Regulation of hippocampal theta activity by corticosterone: opposing functions of mineralocorticoid and glucocorticoid receptors.

Recently, we reported that intrahippocampal cholinergic blockade increased corticosterone (CORT) and adrenocorticotrophin (ACTH) secretion induced by restraint stress. These data suggested to us that CORT may modify hippocampal cholinergic function as part of the negative-feedback control of hypothalamic-pituitary-adrenal (HPA) axis activity. Hippocampal cholinergic theta is a rhythmic, sinusoidal waveform that occurs in alert, immobile rats presented with threatening stimuli and is reliably expressed in urethanized rats. We reasoned that if hippocampal cholinergic systems regulate HPA axis activity, perhaps CORT acts to modulate theta activity. In the present study we have examined the effects of blocking mineralocorticoid receptors (MR) and glucocorticoid receptors (GR) on theta activity in urethane-anesthetized rats. Adult male, Lister hooded rats (n=15) were anesthetized with urethane, and a theta recording electrode was positioned in the hippocampus adjacent to an infusion cannula. A bipolar stimulating electrode was placed in the dorsomedial posterior hypothalamus (DMPH) to activate theta. Baseline recordings of DMPH-stimulated activity (0.1-0.5 mA) were obtained. Rats were then administered either the MR antagonist spironolactone or the GR antagonist RU 38486 (150 ng), and DMPH-stimulated activities were monitored for 45 min. Changes in theta frequency (Hz) and amplitude (mV; energy at peak theta frequency) were analyzed using analysis of variance (ANOVA) followed by Bonferroni t-tests. Neither drug affected hippocampal theta frequencies elicited by DMPH stimulation. However, GR blockade produced marked increases in theta amplitudes of approximately 100% above predrug levels. Alternatively, MR blockade produced exactly the opposite response, as amplitude values fell to approximately 50% of predrug levels. Hippocampal cholinergic theta activity is modulated by CORT acting through MR and GR, and the rapidity of the response suggests a nongenomic mechanism. These data raise the possibility that hippocampal cholinergic systems, and theta activity, are involved in CORT-mediated negative-feedback control of the HPA axis.