Olfactory Neophobia and Seizure Susceptibility Phenotypes in an Animal Model of Epilepsy Are Normalized by Impairment of Brain Corticotropin Releasing Factor

Abstract

PURPOSE: The present study explored the causal relationship between stressor exposure/stress neuropeptide activation and avoidant exploratory phenotype/enhanced seizure susceptibility in an animal model of epilepsy. METHODS: The olfactory detection and investigation phenotype of seizure susceptible El (epilepsy) strain and nonsusceptible ddY control mice was first evaluated in untreated mice. In a second series of experiments, the olfactory exploration phenotype, food intake/body weight regulation, circadian locomotor activity, and seizure susceptibility were assessed over a 14-day period following central administration of the neurotoxin saporin alone or a conjugate of the stress neuropeptide, corticotropin releasing factor (CRF), and saporin (CRF-SAP) which impairs CRF system function following central administration. RESULTS: In support of the main experimental hypothesis, administration of CRF-SAP in El mice reduced handling-induced seizure susceptibility by 75% for up to 2 weeks following treatment. Similarly, El mice were slow to detect a cache of buried food pellets relative to ddY controls and this exploratory deficit was reversed 3 days following administration of CRF-SAP. Efficacy of CRF-SAP treatment was confirmed using CRF immunohistochemistry, which revealed suppression of brain CRF content in El mice treated with CRF-SAP relative to El controls. Other functional and persistent effects of CRF-SAP included increased locomotor activity and hyperphagia. CONCLUSIONS: Taken together, these results support strongly the possibility that activated brain stress neuropeptide systems are necessary for the expression of motivational and neurological perturbations in seizure susceptible El mice.