The research proposed here investigates a possible mechanism by which noradrenergic neurons in the brain influence dopaminergic neurons to produce behavioral changes seen in depression. These studies address an important issue related to the neurobiology of depression; namely, that while much evidence shows brain norepinephrine (NE) is important in both the pathogenesis and therapy of depression, basic research implicates dopamine (DA) in depression-related responses (motor activity changes, hedonic responses) much more so than NE. The proposed research derives from, and will continue to use, an animal (rat) model of depression that reproduces characteristics of clinical depression by exposing animals to uncontrollable stressful conditions (called """"""""stress-induced behavioral depression""""""""). Behavioral depression in this model has been traced to heightened """"""""burst"""""""" firing of locus coeruleus (LC) neurons. The proposed hypothesis, based on recent electrophysiological data, is that the rapid firing of LC neurons releases galanin (GAL) from LC-NE terminals in the VTA, which inhibits activity of DA cells that project to forebrain. Because VTA DA neurons mediate motor activity and reward processes, their inhibition causes changes seen in depression (i.e., psychomotor retardation and anhedonia). In testing this hypothesis, previous work has shown that microinjection of GAL into VTA mimics behavioral depression. Studies proposed here will determine if (1) conversely, blockade of GAL receptors in VTA can reverse behavioral depression, and (2) commensurate changes in extracellular DA (measured by microdialysis) in forebrain also occur. All microdialysis studies use a recently-developed methodology that permits continuous microdialysis sampling for several days, and also sampling from multiple brain regions simultaneously. Next, using an animal model that shows long-lasting behavioral depression, studies are proposed to (1) measure changes in monoamines and metabolites (DA, HVA, NE, MHPG, 5-HT, 5-HIAA) in various brain regions thought to be important in depression, and (2) determine whether therapy for the long-lasting behavioral depression occurs if one blocks GAL receptors in VTA. Finally, studies are proposed to measure the consequences of effective antidepressant treatment (i.e., chronic administration of antidepressant drugs or a series of electroconvulsive shocks) on (i) electrophysiological activity of LC neurons (since GAL is released at high rates of depolarization), and (ii) estimates of GAL synthesis in LC (i.e., by measuring GAL mRNA and GAL concentration in LC cell bodies) and GAL levels in VTA.
| Borsody, M K; Weiss, J M (2005) The subdiaphragmatic vagus nerves mediate activation of locus coeruleus neurons by peripherally administered microbial substances. Neuroscience 131:235-45 |
| Borsody, Mark K; Weiss, Jay M (2004) The effects of endogenous interleukin-1 bioactivity on locus coeruleus neurons in response to bacterial and viral substances. Brain Res 1007:39-56 |
| Borsody, Mark K; Weiss, Jay M (2002) Alteration of locus coeruleus neuronal activity by interleukin-1 and the involvement of endogenous corticotropin-releasing hormone. Neuroimmunomodulation 10:101-21 |
| Grant, M M; Weiss, J M (2001) Effects of chronic antidepressant drug administration and electroconvulsive shock on locus coeruleus electrophysiologic activity. Biol Psychiatry 49:117-29 |
| Murrough, J W; Boss-Williams, K A; Emery, M S et al. (2000) Depletion of brain norepinephrine does not reduce spontaneous ambulatory activity of rats in the home cage. Brain Res 883:125-30 |
