The purpose of the proposed experiments is to determine whether kappa-opioid receptor signaling in the amygdala regulates the expression of learned-fear in rats. Our recent data demonstrate that administration of kappa-ligands after fear conditioning bidirectionally regulates expression of fear-potentiated startle (FPS; a sensitive measure of learned-fear in rats): kappa-agonists enhance FPS, whereas kappa-antagonists attenuate it. We hypothesize that kappa-receptor signaling in the amygdala - a brain region extensively involved in fear processing - facilitates expression of FPS. Consistent with this hypothesis, rats with the highest levels of activated CREB (a transcription factor that regulates dynorphin expression) in the amygdala also have the highest levels of FPS. To determine whether CREB-mediated transcription of dynorphin occurs in the amygdala, and whether dynorphin modulates FPS, we will test whether: 1) kappa-receptor activation in the amygdala enhances FPS and 2) alteration of CREB activity in the amygdala (using viral-mediated gene transfer) alters expression of dynorphin or FPS. Our results will further our understanding of the neurobiology of learned-fear and may reveal a role for kappa-antagonists in the treatment of anxiety disorders. ? ? ?
| Knoll, Allison T; Muschamp, John W; Sillivan, Stephanie E et al. (2011) Kappa opioid receptor signaling in the basolateral amygdala regulates conditioned fear and anxiety in rats. Biol Psychiatry 70:425-33 |
| Knoll, Allison T; Carlezon Jr, William A (2010) Dynorphin, stress, and depression. Brain Res 1314:56-73 |
| Carlezon Jr, William A; Béguin, Cécile; Knoll, Allison T et al. (2009) Kappa-opioid ligands in the study and treatment of mood disorders. Pharmacol Ther 123:334-43 |
| Knoll, Allison T; Meloni, Edward G; Thomas, James B et al. (2007) Anxiolytic-like effects of kappa-opioid receptor antagonists in models of unlearned and learned fear in rats. J Pharmacol Exp Ther 323:838-45 |
