Both corticotropin-releasing factor and apomorphine reduce prepulse inhibition following repeated central infusion of corticotropin-releasing factor.

The neuropeptide, corticotropin-releasing factor (CRF) has been shown to disrupt prepulse inhibition of the acoustic startle response in rodents. Prepulse inhibition is deficient in a number of psychiatric disorders. In Experiment 1, we examined whether repeated central infusion of CRF alters the reduction in prepulse inhibition caused by subsequent CRF infusion or apomorphine injection. Repeated intracerebroventricular infusion of CRF (0.3 micro g) did not cause tolerance to the effect of CRF on prepulse inhibition. Additionally, repeated CRF did not alter the effect of apomorphine (0.25 mg/kg, i.p.) on prepulse inhibition. In contrast to other reported results, both CRF and apomorphine reduced baseline startle amplitude in the Brown Norway rats, which show low prepulse inhibition. In Experiment 2, we showed that a CRF-induced change in baseline startle amplitude does not contribute to the CRF-induced decrease in percent prepulse inhibition. In Experiment 3, we found that methylphenidate (20.0 mg/kg, i.p.) increased baseline startle amplitude in Brown Norway rats, yet it also decreased percent prepulse inhibition. These results suggest that CRF can be administered repeatedly without diminution of its effects on prepulse inhibition, and that in Brown Norway rats, compounds that either increase or decrease baseline startle amplitude can reduce percent prepulse inhibition independently of the effects on baseline startle.

Effects of a typical and an atypical antipsychotic on the disruption of prepulse inhibition caused by corticotropin-releasing factor and by rat strain.

Male Wistar-Kyoto (WKY) and Brown Norway (BN) rats (11-12 weeks, n = 184) received an injection of saline, haloperidol, or clozapine, followed by an intracerebroventricular infusion of saline or corticotropin-releasing factor (CRF). Rats were tested for prepulse inhibition (PPI) of the acoustic startle response. BN rats showed less PPI than WKY rats, and neither antipsychotic alone enhanced PPI. In WKY rats, both haloperidol and clozapine attenuated the CRF-induced decrease in PPI. In CRF-treated BN rats, clozapine-enhanced PPI. A clozapine-induced decrease in startle amplitude was seen in CRF-treated BN rats but not in CRF-treated WKY rats. Although the disruption of PPI caused by exogenous CRF administration can be reversed by acute antipsychotic treatment, baseline PPI is not altered.

CNP is required for maintenance of axon-glia interactions at nodes of Ranvier in the CNS.

Axoglial interactions underlie the clustering of ion channels and of cell adhesion molecules, regulate gene expression, and control cell survival. We report that Cnp1-null mice, lacking expression of the myelin protein cyclic nucleotide phosphodiesterase (CNP), have disrupted axoglial interactions in the central nervous system (CNS). Nodal sodium channels (Nav) and paranodal adhesion proteins (Caspr) are initially clustered normally, but become progressively disorganized with age. These changes are characterized by mislocalized Caspr immunostaining, combined with a decrease of clustered Na+ channels, and occur before axonal degeneration and microglial invasion, both prominent in older Cnp1-null mice. We suggest that CNP is a glial protein required for maintaining the integrity of paranodes and that disrupted axoglial signaling at this site underlies progressive axonal degeneration, observed later in the CNS of Cnp1-null mice.