The pharmacology of corticotropin-releasing factor (CRF). Effects on sensorimotor gating in the rat

Exposure to social stress is associated with the onset and relapse of schizophrenia symptoms, including deficits in sensorimotor gating. Impaired sensorimotor gating can be measured by a loss of normal prepulse inhibition of the startle response (PPI), which is associated with hyperactive central dopaminergic and serotonergic systems. CRF is released during stress and regulates levels of CNS monoamines involved in PPI, including dopamine and serotonin. Moreover, elevated levels of CRF and low levels of CRF binding protein have been reported in the schizophrenic brain, suggesting that CRF hyperactivity could be associated with schizophrenia symptoms. Therefore, we investigated the effect of centrally administered human/rat CRF on percent PPI in Sprague-Dawley rats and found that the peptide dose-dependently and acutely impaired this response. Given the known strain differences in sensitivity to dopaminergic effects on sensorimotor gating, we also examined whether Sprague Dawley rats from different vendors exhibit equivalent sensitivity to CRF effects on PPI. PPI disruptive effects of CRF were evident in rats from Harlan but not from Charles River, suggesting a difference in sensitivity which could be exploited to investigate the neurobiological and genetic basis of vulnerability to stress. Next, we explored the pharmacology and the neurotransmitter systems involved in the production of PPI impairments by CRF. Pretreatment with a non-selective CRF receptor antagonist and a selective CRF-1 receptor antagonist restored PPI in rats treated with CRF, while pretreatment with a CRF-2 receptor antagonist was ineffective. Together with preliminary findings suggesting that central CRF-1 receptor blockade can reverse the effects of dopamine agonists on PPI (a model which has been used to identify novel antipsychotic agents), our results provide a rationale for the potential use of a CRF-1 receptor antagonist in the management of stress related symptoms of schizophrenia. Pretreatment with D2, 5-HT2A, or 5-HT1A receptor antagonists alone did not fully restore PPI in rats treated with CRF, although when administered concurrently, D2 and 5-HT2A receptor antagonist successfully reversed CRF effects. Importantly, this finding reproduced the ability of the clozapine, a multi-receptor blocking atypical antipsychotic drug, to reverse CRF-induced PPI deficits, suggesting that 5-HT2A and D2 receptors could play a critical role in producing the favorable therapeutic profile of atypical antipsychotic drugs. In conclusion, our findings highlight the potential involvement of CRF in stress-induced symptoms of schizophrenia and provide insight into potential treatments strategies for the disease.