Studying prepulse inhibition in a stressed system

Onset and course of psychotic disorders are thought to be influenced by stress, although there is no consistent evidence that experience of elevated levels of stress triggers disease onset in healthy individuals. In order to better understand the relation between stress and psychosis, these complex phenomena need to be simplified. Therefore, the aim of this thesis was to investigate the role of corticotropin-releasing factor, a neuropeptide released during stress, in sensorimotor gating processes, which are disrupted in psychosis. In all experiments, prepulse inhibition (PPI) of the acoustic startle response was used as a behavioral read-out of sensorimotor gating. In chapter 2, studies adressing the effects of stress on PPI are reviewed. Interestingly, results were in line with neurodevelopmental theories of schizophrenia. The mood stabilizer valproate is used in the treatment of bipolar disorder and may alter CRF activity via a GABAA-ergic mechanism. Chapter 3 determined the effect of valproate on CRF-disrupted PPI and examined the role of the hypothalamic-pituitary-adrenal axis and GABA-ergic signaling in the effect of valproate. We showed that valproate improves CRF-induced PPI deficits, albeit via a so far unknown mechanism. These marked beneficial effects of valproate on CRF-induced sensorimotor gating deficits suggest that valproate may be of particular value in specific subgroups of bipolar patients that are characterized by alterations in the CRF system. An assay that is used to identify mood stabilizers is supra-additive hyperactivity induced by a mixture of the psychostimulant d-amphetamine and the benzodiazepine chlordiazepoxide. In chapter 4 we evaluated the effects of the mixture on PPI, which is affected in mania. The mixture did not influence this measure, indicating that d-amphetamine-chlordiazepoxide-induced hyperlocomotion does not extend to other dopamine-driven behaviors. In chapter 5 we investigated the possible interaction between CRF and GABAB receptor signaling in the regulation of PPI, as both neurotransmitters are implicated in schizophrenia. The results of these studies indicate that GABAB receptor activation compensates for the PPI deficits induced by acute CRF infusion, and suggest that long-term exposure to elevated CRF levels causes adaptation at the level of mesolimbic dopamine neurons or in the nigroreticular pathway that renders these areas less sensitive to the PPI-enhancing effects of GABAB receptor agonists. In chapter 6 we investigated the actions of CRF1 receptor antagonists in pharmacological models of PPI-disruption responsive to antipsychotics. CRF1 receptor antagonists were without effect in any of the PPI tests, suggesting that CRF1 receptors are not key modulators of sensorimotor gating. However, under conditions of enhanced CRF activity changes may occur in both dopaminergic and glutamatergic neurotransmission, which could be relevant for sensorimotor gating. As chronic stress has been implicated in the development of schizophrenia, and chronic stress may result in enhanced activity of CRF systems, the current findings do not exclude the possibility that CRF1 receptor antagonists, alone or in combination with antipsychotics, could be useful in improving sensorimotor gating under chronic stress conditions.