The El mouse strain provides a non-induced model of idiopathic, multifactorial epilepsy in which seizures are elicited in response to stressful environmental stimuli such as tail suspension handling. In the present studies, genetically seizure susceptible El and non-susceptible ddY control mice were exposed to tail suspension, foot-shock and social stressors in order to test the hypothesis that neural and physiological responses to such stimuli would be exaggerated in the El strain. The first experiment assessed neural cell density, stress neuropeptide (corticotropin releasing factor--CRF) levels, and plasma corticosterone activation in El and ddY mice in an unhandled control condition or following exposure to tail suspension or foot-shock stressors. The second experiment assessed brain electroencephalographic activity using telemetrically monitored skull surface electrodes in El and ddY mice exposed to tail suspension or social interaction stressors. Assessment of El mouse brains revealed higher cell counts in amygdala and elevated CRF peptide content in the paraventricular thalamic nucleus relative to ddY controls. El mice exhibited significantly elevated plasma corticosterone levels 60 min following exposure to tail suspension and foot-shock stressors relative to ddY controls. Finally, El mice exhibited significantly elevated brain electroencephalographic (1-4 Hz) activity in response to tail suspension, but not social interaction, relative to ddY controls. These results indicate that potentiated neural, endocrine and physiological activation arises in the El strain following exposure to a known seizure trigger stimulus, involuntary tail suspension handling. The findings support a diathesis-stress hypothesis in which genetically seizure susceptible El mice exhibit a multifaceted hyperreactivity to noxious environmental stimuli.