Elsevier

Biological Psychiatry

Volume 61, Issue 6, 15 March 2007, Pages 782-796
Biological Psychiatry

Original article
Altered Brain Activation Pattern Associated With Drug-Induced Attenuation of Enhanced Depression-Like Behavior in Rats Bred for High Anxiety

https://doi.org/10.1016/j.biopsych.2006.08.035Get rights and content

Background

The enhanced depression-like behavior in the forced swim test displayed by rats selectively bred for high anxiety-related behavior (HAB) as compared with their low anxiety counterparts (LAB) is abolished by chronic paroxetine treatment. The aim of the present study was to identify neuronal substrates underlying this treatment response in HABs.

Methods

The HAB rats received paroxetine (10 mg/kg/day) for 24 days via drinking water, and drug-induced modulation of neuronal activation patterns in response to forced swimming was mapped with the expression of the immediate early gene c-Fos as marker.

Results

Chronic paroxetine treatment reduced the immobility scores during forced swimming, confirming the previously observed antidepressant-like effect in these animals, and attenuated the forced swim-induced c-Fos response in a restricted set (11 of 70) of brain areas. These included limbic areas such as the prelimbic cortex, parts of the amygdala, the bed nucleus of the stria terminalis, dorsal hippocampus, dorsal lateral septum as well as hypothalamic and hindbrain areas (dorsolateral periaqueductal gray [PAG], locus coeruleus). Untreated LAB rats, which displayed low depression-like behavior comparable to that of treated HABs, also showed low swim stress-induced c-Fos response in most of these same areas, further supporting an association of attenuated neuronal excitability in the identified areas with attenuated depression-like behavior.

Conclusions

These findings indicate that modulation of neuronal activation in a restricted set of defined, mainly limbic as well as selected hypothalamic and hindbrain areas by paroxetine treatment is associated with the reduction of enhanced depression-like behavior in a psychopathological animal model.

Section snippets

Animals

All animals tested were bred in the animal facilities of the Max Planck Institute of Psychiatry in Munich, Germany, as described previously (Landgraf and Wigger 2002). In brief, Wistar rats were selected and mated according to the results of an elevated plus maze test, to establish the lines termed HAB and LAB. Rats that spend < 5% or more than 50% in the open arms are considered as HABs or LABs, respectively. All offspring (including those used for the present study) are tested routinely at an

Results

The addition of paroxetine to the drinking water resulted in paroxetine plasma levels of 170 ± 14 ng/mL (n = 15) after a treatment period of 24 days and did not reduce the daily water intake of 8.5–9.5 ml/100g body weight. Paroxetine treatment did not significantly influence the weight gain of the rats, a result similar to that found in the study of Keck et al (2003). Weight at the start/end of treatment period: untreated HABs: 411 ± 13 g / 437 ± 9 g; paroxetine treated HABs: 409 ± 17 g / 440 ±

Discussion

The present data confirm behavioral findings from a previous study, in which chronic treatment with the clinically potent antidepressant paroxetine was effective in reducing the enhanced depression-like behavior of HAB rats in the forced swim test. We now additionally show that the behavioral effect of paroxetine was associated with a modulation of the swim stress-induced neuronal activation pattern in specific key areas, including limbic (prefrontal cortex, amygdala, bed nucleus of the stria

Conclusions

A major conclusion from these findings using an imaging method with cellular resolution is that an effective antidepressant drug treatment in an animal model of enhanced depression and anxiety affects neuronal responsivity in a rather restricted number (11 of 70) of specific, mainly limbic and hypothalamic, brain areas at different brain levels. It should be born in mind, however, that although c-Fos expression is a widely established marker of neuronal activation, neuronal firing might not

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