The broad long term objectives of the proposed research are to find brain processes that mediate the pathogenesis and the improvement of human endogenous depression (ED). In previous work we found that several antidepressant drugs, administered to neonatal rats, produced a """"""""depression"""""""" in adult rats that modelled behavioral and REM sleep features of human ED and that improved with conventional antidepressant treatments. The proposed research will test hypotheses about brain mediators of human ED and its improvement in this animal model of ED. Human and animal findings suggest that altered serotonergic (5HT) neurotransmission or altered REM sleep may be brain mediators of ED and its improvement. The proposed animal work on 5HT mediators of depression will test hypotheses that ED is mediated by (a) decreased firing rates of 5HT units in the dorsal raphe nucleus (DRN); or (b) random rather than ordered 5HT unit firing rate in the DRN; or upregulation of 5HT1 and/or 5HT2 receptors in the DRN and cortex. The proposed animal work on REM sleep mediators of depression will test the hypothesis that ED is mediated by a neuronal substrate of increased REM sleep found in ED, viz increased firing rate of cholinoceptic units in the gigantocellular tegmental field (FTG). We will determine whether any of these hypothesized mediators cause the rat depression by the following: (1) mediators will show a common effect of several different antidepressant drugs administered to neonates to produce ED; (2) individual differences in brain mediators of pathogenesis will correlate with individual differences in rat depression; (3) antidepressant drug treatments will reverse abnormalities found in mediators of pathogenesis. We hypothesize that mediators of improvement are reversals (opposites) of DRN or FTG mediators of depression. Animal studies of improvement of ED will involve effects of imipramine on animal depression. We will determine whether relation between improvement. and REM sleep variables in animals is the same as the relation between improvement and REM sleep variables previously found in humans. If so, this will be evidence that brain mediators of improvement in animals operate in humans. The proposed work may illuminate brain substrates of pathogenesis and improvement of human ED and thereby contribute to its prevention and successful treatment.
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