Elsevier

Biological Psychiatry

Volume 66, Issue 1, 1 July 2009, Pages 76-83
Biological Psychiatry

Archival Report
Stress-Induced Redistribution of Corticotropin-Releasing Factor Receptor Subtypes in the Dorsal Raphe Nucleus

https://doi.org/10.1016/j.biopsych.2009.02.014Get rights and content

Background

The stress-related neuropeptide corticotropin-releasing factor (CRF) is involved in determining behavioral strategies for responding to stressors, in part through its regulation of the dorsal raphe (DR)-serotonin (5-HT) system. CRF1 and CRF2 receptor subtypes have opposing effects on this system that are associated with active versus passive coping strategies, respectively.

Methods

Immunoelectron microscopy and in vivo single-unit recordings were used to assess CRF receptor distribution and neuronal responses, respectively, in the DR of stressed and unstressed rats.

Results

Here we show that in unstressed rats CRF1 and CRF2 are differentially distributed within DR cells, with CRF1 being prominent on the plasma membrane and CRF2 being cytoplasmic. Stress experience reverses this distribution, such that CRF2 is recruited to the plasma membrane and CRF1 tends to internalize. As a consequence of this stress-induced cellular redistribution of CRF receptors, neuronal responses to CRF change from inhibition to a CRF2-mediated excitation.

Conclusions

Given evidence that CRF1 and CRF2 activation are associated with distinct behavioral responses to stress, the stress-triggered reversal in receptor localization provides a cellular mechanism for switching behavioral strategies for coping with stressors.

Section snippets

Subjects

Adult male Sprague-Dawley rats weighing 250–300 g were housed 2–3 per cage on a 12-hour light schedule in a temperature-controlled (20°C) colony room with free access to standard chow and water. Rats used in fluorescent microscopy studies were obtained from Harlan Laboratories (Indianapolis, Indiana), and rats used in swim stress studies were from Taconic Laboratories (Germantown, New York). All procedures were approved by the Institutional Animal Care and Use Committee (IACUC) of Thomas

CRF Receptor Localization in DR Neurons of Unstressed Rats: Light Microscopy

CRF1 immunoreactivity was robust in the perikarya of DR neurons, where it was associated with both 5-HT- and non-5-HT-containing cell bodies (Figure 1A,1C, and 1E). Within these profiles, CRF1 immunoreactivity was most prominent near the periphery, consistent with a localization on the plasma membrane (Figure 1A, 1C, and 1E).

The appearance of CRF2 immunolabeling in the DR differed from that of CRF1 in being more punctate (Figure 1B, 1F, and 1H). Like CRF1, CRF2 was associated with 5-HT- and

Discussion

These findings are the first to describe the cellular localization of CRF receptor subtypes CRF1 and CRF2 in the DR at an ultrastructural level and demonstrate that these are differentially distributed in cellular compartments, with CRF1 having an increased presence on the plasma membrane compared with CRF2 in unstressed animals. Swim stress results in trafficking of the CRF receptor subtypes in opposing directions such that CRF1 tends to move to the cytoplasm and CRF2 is recruited to the

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