Garth Bissette - US grants

Thyrotropin-releasing hormone (TRH) regulates thyrotropin (TSH) secretion from the anterior pituitary and considerable evidence has implicated TRH as a neurotransmitter in extrahypothalamic brain areas. Recent data suggests that TRH may be involved in the pathophysiology of major depression and in the regulation of body temperature. Two previous studies found TRH concentrations to be increased in the CSF of patients with major depression compared to non-depressed controls, and 40% of drug-free depressed patients are known to exhibit abnormal pituitary responses to exogenously administered TRH. The CNS injection of TRH increases the temperature of birds and mammals and the firing rates of temperature-sensitive neurons of the rat preoptic hypothalamus are altered by direct application of TRH. This proposal seeks to scrutinize the role of TRH in major depression and thermoregulation. The specificity of the elevated TRH concentration in CSF of depressed patients will be studied by measuring CSF concentrations of TRH in patients with dementing disorders, anorexia nervosa, schizophrenia and normal healthy volunteers. The effects of treatment with tricyclic antidepressants or electroconvulsive therapy on CSF concentrations of TRH will be examined, and the relationship between nocturnal temperature, plasma TSH concentration and CSF concentrations of TRH will be investigated. The ability of several successive days of cold adaptation to change TRH concentration, TRH receptor number and affinity, and quantity of TRH messenger RNA in various brain regions of experimental animals will be measured and compared to groups of animals undergoing non-thermal stress as well as normal controls. The anatomic locus of these changes will be sought by specific excitotoxic lesions or deafferenting knife cuts of specific brain nuclei. The ability of tricyclic antidepressant drugs or electroconvulsive shock to alter TRH content, receptors or mRNA levels in laboratory animals will also be evaluated. The magnitude of hypothermia necessary to induce the previously observed changes in TRH content will be determined and different strains of mice will be examined for differences in TRH neuronal markers that could explain previously observed strain differences in cold tolerance. Finally, second and third messenger systems associated with the TRH receptor in brain and pituitary will be examined with and without cold adaptation. These experiments will advance our knowledge of hypothalamic-pituitary-thyroid axis involvement in the pathophysiology of major depression, and the mechanisms by which exposure to cold alters TRH systems in brain.