Repeated norepinephrine receptor stimulation in the BNST induces sensorimotor gating deficits via corticotropin releasing factor

Abstract

Intense stress precipitates symptoms in disorders such as post-traumatic stress (PTSD) and schizophrenia. Patients with these disorders have dysfunctional sensorimotor gating as indexed by disrupted prepulse inhibition of the startle response (PPI), which refers to decreased startle response when a weak pre-stimulus precedes a startling stimulus. Stress promotes release of norepinephrine (NE) and corticotrophin releasing factor (CRF) within the brain, neurotransmitters that also modulate PPI. We have shown that repeated stress causes sensitization of NE receptors within the basolateral amygdala (BLA) via CRF receptors and promotes long-lasting PPI disruptions and startle abnormalities. The bed nucleus of the stria terminalis (BNST) is another crucial brain region that could be involved in stress-induced alterations in NE and CRF functions to promote PPI changes as this anatomical structure is enriched in CRF and NE receptors that have been shown to regulate each other. We hypothesized that repeated infusions of NE into the BNST would cross-sensitize CRF receptors or vice versa to alter PPI. Separate groups of male Sprague Dawley rats received, CRF (200ng/0.5 μl), NE (20μg/0.5 μl), or vehicle into the BNST, once/day for 3 days and PPI was tested after each infusion. Repeated CRF-or vehicle-treated rats were then challenged with a subthreshold dose of NE (0.3μg/0.5 μl) while repeated NE-treated rats were challenged with CRF (200ng/0.5 μl), and PPI was measured. Surprisingly, initial/repeated CRF or vehicle in the BNST had no effects on PPI. In contrast, initial and repeated NE disrupted PPI. Sub-threshold NE challenge in rats that previously received repeated CRF had no effect on PPI. Interestingly though, intra-BNST challenge dose of CRF significantly disrupted PPI in rats that previously had received repeated NE infusions. Taken together, these results indicate that repeated stress-induced NE release could alter the activity of CRF receptors in the BNST to modulate sensorimotor gating as measured through PPI.