This is a request to continue research on the role of central NE systems projecting from the nucleus locus coeruleus (LC) in behavior and the effects of drugs. Prior studies suggested that the LC might be part of the neural substrate for anxiety/fear, for therapeutic actions of anxiolytics, and for some drug withdrawal syndromes. The effects of the alpha-2 adrenoceptor agonist clonidine on anxiety and morphine withdrawal in humans and the anxiety-producing effects of the alpha-2 antagonist yohimbine are consistent with this hypothesis. Proposed experiments will determine (a) whether acute and chronic lesions of the LC will block the behavioral and physiological responses to conditioned """"""""fear"""""""" or (b) to morphine withdrawal in animals, whether activation produces opposite effects in a receptor-specific fashion, and whether fear-inducing stimuli increase LC function measured biochemically and electrophysiologically. (c) Clinical studies will test the therapeutic and NE-system altering effects of three dissimilar compounds, clonidine, alprazolam, and imipramine. Plasma MHPG (the major norepinephrine metabolite which parallels brain concentrations in monkeys), autonomic signs, and anxiety or panic in patients with agoraphobia and panic attacks will be measured during treatment. Patients will be """"""""challenged"""""""" with yohimbine and caffeine, two compounds reported to elicit anxiety, before and after treatment. Emotional and noradrenergic system responses will be compared with healthy control subjects. These studies, together with previous data, may confirm the involvement of central noradrenergic activity and the LC in anxiety and morphine withdrawal, and begin to determine the aspects of neural plasticity or pathophysiology that may underlie anxiety disorders and chronic drug addiction, two of the most common mental disorders.
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