The hypothalamic pituitary-adrenal axis (HPAA) is activated by epileptic events. The hormones released effect areas of the brain which influence propagation of the ictal activity. One area may be the central noradrenergic system (CNAS) which, when activated, retards the seizure progress. Epileptic events, similar to stress, activate both the CNAS and the HPAA. A """"""""gate"""""""" for preventing seizures spread is initially kept closed by a feedback inhibition from the activated CNAS. Recurring epileptic events cause this feedback to fail. Hormones of the HPAA (CRH, ACTH or CORT) either alone or in some combination may interact with the CNAS and other brain areas to reduce the probability of keeping the seizure """"""""gate"""""""" closed. Limbic and noradrenergic (NA) areas are richly endowed with CRH which may change during stress. The CNAS neurons possess CRH and CORT receptors which mediate an excititory effect. Others suggest that CORT acts on NA neurons to increase the presynaptic alpha2 autoreceptors which are vital in medicating a negative feedback on NA activity. Is an increase in alpha2 receptors facilitated by HPAA hormones during recurring seizures? This would reduce the CNAS's ability to keep the seizure gate closed. It may not alone be sufficient but necessary to make the brain prone to further seizure. The general hypothesis is that the stepwise progression in the process toward seizure generalization is influenced by the hormones of the HPAA partly through their effects on the neurons of the CNAS. Therefore, the first specific objective is: 1. To determine if progression through the stages of kindled seizures (dependent variable) is altered by physiological and pharmacological manipulations of the HPAA (independent variables). (Stress and hormone inhibitors.) One possible mechanism will be studied relating HPAA hormones to receptor changes in the CNAS. The second specific objective is: 2. To determine if the binding ability of alpha2 and type II CORT receptors in brain areas containing NA neurons (dependent variable) are altered by the same physiological and pharmacological HPAA manipulations (independent variables). Selective studies will be done to investigate if the previously reported increase in alpha2 receptors during kindling involves HPAA hormones. The third specific objective is: 3. To determine if the binding ability of the alpha2 and type II CORT receptors in the rat kindled to either early or late stages (dependent variable) are altered by these same physiological and pharmacological HPAA manipulation (independent variable).
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