.
