This is a request for a renewal of a collaborative program of basic and clinical research into the neurobiologic basis of major psychiatric disorders. The research program consists of coordinated preclinical and clinical projects focused on the neurobiology of anxiety disorders, depression and psychosis and the mechanism of action of drugs used in their treatment. This grant supports a collaborative team of preclinical and clinical research scientists who conduct studies at the molecular, biochemical, anatomical, histochemical, neurophysiological, behavioral and clinical levels. In anxiety disorders, the research focuses on drugs that effect the noradrenergic (NE), serotonergic (5HT), and the GABA- benzodiazepine (GABA-BZ) systems and that are effective in the treatment of panic disorder. The mechanism of action of these drugs is studied in an experimental model of fear, potentiated startle, measured both in normal and amygdala kindled rats as well as healthy volunteers and psychiatric patients. The importance of these drugs and their effects on the NE and 5HT systems is being investigated in patients with panic disorder. Single photon emission computed tomography (SPECT) is being utilized to study the GABA-BZ system in both laboratory animals and humans. The role of excitatory amino acid regulation of the NE system and the role of buprenorphine in the """"""""anxiety-like"""""""" syndrome produced by opiate withdrawal is being studied in laboratory animals. In depression, our prior research demonstrated that maintenance of clinical improvement to antidepressant treatment (ADT) was dependent on adequate 5HT function. This clinical result has now focused the laboratory research on effects of ADT on the 5HT system, the 5HT receptor subtypes and their interaction with neuropeptides. Parallel studies conducted in depressed patients are investigating the importance of 5HT receptor subtypes and the role of the NE and 5HT systems in the maintenance of the clinical response to ADT. In psychosis, the effects of """"""""typical"""""""" and """"""""atypical"""""""" antipsychotic treatments are being studied in laboratory animals and psychotic patients. SPECT and microdialysis are being utilized to study dopamine release in laboratory animals as a model for understanding brain dopamine function in patients. This research may lead to the discovery of new and more efficacious drugs for the treatment of schizophrenia. This programmatic interaction between basic and clinical research scientists, over the 17 years of support, has resulted in several major discoveries of the mechanism of action of psychotropic drugs, the development of neurotransmitter receptor """"""""challenge tests"""""""" for the neurobiologic evaluation of patients, and the discovery of clonidine for the treatment of opiate withdrawal and lithium augmentation as a treatment for refractory depressed patients.
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