Differential mechanisms for regulation of the stress response across latitudinal gradients.

We examined plasticity of the stress response among three populations of the white-crowned sparrow (Zonotrichia leucophrys). These populations breed at different elevations and latitudes and thus have breeding seasons that differ markedly in length. We hypothesize that in populations where birds raise only one or rarely two broods in a season, the fitness costs of abandoning a nest are substantially larger than in closely related populations that raise up to three broods per season. Thus individuals with short breeding seasons should be less responsive to stressors and therefore less likely to abandon their young. In our study, baseline and handling-induced corticosterone levels were similar among populations, but corticosteroid-binding globulins differed, leading to a direct relationship between stress-induced free corticosteroid levels and length of breeding season. There were also population-specific differences in intracellular low-affinity (glucocorticoid-like) receptors in both liver and brain tissue. Although investigations of population-based differences in glucocorticoid secretion are common, this is the first study to demonstrate population-level differences in binding globulins. These differences could lead to dramatically different physiological and behavioral responses to stress.

Plasma binding proteins as mediators of corticosteroid action in vertebrates.

Stressors elicit a complex but variable suite of endocrine events. Comparative studies of the stress response have focused primarily on the adrenocortical response to stress, in particular the measurement of plasma levels of glucocorticoids. However, a number of other factors contribute to and modify cellular and organismal responses to glucocorticoids. Notably, plasma corticosteroid binding globulins (CBGs) can regulate the general availability of steroid to tissues, and/or direct the delivery of hormones to specific sites. In this paper, we discuss possible functions of CBG and mechanisms of CBG action, review CBG characteristics among vertebrates, and discuss our recent studies indicating that CBG may indeed modulate responses to stressors. For example, in house sparrows, we found that basal and stress-induced concentrations of total corticosteroid (cortisol or corticosterone) (CORT) vary seasonally, but CBG concentrations change proportionally, so that free CORT concentrations appear static year-round. In contrast, in white-crowned sparrows and tree lizards, CBG concentrations change under conditions when total CORT levels do not, resulting in significant changes in circulating free CORT. These differences in free CORT are masked if CBG is not accounted for. We have also found that the binding properties of CBG vary considerably between species and need to be determined empirically. Such studies led to the observation that CBG in several species may also serve as a functional androgen binding protein; this is especially important for birds, because previous studies had concluded that birds lack androgen binding globulins. We propose that consideration of CBG is paramount to understanding the role of glucocorticoids in mediating behavioral and physiological responses to stress.

Seasonal regulation of membrane and intracellular corticosteroid receptors in the house sparrow brain.

A number of studies have demonstrated seasonal regulation of the adrenocortical response to stress, or of corticosteroid binding globulins, but very few studies have examined seasonal regulation of corticosteroid receptor levels. As a result, there have been few attempts to produce an integrated picture of seasonal plasticity of the stress response. We measured baseline and stress-induced corticosterone (CORT), corticosteroid binding globulin and neuronal cytosolic and membrane corticosteroid receptor levels in male and female, wild-caught house sparrows (Passer domesticus) during three different seasons over the annual cycle (nesting, molting and winter). We identified three neuronal corticosteroid receptors in the house sparrow brain: two intracellular receptors and one membrane-associated receptor. Little is known about corticosteroid receptors in neuronal membranes of avian and mammalian species, but we found that the levels of membrane corticosteroid receptors varied seasonally, being lowest during the nesting season. Cytosolic corticosteroid receptor numbers (both low and high affinity receptors) also varied seasonally. In contrast to the membrane bound receptors, however, the numbers of low and high affinity cytosolic receptors were lowest during winter. In addition, mean levels of total basal and stress-induced CORT in the plasma varied seasonally. Both basal and stress-induced levels of total CORT were significantly higher during nesting than during winter or molt. Finally, corticosteroid binding globulin levels in plasma were also seasonally regulated, in a pattern similar to total CORT, so that estimated free CORT levels did not vary between seasons. These data indicate that multiple components of the stress response are seasonally regulated in birds obtained from wild populations. Interactions between these regulated components provide a basis for seasonal differences in behavioural and physiological responses to stress.

Testosterone, corticosterone, and photoperiod interact to regulate plasma levels of binding globulin and free steroid hormone in dark-eyed juncos, Junco hyemalis.

The pharmacology and regulation of corticosteroid binding globulins (CBG) in Dark-eyed Juncos, Junco hyemalis, was investigated. The equilibrium dissociation constant for [(3)H]corticosterone (CORT) binding to plasma was <5 nM. This binding site had a similar high affinity for progesterone, approximately fivefold lower affinity for androgens, and negligible affinity for estradiol. The following data suggested that plasma CBG levels are regulated by both testosterone and day length: (1) CBG binding capacity in free-living adult males was greater in early than in late breeding season and greater in males than in females and (2) CBG levels were higher in testosterone-treated, castrated males than in castrated males receiving no testosterone and still higher in testosterone-treated males exposed to long days than in similar males exposed to short days. Birds apparently lack a sex steroid-specific binding globulin, but it was estimated that more than 90% of testosterone in junco plasma should bind to CBG. An increase in plasma CORT, such as occurs during a stress response, was judged to acutely increase free testosterone levels as much as fivefold. Corticosterone and testosterone may thus interact in a complex manner in species that lack sex hormone binding proteins.

Rapid changes in monoamine levels following administration of corticotropin-releasing factor or corticosterone are localized in the dorsomedial hypothalamus.

Monoaminergic systems are important modulators of the neuroendocrine, autonomic, and behavioral responses to stress-related stimuli. The male roughskin newt (Taricha granulosa) was used as a model system to investigate the effects of corticotropin-releasing factor (CRF) or corticosterone administration on tissue concentrations of norepinephrine, epinephrine, dopamine, 3,4-dihydroxyphenylacetic acid, serotonin, and 5-hydroxyindoleacetic acid (5-HIAA) in microdissected brain areas. Intracerebroventricular infusion of 25 or 50 ng of CRF increased locomotor activity and site-specifically increased dopamine concentrations within the dorsomedial hypothalamus 30 min after treatment when compared to vehicle-treated controls. In further studies, male newts were treated as follows: (1) no injection, no handling, (2) saline injection, or (3) 10 microg corticosterone and then placed in a novel environment. Monoamine and monoamine metabolite concentrations were similar in the unhandled and saline-injected controls 20 min after treatment. In contrast, corticosterone-injected newts had elevated concentrations of dopamine, serotonin, and 5-HIAA in the dorsomedial hypothalamus (a region that contains dopamine- and serotonin-accumulating neuronal cell bodies in representatives of all vertebrate classes) but not in several other regions studied. These site-specific neurochemical effects parallel neurochemical changes observed in the dorsomedial hypothalamic nucleus of mammals following exposure to a variety of physical and psychological stress-related stimuli. Therefore, these changes may reflect highly conserved, site-specific neurochemical responses to stress and stress-related neurochemicals in vertebrates. Given the important role of the dorsomedial hypothalamus in neuroendocrine, autonomic, and behavioral responses to stress, and a proposed role for this region in fast-feedback effects of glucocorticoids on the hypothalamo-pituitary-adrenal axis, these stress-related monoaminergic changes are likely to have important physiological or behavioral consequences.

Heterogeneity of hippocampal GABA(A) receptors: regulation by corticosterone.

Chronic stressors produce changes in hippocampal neurochemistry, neuronal morphology, and hippocampal-dependent learning and memory processes. In rats, stress-induced changes in CA3 apical dendritic structure are mediated by corticosterone (CORT) acting, in part, on excitatory amino acid neurotransmission. CORT also alters GABA-mediated inhibitory neurotransmission, so the GABA(A) receptor system may also contribute to dendritic remodeling and other stress-related changes in hippocampal function. A previous study indicated that chronic CORT treatment produces complex changes in GABA(A) receptor subunit mRNA levels, so we hypothesized that CORT alters the pharmacological properties of hippocampal GABA(A) receptors. To test this, adult male rats were treated with CORT or vehicle pellets for 10 d, after which we quantified [(35)S]t-butylbicyclophosphorothionate ([(35)S]TBPS) and [(3)H]flunitrazepam binding to GABA(A) receptors using in vitro receptor autoradiography. Pharmacological properties of receptors were assessed by examining the allosteric regulation of binding at both sites by GABA and 5alpha-pregnane-3alpha,21-diol-20-one (THDOC), an endogenous anxiolytic steroid. We found striking regional differences in the modulation of [(35)S]TBPS binding, particularly between strata radiatum and strata oriens, suggesting a functional heterogeneity among hippocampal GABA(A) receptors even within the apical versus basal dendrites of pyramidal neurons. Furthermore, we found that CORT treatment decreased the negative modulation of hippocampal [(35)S]TBPS binding by both GABA and THDOC and increased the enhancement of [(3)H]flunitrazepam binding by GABA and THDOC in the dentate gyrus. Together, these data suggest that prolonged exposure to stress levels of corticosteroids may alter hippocampal inhibitory tone by regulating the pharmacological properties of GABA(A) receptors in discrete dendritic subfields.

Plasma steroid-binding globulin mediation of differences in stress reactivity in alternative male phenotypes in tree lizards, Urosaurus ornatus.

Plasma steroid-binding globulins, for example, corticosteroid-binding globulin and sex hormone-binding globulin (SHBG), have been identified in a number of vertebrates. One possible function of these proteins is to regulate the amount of steroid delivery to target tissues, as only free steroids are believed to diffuse from the circulation to target cells. Male tree lizards, Urosaurus ornatus, exhibit alternative male reproductive tactics correlated with dewlap (throat-fan) coloration. Males with orange-blue dewlaps are aggressive and territorial, whereas males with orange dewlaps are less aggressive and employ a satellite strategy. The two types of males have similar basal levels of total plasma corticosterone and testosterone. However, testosterone levels of nonterritorial males are more sensitive than those of territorial males to negative regulation by stress-induced increases in corticosterone. We tested the hypothesis that this difference in corticosterone feedback on testosterone could be mediated, in part, by differences in binding globulin levels between the two types of males. We have identified two steroid-binding globulins in male tree lizards. The first binds androgens and estradiol with high affinity (10(-9) M) and is similar to previously described sex hormone-binding globulins. The second binds both androgens and C(21) steroids, such as progesterone and corticosterone, with higher specificity than estradiol and is best described as an androgen-glucocorticoid-binding globulin (AGBG). In both types of males, the capacity of AGBG is much higher than SHBG. In addition, AGBG capacity is significantly greater in territorial than nonterritorial males, whereas the capacity of SHBG does not differ between the two types of males. Calculations of free steroid levels based on the affinity and capacity measures suggest that although most testosterone circulates bound to binding globulins, binding capacity is high enough that binding globulins are also able to bind to other steroids such as corticosterone. Thus, differences in binding capacity between the two types of males could result in higher levels of free corticosterone in nonterritorial males than in territorial males, especially during stress-induced increases in corticosterone, and may explain why testosterone levels of nonterritorial males are more sensitive to negative feedback by corticosterone.

Pharmacological adrenalectomy with mitotane.

The potential of mitotane (ortho, para'-DDD, commonly used to treat adrenal carcinomas in humans and dogs) was investigated as an alternative to surgical adrenalectomy in birds, salamanders, and lizards. House sparrows (Passer domesticus) were injected twice daily with vehicle or one of two doses of mitotane (225 or 450 mg/kg), and basal and stress-induced levels of corticosterone (CORT) were measured 3 and 5 days after injections. Mitotane reduced basal CORT levels to nondetectable and abolished stress-induced CORT increases by the 3rd day of treatment. In another study, a single injection of mitotane was effective in lowering endogenous CORT levels 36 h later, but levels had apparently recovered by 10 days after the injection. Mitotane did not effect testicular weights and had no detectable effect on testosterone levels. In contrast to its effects on house sparrows, mitotane did not lower endogenous CORT levels in either tiger salamanders (Ambystoma tigrinum) or tree lizards (Urosaurus ornatus), even at doses much higher than those used in house sparrows.

Distinct specificity for corticosteroid binding sites in amphibian cytosol, neuronal membranes, and plasma.

To address mechanisms of corticosteroid action, one needs tools for distinguishing between the major classes of corticosteroid binding sites: neuronal membrane-associated receptors, intracellular ligand-activated transcription factors, and corticosteroid binding globulins (CBG) in plasma. We characterized the binding parameters for three classes of binding sites in an amphibian, Ambystoma tigrinum, and found that each class had a distinct pharmacological specificity. Equilibrium saturation and kinetic experiments indicated that [3H]corticosterone binds to neuronal membranes with high affinity (Kd approximately 0.37 nM). Aldosterone and two synthetic ligands for mammalian intracellular receptors, dexamethasone and RU486, displayed low affinity for brain membrane sites. In cytosol prepared from brain and liver, [3H]corticosterone bound to a single class of receptors with high affinity (Kd approximately 0.75 and 4.69 nM, respectively) and the rank order potencies for steroid inhibition of [3H]corticosterone binding was RU486 > dexamethasone approximately = corticosterone > aldosterone. In kidney and skin cytosol, [3H]corticosterone binding was best fit with a model having a high-affinity and a lower-affinity site; these sites are not consistent with the pharmacology of mammalian Type I (MR) and Type II (GR) receptors. [3H]Corticosterone also bound to presumed CBG in plasma with high affinity (Kd approximately 2.7 nM), but dexamethasone and androgens bound to plasma CBG with equivalently high affinity. These data demonstrate that pharmacological specificity can be a useful tool for distinguishing corticosteroid binding to different classes of binding sites. These data also indicate that there may be marked species differences in the specificity of corticosteroid binding sites.

Pharmacological characterization of central and peripheral type I and type II adrenal steroid receptors in the prairie vole, a glucocorticoid-resistant rodent.

The prairie vole (Microtus ochrogaster) has recently been shown to be glucocorticoid resistant; that is, the prairie vole adrenal axis is refractory to dexamethasone challenge, and highly elevated basal corticosterone titers occur without apparent pathophysiology. This study investigates the physiological correlates of glucocorticoid resistance in the prairie vole. We provide a detailed pharmacological characterization of intracellular type I and type II adrenal steroid receptors in peripheral tissues and the hippocampus of the prairie vole and the Sprague Dawley rat, a corticosensitive rodent. Adrenalectomy markedly reduces, but does not eliminate, circulating glucocorticoids in the prairie vole. Nonetheless, molecular, cellular, and physiological assays indicate adrenal insufficiency; salt appetite and dentate gyrus granule cell death are increased after adrenalectomy, suggesting vacancy of the high affinity type I subtype of central adrenal steroid receptor. Analysis of adrenal steroid receptor binding constants and selectivity for endogenous and synthetic steroids in the vole and rat indicated that the vole type I receptor is nearly identical to that of the rat in brain and periphery. However, voles demonstrated a 2-fold lower type I receptor binding density in colon and hippocampus compared with that in rats. The vole type II receptor bound the endogenous glucocorticoid corticosterone with an 8- to 10-fold lower affinity than the rat type II receptor and was expressed in lower densities in thymus and hippocampus. These data indicate physiological adaptations in the prairie vole adrenal axis consistent with other glucocorticoid-resistant species, such as the guinea pig and squirrel monkey.

Morphological changes in the hippocampal CA3 region induced by non-invasive glucocorticoid administration: a paradox.

Repeated stress induces atrophy, or remodeling, of apical dendrites in hippocampal CA3 pyramidal neurons. In rats, the stress effect is blocked by adrenal steroid synthesis inhibitors, and mimicked by daily injection of corticosterone. We report that non-invasive administration of corticosterone in the drinking water (400 micrograms/ml) also produced atrophy of apical dendrites in CA3. Unexpectedly, the combination of daily stress and oral corticosterone negated the effects of either treatment alone, and no changes in the apical dendritic length or branching pattern of CA3 pyramidal neurons were observed compared to control unstressed rats.

Chronic corticosterone treatment induces parallel changes in N-methyl-D-aspartate receptor subunit messenger RNA levels and antagonist binding sites in the hippocampus.

Some of the effects of glucocorticoids on the function and neuronal plasticity of the hippocampus are mediated by N-methyl-D-aspartate receptor activation. We tested the hypothesis that chronic corticosterone administration increases N-methyl-D-aspartate receptor expression in the hippocampus of the rat. We used in situ hybridization histochemistry to measure the messenger RNA levels for the NR1, NR2A and NR2B subunits of the N-methyl-D-aspartate receptor and [3H]dizocilpine maleate (a non-competitive antagonist) binding to measure N-methyl-D-aspartate receptor density. Since corticosterone depresses circulating testosterone levels, we also examined whether the effects of corticosterone are mediated by or interact with the effects of testosterone. In the intact animal, corticosterone increased messenger RNA levels for NR2A and NR2B but not NR1 subunits of the N-methyl-D-aspartate receptor in all regions of the hippocampus. Testosterone had no significant effect on messenger RNA levels of any of the subunits. The subunit composition determines the functional and pharmacological properties of the N-methyl-D-aspartate receptor. We used ifenprodil inhibition of [3H]dizocilpine maleate binding, which has been used to distinguish NR2A- from NR2B-containing receptors, to determine whether corticosterone altered the proportion of high- and low-affinity sites for ifenprodil in parallel with the changes in subunit messenger RNA levels. Corticosterone increased the density of [3H]dizocilpine maleate binding sites without changing the dissociation constant for [3H]dizocilpine maleate or the proportion of high- and low-affinity sites for ifenprodil. These data suggest that the effects of corticosterone on hippocampal function are mediated, in part, by parallel increases in NR2A and NR2B subunit levels and the number of receptor channel binding sites.

High-affinity binding of corticosterone to mammalian neuronal membranes: possible role of corticosteroid binding globulin.

The signal transduction mechanisms mediating rapid steroid actions are poorly understood. To characterize corticosteroid interaction with neuronal membranes in a species with rapid behavioral responses to corticosterone, we examined [3H]corticosterone binding to membranes prepared from prairie vole brains. At 22 degrees C, the rates of association and dissociation of [3H]corticosterone with well-washed synaptosomal membranes were very rapid. Specific binding was characterized by high affinity (Kd = 6.01 nM) and low density (Bmax = 63.1 fmol/mg protein). The binding sites were highly specific for naturally occurring glucocorticoids and the density of binding sites appeared to vary by neuroanatomical region. Unlike most G-protein-coupled receptors, the high-affinity binding of [3H]corticosterone to vole brain membranes was unaffected by the addition of Mg2+ or guanyl nucleotides. Surprisingly, saline perfusion of vole brains before tissue homogenization greatly reduced high-affinity binding. In addition, the affinity and specificity of corticosteroid binding sites were similar in vole neuronal membranes and vole plasma. These data suggest that corticosteroid binding globulins may facilitate [3H]corticosterone binding to neuronal membranes. However, the addition of blood to perfused brains before homogenization did not restore high-affinity binding, so the role of plasma binding globulins is unclear. Whether these binding phenomena represent a technical artifact or a regulatory mechanism for corticosteroid action has yet to be determined.

Chronic exposure to stress levels of corticosterone alters GABAA receptor subunit mRNA levels in rat hippocampus.

Chronic exposure to stress levels of corticosteroids alters many aspects of hippocampal function and may lead to neurodegeneration. Male rats were treated for 10 days with corticosterone (CORT) or vehicle pellets, and mRNA levels for six gamma-aminobutyric acid (GABAA) receptor subunits were measured. Effects of castration on subunit mRNA levels in CORT- and vehicle-treated animals were also examined. In situ hybridization studies demonstrated that mRNA levels for hippocampal GABAA receptor alpha 1, alpha 2, beta 1, beta 2, beta 3, and gamma 2 subunits were differentially altered by CORT treatment. Levels of alpha 1 and alpha 2 mRNA decreased in the dentate gyrus, and beta 1 mRNA levels decreased in CA1 and dentate gyrus of CORT-, compared to vehicle-treated, animals. In contrast, beta 2 subunit levels increased in all hippocampal regions examined, beta 3 levels increased in the dentate gyrus, and gamma 2 levels increased in CA1-CA3. The alpha 1, beta 1, and beta 2 mRNA levels all increased in the cingulate cortex of CORT-treated animals. There was no significant effect of gonadal state on any of the subunits examined, but there was a significant negative correlation between testosterone levels and mRNA levels of alpha 1, alpha 2 and beta 3 in specific regions. These data demonstrate that chronic exposure to stress levels of CORT produces complex changes in the mRNA levels of multiple GABAA receptor subunits, independently of the CORT-induced suppression of circulating testosterone.

Specific subunit mRNAs of the GABAA receptor are regulated by progesterone in subfields of the hippocampus.

The ability of ovarian steroids to regulate the excitability of hippocampal neurons may be mediated by alterations in the inhibitory activity of GABA. We assessed the ability of estradiol, progesterone, and 3 alpha-OH-5 alpha-pregnan-20-one (3 alpha-OH-DHP; a metabolite of progesterone) to regulate gene expression of selected GABAA receptor subunits (alpha 1, alpha 2, beta 1, beta 2, and gamma 2). Using in situ hybridization, we found that progesterone, or 3 alpha-OH-DHP, suppressed mRNA levels for the alpha 1 subunit in the CA2, CA3, and the dentate gyrus subfields of the hippocampus in animals that were pretreated with estradiol. Progesterone had a more limited effect on the alpha 2 subunit, suppressing mRNA levels in estradiol-primed animals only in the CA3 region. In contrast, progesterone increased mRNA levels for the gamma 2 subunit in the CA1, CA2, and CA3 regions of the hippocampus, but only in animals that were not estradiol-primed. Estradiol alone had no significant effect on the expression of any subunit examined. Beta 1 and beta 2 subunit mRNA levels were not altered by any of the hormones tested. These data support the conclusion that progesterone and its metabolites may regulate excitability of the hippocampus by modulating the GABAA receptor gene expression; these effects of progesterone are dependent upon the circulating levels of estradiol. Alterations in the gene expression of selective subunits may lead to changes in the density of GABAA receptor protein or to changes in receptor subunit composition which might alter receptor sensitivity to activation by GABA or modulators such as the benzodiazepines and convulsants.

Functional studies of corticosterone receptors in neuronal membranes.

This work reviews evidence that some physiological and behavioral responses to steroid hormones use membrane-associated receptors. The review emphasizes research with an amphibian model, Taricha granulosa, but also cites examples from mammalian research. Many studies document steroid responses that occur within a time frame of a few milliseconds or minutes. In Taricha, corticosterone rapidly inhibits reproductive behaviors and causes site-specific changes in neurotransmitter concentrations and neuronal activity. Ligand binding assays using radiolabeled corticosterone and neuronal membranes from Taricha (and other animals) provide evidence that there are high-affinity steroid receptors in neuronal membranes. Subcellular fractionation, autoradiography, and immunocytochemistry add support to the conclusion that there are steroid receptors in neuronal membranes. Other studies indicate that, in Taricha and other animals, there are two types of membrane-associated steroid receptors--ligand-gated ion channels (specifically, the GABAA receptor) and G-protein coupled receptors.

Oestrogens and the structural and functional plasticity of neurons: implications for memory, ageing and neurodegenerative processes.

Oestrogens have numerous effects on the brain, beginning during gestation and continuing on into adulthood. Many of these actions involve areas of the brain that are not primarily involved in reproduction, such as the basal forebrain, hippocampus, caudate putamen, midbrain raphe and brainstem locus coeruleus. This paper describes three actions of oestrogens that are especially relevant to brain mechanisms involved in memory processes and their alterations during ageing and neurodegenerative diseases: (1) the regulation of cholinergic neurons by oestradiol in the rat basal forebrain, involving induction of choline acetyltransferase and acetylcholinesterase according to a sexually dimorphic pattern; (2) the regulation of synaptogenesis in the CA1 region of the hippocampus by oestrogens and progestins during the four- to five-day oestrus cycle of the female rat. Formation of new excitatory synapses is induced by oestradiol and involves N-methyl-D-aspartate receptors; removal of these synapses involves intracellular progestin receptors; (3) sex differences in hippocampal structure, which may help to explain differences in the strategies that male and female rats use to solve spatial navigation problems. During the period of development when testosterone is elevated in the male, aromatase and oestrogen receptors are also elevated, making it likely that this pathway is involved in the masculinization of hippocampal structure.

Membrane receptors for corticosterone: a mechanism for rapid behavioral responses in an amphibian.

This paper reviews evidence that, in some cases, steroid hormones rapidly modulate behaviors by binding to specific cell-surface receptors on neurons. The evidence comes from research with an amphibian model, Taricha granulosa. In Taricha, stress and corticosterone inhibit reproductive behaviors with a rapidity that is inconsistent with traditional models for steroid action (models in which intracellular steroid receptors function as transcription factors). A series of radioligand binding assay studies identified a corticosteroid receptor in neuronal membranes that appears to mediate the rapid behavioral responses in Taricha. Studies with various steroids showed a strong correlation between their potencies to inhibit the behavior and their potencies to inhibit corticosterone binding. Neurophysiological studies of caudal brainstem neurons found that corticosterone administration rapidly modulates neuronal activity and selectively suppresses sensory processing. Another series of studies provided evidence that this corticosterone receptor interacts with G proteins in neuronal membranes. The studies suggest that there are G protein-coupled receptors for corticosteroids that provide an alternative mechanism by which this hormone regulates brain functions and behaviors.