The research proposed here will assess how electrophysiological activity of neurons of the major noradrenergic cell-body group of the brain, the locus coeruleus (LC), is altered by effective antidepressant (AD) treatment. The primary impetus for this research is evidence from both preclinical and clinical research that raises the possibility that all presently-known effective AID treatments reduce activity of LC neurons. Recently, we reported that, in experimental animals (rats), both spontaneous firing rate and sensory-evoked """"""""burst"""""""" firing of LC neurons were decreased following all AD treatments examined, including several types of drug therapy and also electroeonvulsive shock (ECS). This change resulted from chronic drug admires"""""""" tration (i.e., for 14 and 30 days by subcutaneous minipump) of five AD drugs (two tricyclics, two SSRIs, and an MAO inhibitor) and a series of 5 ECSs. These findings, together with previously accumulated results, form a sizable body of data indicating that AD treatments decrease LC activity. The present study will continue to measure both spontaneous and sensory-evoked LC electrophysiological activity, extending the number of AD treatments surveyed and addressing important remaining issues. First, effects produced by chronic administration of several AD and non-AD drugs that we have not examined previously as well as by promising new therapies (i.e., a CRH antagonist, NK-1 receptor blocker, and rTMS) will be determined. Particular attention is directed to two AD drugs (mianserin and mirtazapine) that block a2pha adrenergic receptors and thus acutely increase (rather than decrease) LC activity; however, data from chronic administration of these drugs are contradictory. By the conclusion of this experiment, our fmdmgs plus those of others will have determined effects on LC activity of a relatively comprehensive list of known effective AD treatments and also will have begun to assess whether reduced LC activity is specific to ADs (by testing non-AD drugs). Second, because mount of drug (i.e. blood level of drug) may be quite important in determining response, changes in LC activity resulting from different doses of desipramme (a tricyclic), sertraline (an SSRI), and the two drugs that block a2 receptors (mirtazapine and mianserin) will be assessed, with blood levels also measured. Finally, effects on LC activity will be determined for these four drugs when the rats take drug orally in a manner analogous to taking a pill. While minipumps provide reliable and consistent drug delivery for the rat, humans usually take drug in pill form, which introduces drug orally in a bolus. Effects might differ if drug is given in this way and blood levels vary somewhat across the day. Consequently, a method has been developed to induce rats to voluntarily take drug orally in a manner similar to a pill, and effects of this will be assessed.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
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Special Emphasis Panel (ZRG1-BDCN-6 (01))
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Brady, Linda S
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Emory University
Schools of Medicine
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Rovin, Molly L; Boss-Williams, Katherine A; Alisch, Reid S et al. (2012) Influence of chronic administration of antidepressant drugs on mRNA for galanin, galanin receptors, and tyrosine hydroxylase in catecholaminergic and serotonergic cell-body regions in rat brain. Neuropeptides 46:81-91
West, Charles H K; Weiss, Jay M (2011) Effects of chronic antidepressant drug administration and electroconvulsive shock on activity of dopaminergic neurons in the ventral tegmentum. Int J Neuropsychopharmacol 14:201-10
West, Charles Hutchison Keesor; Ritchie, James Carl; Weiss, Jay Michael (2010) Paroxetine-induced increase in activity of locus coeruleus neurons in adolescent rats: implication of a countertherapeutic effect of an antidepressant. Neuropsychopharmacology 35:1653-63
West, Charles H K; Ritchie, James C; Boss-Williams, Katherine A et al. (2009) Antidepressant drugs with differing pharmacological actions decrease activity of locus coeruleus neurons. Int J Neuropsychopharmacol 12:627-41
Weiss, Jay M; Boss-Williams, Katherine A; Moore, Jeffrey P et al. (2005) Testing the hypothesis that locus coeruleus hyperactivity produces depression-related changes via galanin. Neuropeptides 39:281-7