Effect of Audiogenic Kindling on the Central Component of Hypothalamic–Pituitary–Adrenal Axis in Krushinsky–Molodkina Rats

Epilepsy and stress are strongly interrelated: while epilepsy contributes to chronic stress, the latter often triggers epileptic seizures. Temporal lobe epilepsy is frequently associated with hormonal imbalance, particularly, with dysfunction of the hypothalamic–pituitary–adrenal (HPA) axis that governs stress responses. Hormonal alterations can modulate disease severity by affecting the functional activity of brain regions involved in epileptogenesis. We investigated the mechanisms regulating the central component of the HPA axis in a rat model of temporal lobe epilepsy-like states induced by audiogenic kindling in Krushinsky–Molodkina rats. Daily audiogenic stimulation was applied for 24 days. Tissue samples from the hypothalamus and anterior pituitary were collected 24 h post-seizure to assess kindling-induced long-term molecular alterations in CRH neurons of the hypothalamic paraventricular nucleus (PVN) and corticotrophs of the anterior pituitary. No alterations were observed in CRH production, glucocorticoid receptor expression, as well as GABAergic and glutamatergic innervation density, within the PVN, indicating the resilience of the HPA axis central component to audiogenic kindling. In contrast, reduced levels of the GABAA receptor gamma and delta subunits in the PVN, along with decreased CRH and glutamate decarboxylase 67 (GAD67) content in the external layer of the median eminence, indicate diminished GABAergic control of PVN neurons and a suppression of CRH release into the portal circulation. A low CRH drive to the pituitary results in reduced CREB-mediated synthesis of adrenocorticotropic hormone (ACTH) in the anterior pituitary. Thus, the elevated corticosterone secretion into the bloodstream, reported in our earlier work, is likely due to increased sensitivity of adrenal cortical cells to ACTH, rather than to enhanced activity of the HPA axis central component.