Pyramidal neurons in the rat CA1 hippocampal area contain intracellular mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) to which the adrenal hormone corticosterone can bind with differential affinity. The pyramidal neurons also have high amounts of 5-HT1a receptors, which mediate a membrane hyperpolarization. With intracellular recording in vitro, we found that selective occupation of MRs suppresses the 5-HT-induced hyperpolarization of CA1 pyramidal neurons. The suppression of 5-HT responses was observed 1-4 hr after a brief (20-min) application of the steroids. Binding properties of the 5-HT1a receptor were not significantly affected by in vitro steroid application. Furthermore, responses to the GABAB agonist baclofen were not changed after treatment with MR ligands, implying that the K+ conductance to which both GABAB and 5-HT1a receptors are linked is also no target for the steroid action. The MR-mediated effect on 5-HT responsiveness potentially enhances cellular activity. Because activation of GRs was previously found to suppress norepinephrine-induced excitability in the same neurons, the data support the concept that cellular homeostasis in the hippocampus is under control of corticosterone via coordinative, antagonistic MR- and GR-mediated events.

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Previous studies in rats have shown that cellular properties of hippocampal CA1 neurons are under coordinative control of mineralocorticoid and glucocorticoid receptors (MRs and GRs, respectively). In the present study, we examined electrical properties under conditions of exclusive MR occupation, by using mice with a genetic defect in GRs obtained by homologous recombination techniques. It appeared that in the animals homozygous for the genetic defect, the properties studied, i.e., the voltage-gated Ca currents and responses to serotonin and the cholinergic analog carbachol, resembled the effects observed in adrenalectomized mice, i.e., when no steroid receptors are activated. This may point to the necessity of functional GRs for the development of MR-induced actions. Ca current amplitude and transmitter responses in the heterozygous animals, which combine a reduced amount of GRs in the hippocampus with relatively high circulating levels of corticosterone, were large compared with those in the wild-type controls; this resembles the responses that were observed previously in rats subjected to a very high dose of corticosterone. These findings exemplify the use of GR knockout mice for the study of cellular properties in the brain. Further substantiation of the observations, however, awaits the development of site-specific, inducible GR knockouts.

In this study we describe modulatory effects exerted by in vivo activation of corticosteroid receptors on 5HT responsiveness of rat CA1 pyramidal neurons. In the first series of experiments, adrenalectomized (ADX) rats were injected with corticosterone one hour prior to decapitation (1-1000 micrograms/100 g body weight) after which 5HT1A induced hyperpolarizations were determined in vitro by means of intracellular recordings. It appeared that 5HT responsiveness was dose-dependently affected by corticosterone injections: 5HT responses were relatively large when no corticosteroid receptors were activated (ADX); similar 5HT responses were observed or when both mineralocorticoid receptors (MR) and glucocorticoid receptors (GR) were occupied by injection of high doses of corticosterone (100-1000 micrograms/100 g body weight). However, compared to the latter group, 5HT hyperpolarizations were significantly suppressed in slices from rats that received moderate amounts of corticosterone (10-30 micrograms/100 g). Next, we investigated whether physiological variations of plasma corticosterone levels as occurring in intact rats correlated with the transmitter responsiveness. It was found that high plasma levels of corticosterone due to either stress or exogenous application of high doses of corticosterone correlated with large 5HT-responses in vitro. Interestingly, the large 5HT responses recorded after stress were clearly suppressed by pretreatment with RU38486, a GR antagonist. Altogether, this study presents further evidence that 5HT transmission in hippocampal CA1 area is modulated by differential steroid receptor activation as may occur under physiological circumstances due to different plasma concentrations of corticosterone.