Prepulse inhibition (PPI), a form of sensorimotor gating, is reduced in a number of psychiatric disorders. Two experiments were conducted to determine whether corticotropin-releasing factor (CRF), which decreases PPI, does so via effects on serotonin (5-HT). Wistar Kyoto (WKY) and Brown Norway (BN) rats were used in both experiments in order to examine whether straindependent differences would be apparent in response to manipulations of the CRF and 5-HT systems. In the first experiment, WKY and BN rats received a subcutaneous injection of the 5-HT 2A/C receptor antagonist, ketanserin (2.0 mg/kg). Ten minutes later, rats received an intracerebroventricular (ICV) infusion of either 6.0 μl saline or CRF (0.3 μg or 3.0 μg). CRF decreased PPI despite blockade of 5-HT 2A/C receptors with ketanserin. In the second experiment, WKY and BN rats received an intraperitoneal injection of the 5-HT synthesis inhibitor, p-chlorophenylalanine (PCPA, 150 mg/kg), 48 and 24 hours prior to testing. On testing day, rats received an ICV infusion of either 6.0 μl saline or CRF (0.3 μg or 3.0 μg). CRF decreased PPI despite 5-HT depletion. These findings suggest that CRF does not decrease PPI via effects on 5-HT, since neither blockade of 5-HT 2A/C receptors nor 5-HT depletion attenuated this decrease.

Stress plays a role in many psychiatric disorders that are characterized by deficits in prepulse inhibition (PPI), a form of sensorimotor gating. Corticotropin-releasing factor (CRF) is one of the most important neurotransmitters involved in behavioral components of the stress response. Central infusion of CRF reduces PPI in both rats and mice. In mice, it has been shown that CRF1 receptor activation mediates the effect of exogenous CRF on PPI. However, the roles of the two CRF receptors in a stress-induced reduction in PPI are not known. We sought to determine whether CRF1 and/or CRF2 receptor blockade attenuates a stress-induced reduction of PPI in rats. In separate experiments, we assessed PPI in Brown Norway rats after exposure to five days of 2-hour restraint, and after pretreatment with the CRF1 receptor antagonist, CP-154,526 (20.0 mg/kg), or the CRF2 receptor antagonist, antisauvagine-30 (10.0 µg). Repeated, but not acute, restraint decreased PPI and attenuated the increase in PPI caused by repeated PPI testing. Blockade of the CRF1 receptor did not attenuate the effect of repeated restraint on PPI or grooming behavior. While CRF2 receptor blockade did attenuate the effect of repeated restraint on PPI, repeated ICV infusion of the selective CRF2 receptor agonist urocortin III, did not affect PPI. These findings demonstrate the effect of stress on sensorimotor gating and suggest that the CRF2 receptor mediates this effect in rats.

Stress plays a role in many psychiatric disorders that are characterized by deficits in prepulse inhibition (PPI), a form of sensorimotor gating. Corticotropin-releasing factor (CRF) is one of the most important neurotransmitters involved in behavioral components of the stress response, and central infusion of CRF decreases PPI in rodents. We recently demonstrated that restraint stress decreases PPI and attenuates the increase in PPI caused by repeated testing. To broaden our investigation into how restraint affects PPI, we subjected Wistar-Kyoto (WKY) and Brown Norway (BN) rats to 10 consecutive days of 2-hour restraint, or to brief handling, prior to assessing PPI. We next examined the effects of 1 or 10 days of 2-hour restraint on plasma corticosterone levels in order to determine whether the endocrine response to stress parallels the behavioral effect of stress. Finally, we examined the effects of 1 or 10 days of 2-hour restraint on CRF and CRF receptor gene expression in the amygdala, hippocampus, frontal cortex, and hypothalamus in order to determine whether a temporal pattern of gene expression parallels the change in the behavioral response to stress. The major findings of the present study are that 1) restraint stress attenuates the increase in PPI caused by repeated testing in both WKY and BN rats, and BN rats are more sensitive to the effects of restraint on PPI than WKY rats, 2) restraint-induced increases in corticosterone levels mirror the effect of restraint on PPI in WKY rats but not in BN rats, 3) laterality effects on gene expression were observed for the amygdala, whereby restraint increases CRF gene expression in the left, but not right, amygdala, and 4) some restraint-induced changes in CRF and CRF receptor gene expression precede changes in PPI while other changes coincide with altered PPI in a rat strain-and brain regiondependent manner.

Levels of prepulse inhibition (PPI) depend on the interval between the startling and prepulse stimuli. Brown Norway rats show less PPI of the acoustic startle response than Wistar-Kyoto (WKY) rats when the interval between the prepulse and startling stimulus is 100 msec. Central administration of corticotropin-releasing factor (CRF) decreases PPI at this inter-stimulus interval. Here, the effect of CRF on PPI over a range of inter-stimulus intervals was examined in WKY and BN rats, and in the F1 generation of a cross between them. Rats received an intracerebroventricular infusion of either saline or CRF 30 min prior to testing PPI. Test trials included startle stimulus alone trials, and trials on which a prepulse stimulus of either 6, 12, or 15 dB above background preceded the startling stimulus by either 20, 75, 100, 500 or 2000 msec. CRF decreased PPI in WKY rats at all inter-stimulus intervals and all prepulse intensities, while the effect of CRF on PPI in BN rats only occurred at intermediate intervals. BN and WKY rats showed different levels of PPI only at the intermediate intervals. Baseline PPI in the F1 rats resembled the WKY phenotype. The CRF-induced change in PPI in the F1 generation has some qualities of the effects in each of the progenitor strains. These results suggest that both the effect of rats strain and of CRF on PPI depend on the inter-stimulus interval, and that there is an interaction between prepulse stimulus intensity and the inter-stimulus interval.