Effects Of Adrenal Steroids Research Articles

Effects of adrenal steroids on basal ganglia neuropeptide mRNA and tyrosine hydroxylase radioimmunoreactive levels in the adrenalectomized rat.

To investigate the effects of type I (mineralocorticoid) and type II (glucocorticoid) receptor activation on striatal neuropeptide [preproenkephalin (PPE), preprotachykinin (PPT), and preprodynorphin (DYN)] mRNA and midbrain cholecystokinin (CCK) mRNA as well as striatal tyrosine hydroxylase radioimmunoreactivity (TH-RIC) levels, we administered either replacement levels of corticosterone (CORT; 0.5 mg/kg/day, s.c.) or pharmacological levels of deoxycorticosterone acetate (DOCA; a mineralocorticoid steroid with ability to bind to type I and type II receptors; 5 mg/kg, s.c.) to adrenalectomized adult male rats. After 1 week of recovery from adrenalectomy surgery, animals were injected daily with sesame oil or CORT for 1, 3, or 7 days or DOCA for 3 or 7 days and killed 16 h after the last injection. Adrenalectomy resulted in a decrease in all three striatal neuropeptide mRNA levels, compared with sham-operated rats. CORT replacement resulted in recovered PPE and PPT mRNA levels after 1 day and elevated PPE mRNA levels over those in sham-operated controls after 3 days. In contrast, DYN mRNA levels showed recovery after 7 days of CORT replacement. Results after DOCA treatment largely paralleled those after CORT replacement. There were no significant treatment effects on indirect markers of midbrain dopaminergic activity, i.e., CCK mRNA and TH-RIC. From these results we conclude that compared with striatal tachykinin and dynorphinergic neurons, enkephalinergic cells show greater sensitivity, whereas the dopaminergic system, including mesencephalic CCK, demonstrates an insensitivity to physiological CORT and to pharmacological DOCA treatment.

Ageing and adrenal cortical function

Ageing is associated with changes in the secretion of adrenal cortical steroids. In the elderly, cortisol secretion increases after stimulation, while the secretion of dehydroepiandrosterone (DHEA) decreases. Each of these hormones influences the age-related processes of energy metabolism, fat depot distribution, immune function and neurodegeneration. In animals the effects of adrenal steroids are dramatic and easily measured. In humans the effects are more subtle. This review summarizes these actions and emphasizes the differences of dosages used in various experimental designs. It is concluded that adrenal hormones may play a significant role in human ageing, but research is hindered because the molecular pathways of DHEA action are not known.

Effects of adrenal steroids on the concentration of Na(+)-K+ pumps in rat skeletal muscle.

Since adrenal steroids have been shown to upregulate the concentration of Na(+)-K(+)-ATPase in cardiac muscle, similar effects could be expected in skeletal muscle. Following infusion of dexamethasone (0.02-0.1 mg/kg per day) for 7 days in 10-week-old rats, the total concentration of [3H]ouabain-binding sites rose by up to 22-42% in soleus, extensor digitorum longus, gastrocnemius and diaphragm muscle. Dexamethasone produced no or minute changes in the Na(+)-K+ contents of skeletal muscle. In contrast, infusion with aldosterone (0.02-0.5 mg/kg per day) for 7 days produced hypokalemia and a graded reduction in the K+ content of skeletal muscle, which was closely correlated to a downregulation of the [3H]ouabain-binding site concentration (r = 0.65-0.70; P < 0.001). The results indicate that in skeletal muscle high doses of glucocorticoids upregulate the concentration of Na(+)-K+ pumps whereas mineralocorticoids induce a downregulation, which is secondary to the concomitant K+ deficiency. Since adrenalectomy produced no significant change in [3H]ouabain-binding site concentration, basal levels of endogenous adrenal steroids seem to be of minor importance for the regulation of Na(+)-K+ pump concentration in skeletal muscle.

Angiotensinogen and Natriuretic Peptide mRNAs in Rat Brain: Localization and Differential Regulation by Adrenal Steroids in Hypothalamus

Ryan, M. C., P.-J. Shen and A. L. Gundlach. Angiotensinogen and natriuretic peptide mRNAs in rat brain: localization and differential regulation by adrenal steroids in hypothalamus. Peptides 18(4) 495–504, 1997.—Adrenal steroids have been shown to modulate angiotensin II and natriuretic peptide systems—peptide synthesis and metabolism—in vitro. In the present study the effects of adrenal steroids on mRNA encoding the angiotensin II precursor, angiotensinogen (AOGEN), and the natriuretic peptides, atrial natriuretic peptide (ANP) and C-type natriuretic peptide (CNP) in the rat hypothalamus were investigated using quantitative in situ hybridization histochemistry of [ 35S]- and [ 33P]-labeled oligonucleotide probes. Adrenalectomy produced an apparent overall decrease in preproAOGEN (ppAOGEN) mRNA in presumed astrocytes in the anterior hypothalamus with significant decreases (ANOVA) measured in the medial preoptic area, the ventral region of the medial preoptic area, the paraventricular, suprachiasmatic, supraoptic, and periventricular nuclei. ppAOGEN mRNA levels were restored by both glucocorticoid (dexamethasone; 2 μg/ml in drinking water) and mineralocorticoid (aldosterone; 50 μg/kg, SC) replacement. Treatment of intact animals with dexamethasone (2 μg/ml in drinking water for 5 days) and aldosterone (100 μg/kg, SC, daily for 10 days) produced a significant increase in ppAOGEN mRNA in those hypothalamic regions affected by adrenalectomy. ppANP and ppCNP mRNA-positive neurons were successfully detected using [ 35S]- and [ 33P]-labeled probes, respectively, and were abundant in the anterior hypothalamus, particularly in the anteromedial preoptic nucleus of the medial preoptic area. In contrast to the effects on ppAOGEN mRNA, however, alterations in adrenal steroid levels did not significantly change ppANP or ppCNP mRNA levels in neurons of the anteromedial preoptic nucleus or in the arcuate nucleus. These results indicate that adrenal steroids modulate AOGEN gene transcription in vivo, consistent with previous reports of increased levels of ppAOGEN mRNA in a number of brain regions in response to acute dexamethasone treatment and reports of decreased AOGEN immunoreactivity in brain regions of adrenalectomized rats. In contrast, despite reports of modulation of hypothalamic ANP immunoreactivity following adrenalectomy and dexamethasone treatment, it would appear that adrenal steroids do not alter the transcription or stability of hypothalamic natriuretic peptides mRNA in vivo.

High glucose stimulates aldosterone-induced hypertrophy via type I mineralocorticoid receptors in neonatal rat cardiomyocytes.

Previous studies have shown that aldosterone plus salt loading cause cardiac hypertrophy in rats in vivo, and that in vitro, both aldosterone and glucose stimulate fibroblast growth. The present studies examined the effects of adrenal steroids via mineralocorticoid and glucocorticoid receptors (MR and GR) on [3H]leucine incorporation by neonatal rat cardiomyocytes in culture and the role of elevated glucose in modulating such effects. GR occupancy by corticosterone, the highly selective type II (glucocorticoid) receptor agonist RU28362, or high doses of aldosterone lowers incorporation; when this effect is blocked by coincubation with the glucocorticoid antagonist RU486, aldosterone, but not corticosterone, markedly elevates leucine incorporation, indicating a specific mineralocorticoid effect via MR. Incubation with high glucose alone does not increase incorporation, but markedly increases the hypertropic effect of aldosterone in terms of both threshold and maximum response. The glucose-aldosterone synergy is via MR and is completely blocked by spironolactone. The time course of increased incorporation is identical for aldosterone acting alone or with elevated glucose, consistent with widespread transcriptional effects and suggesting that the contribution of high glucose is not rate limiting. The glucose effect reflects neither induction of MR synthesis nor an increase in their affinity; it is specific, in that it is not mimicked by L-glucose or mannitol at equal concentrations, and is mediated via an increase in protein kinase C activity that can be measured in both soluble and particulate compartments. The role of this synergy in the cardiac sequelae of diabetes remains to be explored.

Glucocorticoid regulation of vasopressin V1a receptors in rat forebrain.

Vasopressin V1a receptors (V1aRs) are expressed in the septum of the rat brain where they are thought to mediate several of the physiologic and behavioral effects of this neuropeptide. We have investigated the effects of adrenal steroids on forebrain V1aRs. Rats were bilaterally adrenalectomized (ADX) and hormone replaced with either corticosterone (CORT), dexamethasone (DEX) or aldosterone (ALDO) at different concentrations. V1aR mRNA was evaluated using in situ hybridization, and V1aR binding site density was quantified using a specific iodinated V1aR antagonist [125I]d(CH2)5Sar7-AVP (125I-SAVP). V1aR density in the dorsolateral septum and the bed nucleus of the stria terminalis (BNST) decreased significantly with adrenalectomy, and 5 micrograms/100 g b.wt. of DEX was able to restore V1aR binding to levels comparable to those of sham operated controls in both regions. ALDO replacement also elevated V1aR binding in the BNST but not in the septum. In ADX animals given corticosterone in their drinking water, V1aR mRNA levels detected by in situ hybridization increased significantly over the ADX rats given saline. In order to understand the molecular basis of this effect, a putative genomic clone encoding the rat V1aR was isolated, and sequence analysis of the 5' flanking region has revealed the presence of several putative glucocorticoid response elements (GREs). Gel retardation assays were performed using these putative GREs, and two appear to be active in protein binding in glucocorticoid receptor containing nuclear extracts. The glucocorticoid effects on V1aR mRNA and binding, and the presence of putative active GREs in the promoter of the V1aR gene strongly implicate a role for adrenal steroids in the regulation of V1a receptor gene expression in glucocorticoid receptor and/or mineralocorticoid receptor expressing tissues.

Hippocampal homosynaptic long-term depression/depotentiation induced by adrenal steroids.

The effects of adrenal steroids on synaptic plasticity were investigated in the dentate gyrus of the hippocampus. Experiments were performed in either adrenalectomized or intact (non-adrenalectomized), anesthetized rats. High-frequency stimulation was applied to the medial perforant pathway at three different frequencies; 100, 200 or 400 Hz, either post- or pre- and post-administration of the specific Type-II adrenal steroid receptor agonist RU 28362. High-frequency stimulation prior to RU 28362 administration produced a frequency-dependent long-term potentiation of the population spike, with 100 Hz showing no long-term potentiation and 400 Hz the highest degree of potentiation. In contrast, following administration of RU 28362, high-frequency stimulation produced a long-term depression (in comparison to baseline). In the experiments in which high-frequency stimulation was applied both pre- and post-RU 28362 administration, the size of the population spike was initially potentiated and then depotentiated after the RU 28362 injection. This effect was also frequency dependent, although opposite to the long-term potentiation effect. That is, 400 Hz was the least effective frequency for inducing long-term depression/depotentiation, while 100 Hz was the most effective. Long-term depression/depotentiation was immediate following high-frequency stimulation and lasted for the extent of the recording session, in some cases longer than 1 h. Similar to the finding reported in the accompanying paper, induction of long-term potentiation was substantially suppressed by RU 28362. However, in a number of experiments long-term potentiation could still be induced after RU 28362 administration, even after long-term depression/depotentiation had been established. In these cases, stimulation at the higher frequencies was necessary.(ABSTRACT TRUNCATED AT 250 WORDS)

Opposing roles of type I and type II adrenal steroid receptors in hippocampal long-term potentiation.

Studies were performed in vivo on the dentate gyrus to investigate the possible involvement of Type I and Type II adrenal steroid receptors in the mediation of reported adrenal steroid effects on long-term potentiation, through the use of specific Type I and Type II receptor agonists and antagonists. In adrenalectomized rats, administration of aldosterone, a specific Type I agonist, produced a marked enhancement in long-term potentiation, in comparison to either the adrenalectomized or sham adrenalectomized controls. Administration of RU 28318, a Type I antagonist, which by itself had minimal effects, blocked the aldosterone enhancement. In contrast, administration of the specific Type II agonist, RU 28362, produced a marked decrement in the induction of long-term potentiation. The RU 28362 effect was blocked by a prior injection of the Type II antagonist, RU 38486. Neither adrenalectomy nor administration of any of the steroid agonists or antagonists had noticeable effects on neuronal excitability (as determined by the field potentials), nor on post-tetanic potentiation. These findings are consistent with other studies that have shown a biphasic effect of increasing levels of corticosterone on long-term or prime burst potentiation. Taken together, these studies suggest that Type I receptors, with a high affinity for corticosterone, and Type II receptors, having a lower affinity for corticosterone, form a two-level recognition system to modulate induced synaptic plasticity in opposite directions in the dentate gyrus and possibly also in Ammon's horn.

Anabolic-androgenic steroid and adrenal steroid effects on hippocampal plasticity

Anabolic-androgenic steroids (AAS) are synthetic androgen-like compounds which are taken in high doses by athletes with the intention of enhancing muscular appearance, strength and/or athletic performance. Recent research indicates that high doses of AAS may influence the functions of the hippocampus. This evidence led us to explore the extent to which chronic AAS treatments influence spatial memory and the integrity of the hippocampus in the rat. Gonadally intact adult male Long-Evans rats were treated with either the AAS methandrostenolone, a steroid ‘cocktail’ (TNB; testosterone cypionate, boldenone undecylenate and nandrolone decanoate), or the oil vehicle daily for 12 weeks. A group of male rats treated with corticosterone (CORT; 10 mg/day) was also examined. Spatial memory was assessed in the Morris water maze after 10 weeks of hormone treatment. At 12 weeks, the animals were sacrificed, blood collected and the brain sectioned to assess hippocampal cell number. There were no impairments in the acquisition or retention of the Morris water maze in any hormone treatment group. Although serum testosterone levels were elevated in rats treated with TNB relative to the oil controls, neither the TNB or methandrostenolone treatments produced changes in hippocampal cell number. Serum CORT levels were significantly elevated in the rats treated with CORT and cell loss (15%) was detectable in the CA3b subfield in this group of animals. These results indicate that the AAS administered in the present study were not detrimental to hippocampal spatial memory or cell survival and that, while chronic CORT may produce mild hippocampal cell loss, this loss is not accompanied by deficits on a spatial memory task.

Bicarbonate transport along the loop of Henle effects of adrenal steroids.

The role of adrenal steroids in the regulation of bicarbonate absorption in the loop of Henle was studied by in vivo microperfusion. Bicarbonate transport (JHCO3) was measured by microcalorimetry and fluid reabsorption by [14C]inulin, 7-10 days after surgery, in 1) sham-operated control rats, 2) adrenalectomized (Adx) rats, 3) Adx rats receiving dexamethasone (1.2 micrograms.100 g body wt-1.24 h-1) and a low dose of aldosterone (0.5 micrograms.100 g body wt-1.24 h-1), 4) Adx rats receiving dexamethasone, 5) Adx rats receiving a low dose of aldosterone, and 6) Adx rats receiving a high dose of aldosterone (1.0 micrograms.100 g body wt-1.24 h-1). JHCO3 along the loop of Henle was decreased by 40% in Adx rats. JHCO3 was increased by dexamethasone alone and by dexamethasone plus a low dose of aldosterone to rates observed in fully supplemented Adx rats. Aldosterone given alone at a low physiological dose had no effect, but, when administered at a high dose, returned JHCO3 to normal.

Stress and the Brain: A Paradoxical Role for Adrenal Steroids

Publisher Summary This chapter discusses paradoxical effects of adrenal steroids in the hippocampus. Stress is common in everyday life and is blamed for many problems. There is mounting evidence that stressful experiences exacerbate disease processes. Adrenal steroids represent only one of several neurochemical systems that mediate the delicate balance between hippocampal function and dysfunction. To explore the role of endogenous corticosterone (CORT) release in dendritic atrophy evoked by stress, the steroid synthesis inhibitor cyanoketone was used to reduce the magnitude of CORT secretion in response to restraint stress. Another important issue is the relationship between the atrophy of CA3c neurons induced by repeated CORT treatment or repeated restraint stress and the loss of pyramidal neurons that has been reported after both 12 weeks of CORT treatment and severe social stress. Repeated restraint stress in rats for 3 weeks causes changes in the hippocampal formation, including atrophy of the dendrites of CA3c pyramidal neurons, as well as suppression of serotonin 1A (5-HT1A) receptor binding.

Effects of selective type I and II adrenal steroid agonists on immune cell distribution.

Adrenal steroids exert their effects through two distinct adrenal steroid receptor subtypes; the high affinity type I, or mineralocorticoid, receptor and the lower affinity type II, or glucocorticoid, receptor. Adrenal steroids have well known effects on immune cell distribution, and although both type I and II receptors are expressed in immune cells and tissues, few data exist on the relative effects mediated through these two receptor subtypes. Accordingly, we administered selective type I and II adrenal steroid receptor agonists to young adult male Sprague-Dawley rats for 7 days and then measured immune cell distribution in the peripheral blood and spleen. Results were compared with those of similar studies using the naturally occurring glucocorticoid of the rat, corticosterone, which binds both type I and II receptors. The majority of the well characterized effects of adrenal steroids on peripheral blood immune cells (increased neutrophils and decreased lymphocytes and monocytes) were reproduced by the type II receptor agonist, RU28362. RU28362 decreased the numbers of all lymphocyte subsets [T-cells, B-cells, and natural killer (NK) cells] to very low absolute levels. The largest relative decrease (i.e. in percentage) was seen in B-cells, whereas NK cells exhibited the least relative decrease and actually showed a 2-fold increase in relative percentage during RU28362 treatment. Similar to RU28362, the type I receptor agonist, aldosterone, significantly reduced the number of lymphocytes and monocytes. In contrast to RU28362, however, aldosterone significantly decreased the number of neutrophils. Moreover, aldosterone decreased the number of T-helper cells and NK cells, while having no effect on the number of B-cells or T-suppressor/cytotoxic cells. Corticosterone at physiologically relevant concentrations had potent effects on immune cell distribution, which were indistinguishable from those of the type II receptor agonist, RU28362. Taken together, these results indicate that effects of adrenal steroids on immune cell distribution are dependent on the receptor subtype involved as well as the specific cell type targeted. These factors allow for varied and complex effects of adrenal steroids on the immune system under physiological conditions.

The effects of adrenal steroids and excitatory input on neuronal birth and survival.

The dentate gyrus of the rat forms in three developmental phases, each of which is characterized by neuronal birth, migration and death. Recent evidence indicates that adrenal steroids regulate neuronal birth, death, and possibly migration throughout the life of the animal. However, the observation that very few neuroblasts in the developing or adult dentate gyrus express adrenal steroid receptors suggests that the effects of adrenal steroid manipulations on neurogenesis are indirect. Additional evidence indicates that NMDA receptor activation regulates neuronal birth and death in this brain region presenting the possibility that adrenal steroids influence these processes through direct actions on excitatory afferents. Future studies will address this possibility.

Effects of adrenalectomy and Type I or Type II glucocorticoid receptor activation on AVP and CRH mRNA in the rat hypothalamus

The brain contains two types of adrenal steroid receptors, which play a role in mediating adrenal steroid effects on neuropeptide and other types of gene expression in discrete brain regions. Because the paraventricular nuclei of the hypothalamus (PVN) have adrenal steroid-sensitive neuropeptide systems, they provide a bench-mark to assess the doses of receptor agonists that may act selectively via Type I and Type II receptors. In the present study, in situ hybridization histochemistry was used to examine the effects of adrenalectomy (ADX) and Type I and Type II receptor agonists on arginine vasopressin (AVP) mRNA and corticotropin-releasing hormone (CRH) mRNA in rat brain. In agreement with previous reports, adrenal steroid regulation of AVP and CRH mRNA was found to be mediated primarily through the Type II receptor. Furthermore, adrenalectomy significantly increased AVP mRNA in the parvocelluar region of the hypothalamic paraventricular nucleus (PVN), and systemic administration of the specific Type II agonist, RU28362 (10 μg/μ1/h), as well as corticosterone (CORT) pellets of 50 and 300 mg, prevented this increase. CRH mRNA was not significantly increased after ADX, but was markedly decreased in the PVN of rats receiving either RU28362 or a 300 mg pellet of CORT. Aldosterone, a specific Type I agonist, did not significantly affect either AVP or CRH mRNA levels when administered at 10 μg/h. Moreover, in the magnocellular regions of the PVN and SON AVP mRNA did not vary as a function of steroid manipulation. Results for PVN are compared to changes in gene products in hippocampus produced by the same doses of Type I and Type II agonists, in which Type I receptors appear to have a significant role.

Effects of adrenal steroids on preprotachykinin-a gene expression in the rat brain

channel agonist BayK 8644 also changes the biosynthesis of the various constituents in a distinct pattern. The soluble proteins chromogranin B, neuropeptide Y and VGF show a significant induction of their mRNAs already within 24 h. The mRNA levels of the partly membranebound components carboxypeptidase H and glycoprotein III are significantly enhanced after 6 days, while the peptidylglycine a-amidating monooxygenase mRNA increases already after 1 day.

O-244 - The role of vasopressin receptor in the rat hippocampus: effect of adrenal steroids.

O-244 - The role of vasopressin receptor in the rat hippocampus: effect of adrenal steroids.

Stress, ageing and dementia

It is well established that stress causes neuroendocrine changes. In particular, the central role of the hypothalamic-pituitary-adrenal axis in the stress response, and the multiple effects of adrenal steroids on neuronal activity, structure and chemistry suggests that the hypothalamic-pituitary-adrenal axis may form a link between environmental stress and psychiatric disease. We review the evidence for a theoretical relationship suggesting that through abnormalities of the hypothalamic-pituitary-adrenal axis, potential mechanisms exist whereby stress and ageing may contribute to neuronal damage and dementia.

Effects of adrenocortical steroids on long-term potentiation in the limbic system: basic mechanisms and behavioral consequences.

Hippocampal structures are a major target for adrenal steroid hormones, and hence these neural regions are some of the most likely mediators of the effects of adrenocortical steroids on behavior. Memory disturbance, in particular biasing toward negative contents, are part of the symptomatology presented by depressive patients. In turn, a sizeable subset of depression also presents with hypercortisolemia. Adrenocortical hormones are also known to affect memory processes. Hippocampal formation is essential for declarative memory. We thought it appropriate then to study the effects of adrenal steroids on long-term potentiation, a putative memory mechanism in the hippocampus. Two clearly distinguished components of the evoked response to perforant path stimulation can be studied in the hippocampus: the excitatory postsynaptic potential (EPSP) which denotes the graded depolarization of the somatodendritic region of the neuron and the population spike (PS), a manifestation of the all-or-none-discharge of the cell action potential. Corticosterone had a significant depressant effect on the EPSP component of the evoked response immediately and 15 min after injection. Thereafter EPSP amplitudes were within normal values. Corticosterone significantly decreased the PS immediately after the train, the component remaining low 30 min after the train. 5 alpha-Dihydrocorticosterone (a ring A-reduced metabolite of corticosterone) significantly reduced the PS component of the response at all times after injection. 18-Hydroxydeoxycorticosterone and deoxycorticosterone significantly decreased both EPSP and PS components of the evoked response from the time of infusion. Contrary to expectation, tetrahydrodeoxycorticosterone was ineffective in decreasing and if anything, enhanced the development of long-term potentiation. 18-Hydroxydeoxycorticosterone 21-acetate behaved like vehicle, except for the first 30 min after injection when the EPSP was decreased. Allotetrahydroprogesterone decreased all EPSP's values and had no effect in the PS development in comparison with vehicle. The suggestion is made that the study of steroidal effects on hippocampal LTP can serve as a preclinical model of some aspects of depression in a specific subset of the disease.

Stress and antidepressant effects on hippocampal and cortical 5-HT 1A and 5-HT 2 receptors and transport sites for serotonin

The interactions between 14 days of repeated restraint stress and daily administration of imipramine or tianeptine (2 h before the beginning of stress) were investigated in rats to assess responses of 5-HT2 and 5-HT1A receptors and serotonin transporter sites labelled by [3H]paroxetine in the cerebral cortex and hippocampus, two brain regions in which adrenal steroid effects on serotonin receptor-binding have been reported. 5-HT2 sites, labelled by [125I]7-amino-8-iodo ketanserin, were decreased in parietal cerebral cortex layers 3 and 5 by imipramine treatment, but not by tianeptine treatment and not by daily restraint stress. Stress, but not antidepressant, depressed 5-HT1A sites labelled with [3H]8-hydroxy-DPAT in hippocampal fields CA3, CA4 and dentate gyrus. [3H]paroxetine-binding to serotonin transporter sites was decreased by tianeptine treatment as well as by imipramine in both hippocampus and cerebral cortex, with some overlap of the fields that were significantly affected, whereas there were no effects of stress per se and no evidence of a stress x drug interaction. These results are discussed in relation to similarities and differences in the effects of different antidepressant drugs on the serotonergic system of the rat brain. Whereas the actions of imipramine and tianeptine on 5-HT2 and 5-HT1A receptors are specific to each drug, the surprising finding of a similar effect of both drugs to reduce serotonin transporter sites labelled by [3H]paroxetine suggest the possibility of a common action for these two drugs in spite of their opposite effects on serotonin re-uptake.

Adrenalectomy enhances Fos-like immunoreactivity within the spinal trigeminal nucleus induced by noxious thermal stimulation of the cornea

Immunocytochemistry was used to assess the distribution of neurons within the spinal trigeminal nucleus that expressed the protein product of the proto-oncogene c- fos after thermal stimulation of the cornea in barbiturate-anesthetized rats. The influence of adrenal steroids on Fos-like immunoreactivity induced by corneal stimulation also was examined by comparison of the results obtained in adrenal intact rats to those in adrenalectomized rats and to those in adrenalectomized rats given corticosterone replacement therapy. Stimuli (42 or 52°C, 20 s per min, 15 min) were applied unilaterally to the cornea by a contact thermode. At 2 h after stimulation animals were perfused with 4% paraformaldehyde and tissue sections were incubated with primary antiserum against the Fos protein and processed with the avidin-biotin method. The pattern of Fos-like immunoreactivity after 52°C stimulation revealed a dominant group of cells ipsilaterally within the superficial laminae of the caudalmost portion of trigeminal subnucleus caudalis that was greatly enhanced in adrenalectomized rats. Low-intensity stimulation did not induce Fos-like immunoreactivity among cells in this caudal region. A second significant group of cells was seen more rostrally at periobex levels within the ventrolateral pole of the nucleus. The number of cells in the periobex grouping was increased after 52 or 42°C corneal stimulation when compared to unstimulated controls and was not affected by levels of corticosterone. The results indicated a discontinuous pattern of Fos-like immunoreactivity within the spinal trigeminal nucleus after thermal stimulation of the cornea and a differential effect of adrenal steroids. The appearance of Fos-like immunoreactivity within caudal portions of the nucleus was increased only by noxious intensities of stimulation and was further enhanced in animals with low levels of corticosterone. In contrast, the Fos-like immunoreactivity at periobex levels was increased after noxious and innocuous thermal stimuli and was independent of the level of corticosterone. The results were consistent with the hypothesis that glucocorticoids modify the expression of immediate early genes among a select group of central trigeminal neurons. Such steroid modulation may contribute to the mechanisms that underlie long-term adaptation to noxious sensory input.