RT Journal Article SR Electronic T1 Uncontrollable, But Not Controllable, Stress Desensitizes 5-HT1A Receptors in the Dorsal Raphe Nucleus JF The Journal of Neuroscience JO J. Neurosci. FD Society for Neuroscience SP 14107 OP 14115 DO 10.1523/JNEUROSCI.3095-11.2011 VO 31 IS 40 A1 Rozeske, Robert R. A1 Evans, Andrew K. A1 Frank, Matthew G. A1 Watkins, Linda R. A1 Lowry, Christopher A. A1 Maier, Steven F. YR 2011 UL http://www.jneurosci.org/content/31/40/14107.abstract AB 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 neurons in the dorsal raphe nucleus (DRN), but the mechanisms involved have not been determined. We used ex vivo single-unit recording in rats to test the hypothesis that the effects of uncontrollable stress are produced by desensitization of DRN 5-HT1A autoreceptors. These studies revealed that uncontrollable, but not controllable, tail shock impaired 5-HT1A 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 inactivation of the medial prefrontal cortex with the GABAA receptor agonist muscimol, which eliminates the protective effects of control on behavior, led even controllable stress to now produce functional desensitization of DRN 5-HT1A 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-HT1A receptors by uncontrollable stress. Last, Western blot analysis revealed that uncontrollable stress leads to desensitization rather than downregulation of DRN 5-HT1A receptors. Thus, treatments that prevent controllable stress from being protective led to desensitization of 5-HT1A receptors, whereas treatments that block the behavioral effects of uncontrollable stress also blocked 5-HT1A receptor desensitization. These data suggest that uncontrollable stressors produce a desensitization of DRN 5-HT1A autoreceptors and that this desensitization is responsible for the behavioral consequences of uncontrollable stress.