Roles of the bed nucleus of stria terminalis and of the amygdala in N/OFQ-mediated anxiety and HPA axis activation

Nociceptin/orphanin FQ (N/OFQ) is an opioid-related neuropeptide that is widely distributed in limbic regions of the brain. After intracerebroventricular (icv) injections in rodents, N/OFQ produces elevations in hypothalamic-pituitary-adrenal (HPA) axis activity, and has been reported to produce both anxiogenic and anxiolytic actions. We examined the neuroanatomical basis of these effects with injections of N/OFQ (0.01-1.0nmol) into the lateral ventricle, the amygdala, and the bed nucleus of stria terminalis (BNST) in independent groups of well-handled rats under low stress conditions. Anxiety-related behaviors were evaluated in a neophobic test of anxiety. The latency to enter, total time spent in, and number of entries into an unfamiliar open field and its central zone were measured. After the open field testing, plasma samples were obtained for analysis of HPA axis activity. The N/OFQ-treated rats displayed more anxiety-related behaviors than vehicle-treated rats did with all three of the injection types. However, these effects were greater and more consistent after the icv injections (0.01-1.0nmol) than they were after the amygdala (0.10-1.0nmol) or BNST (1.0nmol) injections. The icv and BNST injections also produced elevations in circulating corticosterone, indicating that the HPA axis was activated in these rats. Intra-amygdaloid injections did not affect corticosterone levels during the open field testing. These results indicate that the amygdala and BNST participate in the anxiogenic behavioral effects of N/OFQ. However, since the most potent effects were seen after icv N/OFQ injections, the anxiogenic and HPA axis-activating effects of N/OFQ appear to occur through additive actions in multiple limbic (and perhaps cortical and brainstem) sites.