NEUROBIOLOGY OF PANIC AND ANXIETY DISORDERS

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DESCRIPTION (Adapted from applicant's abstract): Panic disorder is a severe anxiety disorder characterized by recurrent panic attacks affecting about 1 to 2% of the population. The neurobiological mechanisms involved in the development of panic attacks are poorly understood. The long range objectives are to provide a clearer understanding of the abnormalities in the neuronal circuits underlying severe anxiety states and panic attacks. The objective of the present study is to characterize the abnormalities in the neural circuits underlying the production of panic attacks. The hypothesis to be tested is that there is a chronic imbalance in the neuronal function within the dorsomedial hypothalamus (DMH) which underlies the production of panic attacks. This imbalance could be a result of a net reduction in a tonic inhibitory influence, a net increase in excitatory function, or combination of both. This hypothesis will be tested in rats within experimentally induced GABA dysfunction in the DMH. The specific aims are designed to determine: 1) the time course, anatomical specificity and pharmacological profile of the animals with chronic DMH GABA dysfunction; 2) the interaction of excitatory amino acid neurotransmission and GABA within the DMH in rats with chronic GABA dysfunction; 3) the effects of GABA dysfunction in the DMH on the extracellular levels of norepinephrine (NE) in this region and the potential circuits between the DMH and the locus ceruleus; 4) the involvement of the circumventricular organ, organum vasculosum lamina terminalis (OVLT) in the lactate induced panic-like responses elicited by GABA dysfunction in the DMH. Behavioral measures of anxiety will be undertaken with social interaction and elevated plus-maze tests. Measurements of heart rate, blood pressure and respiratory rate will be used to assess the onset of a panic attack induced by i.v. lactate infusions. Stereotaxic procedures will be used a) for site specific microinfusions to produce chronic GABA dysfunction with Alzet minipumps and to undertake pharmacological studies and b) for implanting microdialysis probes. HPLC-EC procedures will be used to measure GABA tissue levels and extracellular concentrations of NE. The results of this study will hopefully enhance our current understanding of the neurobiology of panic disorder.