PT  - JOURNAL ARTICLE
AU  - Rozeske, Robert R.
AU  - Evans, Andrew K.
AU  - Frank, Matthew G.
AU  - Watkins, Linda R.
AU  - Lowry, Christopher A.
AU  - Maier, Steven F.
TI  - Uncontrollable, But Not Controllable, Stress Desensitizes 5-HT<sub>1A</sub> Receptors in the Dorsal Raphe Nucleus
AID  - 10.1523/JNEUROSCI.3095-11.2011
DP  - 2011 Oct 05
TA  - The Journal of Neuroscience
PG  - 14107--14115
VI  - 31
IP  - 40
4099  - http://www.jneurosci.org/content/31/40/14107.short
4100  - http://www.jneurosci.org/content/31/40/14107.full
SO  - J. Neurosci.2011 Oct 05; 31
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.