Uncontrollable, but not controllable, stress desensitizes 5-HT 1A receptors in the dorsal raphe nucleus

Abstract

Uncontrollable stressors produce behavioral changes that do not occur if the organism can exercise behavioral control over the stressor. Previous studies suggest that the behavioral consequences of uncontrollable stress depend on hypersensitivity of serotonergic neuronsin the dorsal raphe nucleus (DRN), but the mechanisms involved have not been determined. We used exvivosingle-unit recording in rats to test the hypothesis that the effects of uncontrollable stress are produced by desensitization of DRN 5-HT 1A auto receptors. These studies revealed that uncontrollable, but not controllable, tail shock impaired 5-HT 1A receptor-mediated inhibition of DRN neuronal firing. Moreover, this effect was observed only at time points when the behavioral effects of uncontrollable stress are present. Furthermore, temporary in activation of the medial prefrontal cortex with the GABAA recept or agonistmuscimol, which eliminates the protective effects of control on behavior, led even controllable stress to now produce functional desensitization of DRN 5-HT 1A receptors. Additionally, behavioral immunization, an experience with controllable stress before uncontrollable stress that prevents the behavioral outcomes of uncontrollable stress, also blocked functional desensitization of DRN 5-HT 1A receptors by uncontrollable stress. Last, Western blot analysis revealed that uncontrollable stress leads to desensitization rather than down regulation of DRN 5-HT 1A receptors. Thus, treatments that prevent controllable stress from being protective ledtodesensitizationof5-HT 1A receptors, whereas treatments that block the behavioral effects of uncontrollable stress also blocked 5-HT 1A receptor desensitization. These data suggest that uncontrollable stressors produce a desensitization of DRN 5-HT 1A autoreceptors and that this desensitization is responsible for the behavioral consequences of uncontrollable stress. © 2011 the authors.