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


Address correspondence and reprint requests to Dr. Stephen. C. Heinrichs at VA Medical Center, Research 151—Neuropharmacology, Boston, MA 02130-4817, U.S.A. E-mail: sheinr4143@verizon.net


Summary: 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.