Adrenal Activation Research Articles

Total body catecholamine kinetics before and after birth in spontaneously hypoxemic fetal lambs.

To study the effect of fetal hypoxemia on perinatal norepinephrine and epinephrine total body kinetics, 13 near-term fetal lambs were instrumented with vascular catheters under general anesthesia. One week later, norepinephrine and epinephrine kinetics were measured in normoxemic (n = 7) or spontaneously hypoxemic fetuses (n = 6) with isotope dilution methodology. Hypoxemic fetuses had lower body (P < 0.02) and placental (P = 0.01) weights and a threefold elevation in plasma norepinephrine (P < 0.005) and epinephrine (P < 0.025) associated with correspondingly higher total body norepinephrine (P < 0.005) and epinephrine (P < 0.05) spillovers. After birth, total body norepinephrine and epinephrine spillover increased 45% and 3.2-fold, respectively, in normoxemic animals (both P < 0.001). However, in the hypoxemic group, norepinephrine total body spillover was unchanged between fetal and 1-h lambs and then fell in 4-h lambs (P < 0.005). In addition, total body epinephrine release rose postnatally (P < 0.05) but less than in the normoxemic group (P < 0.02). No differences in norepinephrine or epinephrine total body clearance occurred between normoxemic and hypoxemic groups in either fetal or newborn lambs. These findings indicate that in hypoxemic and growth-restricted fetuses 1) elevated circulating norepinephrine and epinephrine levels are related to increased sympathoadrenal activity and 2) birth is associated with an initial maintenance and subsequent decline in global sympathetic activity but a blunting of adrenal medullary activation.

Sex differences in expression of serotonin receptors (subtypes 1A and 2A) in rat brain: a possible role of testosterone

Sexual differences in the expression of messenger RNA and in the binding of serotonin receptors (subtypes 1A and 2A) were studied by in situ hybridization and autoradiography {[ 3H]8-hydroxy-2(di-n-propylamino)tetralin and [ 3H]ketanserin binding} in the rat brain. Serotonin-1A receptor messenger RNA showed distinct expression patterns for female and male rats. Expression of serotonin-1A receptor messenger RNA was greater in males in subregions of the hypothalamus and amygdala, and less in males in subregions of the hippocampus. No significant differences in the distribution of serotonin-1A receptor binding sites were found between the sexes. Serotonin-2A receptor messenger RNA expression was comparable in males and females in all brain regions except the ventromedial hypothalamic nuclei, where lower levels were seen in females. However, the binding of serotonin-2A receptor measured with [ 3H]ketanserin was significantly higher in females in all regions of the hippocampus. In a separate study, gonadectomy in males significantly increased serotonin-1A messenger RNA content in the cortex, hypothalamus, hippocampus, amygdala and dorsal raphe, and decreased serotonin-2A messenger RNA in ventromedial hypothalamic nuclei only. Almost all gonadectomy-induced changes were reversed by concomitant administration of testosterone. Our data provide evidence for region-specific sex differences in serotonin receptor subtype 1A and 2A transcription and concentration in the rat brain, and further suggest a modulatory role of testosterone in serotonin (particularly subtype 1A) receptor expression. Gender and gonadal steroid effects on central serotonergic systems may underlie the reported sexual dimorphisms in affective state regulation, response to psychopharmacological agonists or pituitary adrenal activation.

Panic induced by carbon dioxide inhalation and lack of hypothalamic–pituitary–adrenal axis activation

It has been hypothesized that spontaneous panic is distinct from anticipatory anxiety, which activates the hypothalamic–pituitary–adrenal (HPA) axis. Panic attacks characterized by prominent respiratory symptoms, such as those induced by sodium lactate, are not associated with increases in cortisol. We examined blood cortisol responses to CO 2-induced panic. Cortisol levels did not increase and actually decreased significantly in 10 panicking subjects with panic disorder. No reductions were noted after 20 min of CO 2 inhalation in either eight normal comparison subjects or six non-panicking panic disorder patients. These results lend support to the hypothesis that the pathophysiological mechanism underlying CO 2-induced panic is different from that underlying general or anticipatory anxiety.

The inhibitory effect of intracerebroventricularly injected interleukin 1beta on testosterone secretion in the rat: role of steroidogenic acute regulatory protein.

Exposure to disease or injury often results in impaired reproductive activity accompanied by decreased testosterone levels. After immune activation, the cytokine interleukin 1-beta (IL-1beta) circulates in high concentrations, and its exogenous administration evokes many of the sequelae of immune activation. Previously, we have shown that the administration of this cytokine into the cerebral ventricles blunts hCG-stimulated testosterone secretion. This effect, though time-dependent, occurs before significant elevation of interleukin 6 in the peripheral bloodstream, does not depend on adrenal activation, and/or changes in LH concentrations, leading us to hypothesize a direct connection between the brain and testis. To explore this mechanism further, we isolated testicular tissue from rats treated intracerebroventricularly (icv) with vehicle or IL-1beta 30 or 90 min before they were killed. We found that in vivo cytokine treatment blunted ex vivo testosterone secretion in response to hCG, showing that the mechanism is independent of circulating cytokines. Though hCG binding was moderately reduced by icv IL-1beta in these preparations, the extent of this inhibition did not explain our observations. As the first acutely and hormonally regulated step in the biosynthesis of testosterone is the transfer of cholesterol into the inner mitochondrial membrane, which is mediated by steroidogenic acute regulatory (StAR) protein, we hypothesized that the rapid effects of icv IL-1beta on testicular responsiveness to hCG might be due to reduced levels of StAR. We report here that StAR protein was indeed reduced in Leydig cells isolated from rats treated in vivo with IL-1beta. Furthermore, treatment with a water-permeable form of cholesterol that bypasses the requirement for StAR partially restored hCG-stimulated testosterone secretion from testes isolated from rats treated icv with IL-1beta. Taken together, our data indicate that StAR plays a role in the suppression of testicular function evoked by central administration of IL-1beta.

Gender differences in sympathetic nervous system regulation.

1. Females are protected against the development of hypertension. The purpose of the current review is to present the evidence for gender differences in the regulation of the sympatho-adrenal nervous system and to determine if these differences support the hypothesis that, in females, the regulation of the sympathetic nervous system (SNS) is altered such that sympatho-adrenal activation is attenuated or sympatho-adrenal inhibition is augmented. 2. The central control of sympatho-adrenal function is different in females and responses vary during the oestral and menstrual cycles. Pathways regulating the SNS appear to be less sensitive to excitatory stimuli and more sensitive to inhibitory stimuli in females compared with males. 3. Gender differences in arterial baroreflex sensitivity suggest that females may have a greater baroreflex sensitivity, such that alterations in blood pressure are more efficiently controlled than in males. Cardiopulmonary reflex inhibition of sympathetic nerve activity is greater in females, possibly resulting in a greater renal excretory function. 4. An attenuated sensitivity to adrenergic nerve stimulation, but not to noradrenaline (NA), suggests that gender differences in noradrenergic neurotransmission may protect females against sympathetic hyperactivity. Gender differences in the regulation of NA release via presynaptic alpha 2-adrenoceptors, the vasoconstrictor response to the cotransmitter neuropeptide Y and the clearance of catecholamines are consistent with this hypothesis. 5. Similarly, attenuated stress-induced increases in plasma catecholamines in women suggest that females are less sensitive and/or less responsive to adrenal medullary activation. This is supported by findings of gender differences in adrenal medullary catecholamine content, release and degradation. 6. We conclude that there is strong evidence that supports the hypothesis that, in females, the regulation of the SNS is altered such that sympatho-adrenal activation is attenuated or sympatho-adrenal inhibition is augmented.

Interleukin-1 alpha (IL-1 alpha) and tumor necrosis factor alpha (TNF alpha) regulate insulin-like growth factor binding protein-1 (IGFBP-1) levels and mRNA abundance in vivo and in vitro.

TNF alpha and IL-1 alpha are thought to contribute to impaired anabolism in a variety of clinical states, including sepsis, cancer cachexia and the AIDS wasting syndrome. We asked whether cytokines exert direct effects on hepatic production of IGFBP-1, an important modulator of IGF bioavailability. C57BL/6 mice were treated with 100 micrograms/kg of recombinant IL-1 alpha or TNF alpha by intraperitoneal injection. Western ligand blotting and immunoprecipitation with specific antisera revealed that serum levels of IGFBP-1 (but not IGFBP-2, -3, -4, -5 or -6) are increased approximately 4 fold 2 h after treatment and then decline. Northern blotting confirms that hepatic IGFBP-1 mRNA abundance also is increased acutely in both IL-1 alpha- and TNF alpha-treated animals. Similar results obtained in adrenalectomized mice indicate that adrenal activation is not required for this effect. Cell culture studies show that cytokines exert direct effects on the production of IGFBP-1 by HepG2 hepatoma cells, increasing IGFBP-1 levels in conditioned medium and the abundance of IGFBP-1 mRNA approximately 3-fold. In contrast, transient transfection studies with IGFBP-1 promoter/luciferase reporter gene constructs show that IGFBP-1 promoter activity is reduced after 18 hr cytokine treatment. We conclude that IL-1 alpha and TNF alpha increase circulating levels of IGFBP-1, reflecting direct effects on hepatic IGFBP-1 mRNA abundance. Stimulation of hepatic IGFBP-1 production may contribute to alterations in IGF bioactivity and impaired anabolism in clinical conditions where cytokine production is high. Additional studies are required to identify specific mechanisms mediating effects of cytokines on hepatic production of IGFBP-1.

The relationship between salivary secretory immunoglobulin A and cortisol: neuroendocrine response to awakening and the diurnal cycle

The level of secretory immunoglobulin A (sIgA) measured in saliva is downregulated during periods of chronic stress. In contrast, the response to an acute stress challenge is a transient increase. The process of awakening is associated with stress neuroendocrine activation characterised by increases in salivary cortisol. We therefore examined if this period of hypothalamic–pituitary–adrenal (HPA) activation was associated with changes in salivary sIgA. Associations of sIgA with the diurnal cortisol cycle were also investigated in a separate study. The awakening cortisol response was measured in 30 healthy day-active young adults. There was a marked elevation from the first awakening level over the succeeding 30 min. SIgA showed the opposite response with a marked fall from the highest first awakening concentration in the same samples over the same period. The cortisol rise was significantly correlated with the sIgA fall ( r=0.42). Salivary sIgA showed a similar diurnal cycle to cortisol in a study on eight healthy young adults. An early morning acrophase was followed by a decline to a stable base some 6 h after awakening. The physiological significance of these relationships and possible implications for vulnerability to infection are discussed.

Detrimental effects of chronic hypothalamic-pituitary-adrenal axis activation. From obesity to memory deficits.

Increasing evidence suggests that the detrimental effects of glucocorticoid (GC) hypersecretion occur by activation of the hypothalamic-pituitary-adrenal (HPA) axis in several human pathologies, including obesity, Alzheimer's disease, AIDS dementia, and depression. The different patterns of response by the HPA axis during chronic activation are an important consideration in selecting an animal model to assess HPA axis function in a particular disorder. This article will discuss how chronic HPA axis activation and GC hypersecretion affect hippocampal function and contribute to the development of obesity. In the brain, the hippocampus has the highest concentration of GC receptors. Chronic stress or corticosterone treatment induces neuropathological alterations, such as dendritic atrophy in hippocampal neurons, which are paralleled by cognitive deficits. Excitatory amino acid (EAA) neurotransmission has been implicated in chronic HPA axis activation. EAAs play a major role in neuroendocrine regulation. Hippocampal dendritic atrophy may involve alterations in EAA transporter function, and decreased EAA transporter function may also contribute to chronic HPA axis activation. Understanding the molecular mechanisms of HPA axis activation will likely advance the development of therapeutic interventions for conditions in which GC levels are chronically elevated.

AFFECTIVE MODULATION OF HPA AXIS ACTIVATION IN RESPONSE TO EXHAUSTIVE EXERCISE

675 Psychoneuroendocrinological research has provided substantial evidence regarding the role of affective factors in hypothalamic - pituitary - adrenal(HPA) axis activation. These findings are further substantiated by recent neuroanatomical and neuropharmacological research, which strongly implicates the amygdala (a limbic structure known to play a key role in the generation of affective responses) in modulating the activation of the HPA axis during stress. However, investigations of the affect - HPA axis relationship in the context of acute exercise have been scarce. In the present study, 8 well-trained male cyclists (24.0 ± 0.1 yr; VO2peak = 61.4± 0.8 ml·kg-1·min-1) underwent dehydration(≈4% reduction of body weight) and the following day exercised on a cycle ergometer at ≈74% VO2peak to exhaustion, in an ambient temperature of 37 °C (mean duration = 19 mins). Blood samples were drawn before the exercise bout and immediately upon exhaustion, concurrently with the administration of the Circumplex Affect Inventory (CAI; Ekkekakis, 1996). Changes in plasma cortisol (CORT; r = -0.816, P<0.01, 1-tailed), plasma adrenocorticotropin (ACTH; r = -0.707, P<0.05, 1-tailed), and the testosterone: CORT ratio ( r= 0.793, P<0.01, 1-tailed) were associated with shifts along the deactivated pleasant - activated unpleasant affect (DPAU) dimension of the CAI(larger concentration increases and ratio decreases were associated with more activated unpleasant affect, and vice versa). The correlation between DPAU and CORT remained after variance due to changes in rectal temperature( r2 = 0.42, part r = -0.65), plasma lactate( r2 = 0.56, part r = -0.75), heart rate( r2 = 0.58, part r = -0.76), and plasma volume( r2 = 0.58, part r = -0.76) was partialled out of CORT, but not after the variance of an aggregate of these variables was partialled out ( r2 = 0.15, part r = -0.38). These findings indicate a substantial degree of covariation between self-reported affective responses and plasma indices of HPA axis activity in the context of exhaustive exercise and are suggestive of a possible functional relationship.

Insulin and glucagon secretion by ganglionic nicotinic activation in adrenalectomized mice

The pancreatic islets are innervated by nerves emanating from intra- and extrapancreatic ganglia. However, the effects of ganglionic activation on insulin and glucagon release in vivo have not been established. We therefore investigated the effects of pharmacological ganglionic activation by the nicotinic agonists DMPP (1,1-dimethyl-4-phenylpiperazinium iodide) and nicotine on insulin and glucagon release in sham-operated and adrenalectomized mice. In sham-operated animals, DMPP (0.5 or 1.6 μmol/kg, i.v.) or nicotine (0.075 or 0.75 μmol/kg, i.v.), did not affect plasma insulin levels, but markedly increased plasma glucagon levels ( P<0.05). In contrast, after adrenalectomy or α 2-adrenoceptor blockade by yohimbine (3.6 μmol/kg), nicotinic activation markedly increased plasma insulin levels ( P<0.05), whereas the glucagon response to nicotinic activation was inhibited under these conditions ( P<0.05). We conclude that pharmacological ganglionic nicotinic activation in mice stimulates insulin and glucagon secretion. The insulinotropic effect is, however, counteracted by a concomitant adrenal activation through an α 2-adrenoceptor-mediated mechanism.

Adrenal axis activation by chronic social stress fails to inhibit gonadal function in male rats.

Stress in males via the hypothalamic-pituitary-adrenal (HPA) axis may set into motion varied physiological alterations, including dysfunction of the hypothalamic-pituitary-gonadal (HPG) axis. However, the influence of the HPA on the HPG axis may not always be inhibitory. Presence or absence of stimuli of sexual significance that typically activates the HPG axis may alter the influence of the adrenal axis on gonadal axes. In this project, we used male rats and chronic social stimulation that included brief or extended periods with female rats to examine HPA-HPG axes interactions. In experiment 1, we used intact males and a 'chronic social stress' paradigm developed in our previous research that induces social instability by daily changing the membership of group-housed males with females. Thymus weight was reduced and corticosterone levels were marginally increased by chronic social stress, indicating a HPA axis hyperactivity. The HPG axis was also activated as shown by the increased weight of the androgen-sensitive sex structures. These results indicate that when these two axes are stimulated together, neither interferes with nor suppresses activities of the other. Implants of corticosterone pellets to adrenalectomized animals that maintained constant, high corticosterone levels failed to reverse the gonadal hyperactivity induced by sexual stimulation. In a second experiment, we studied the influence of different intensity of sexual stimulations on HPA-HPG axes interactions. Increased corticosterone levels and adrenal weight, indicating a HPA hyperactivity, failed to inhibit HPG hyperactivity as measured by the increased sexual organs weight, whatever the sexual intensity of the stimulation. This work demonstrates that the gonadal axis is freed from suppression when sexual stimulation occurs together with stress. The general conclusion is that the nature of complex social settings is important in determining interactions between the two neuroendocrine axes.

Consequences of Surprising Reward Omissions

A surprising reward omission (SRO) occurs when an appetitive reinforcer is not presented (or it is reduced in magnitude or quality) even though there are signals for its impending presentation. Evidence supporting the hypothesis that SROs produce an aversive emotional reaction with physiological and behavioral consequences is reviewed. SROs are followed by pituitary–adrenal activation; changes in immune function; odor emissions in rodents; distress vocalizations in rodents and primates; and increases in locomotion, aggressive behavior, drinking, and eating. SROs can support the acquisition of new escape responses and invigorate previously acquired responses. The review identifies common aspects of these phenomena and areas in which more research is needed.

Effect of alpha-helical-CRF[9-41] on feeding in goldfish: involvement of cortisol and catecholamines.

The anoretic effect of corticotropin-releasing factor (CRF) was not dependent on adrenal activation in goldfish (Carassius auratus). Moreover, an interaction between CRF and the hypothalamic catecholaminergic system in the central regulation of food intake was observed. The intracerebroventricular (icv) administration of CRF increased cortisol levels and reduced food intake and hypothalamic norepinephrine and dopamine content at 2 hr postinjection, with these effects reversed by alpha-helical CRF[9-41] pretreatment. The anoretic effect of CRF was independent of the circulating cortisol increase, because it was only evoked after icv injections but not after intraperitoneal (ip) administration. Furthermore, the increase in plasma cortisol levels induced by ip administration of this steroid did not modify feeding.

Characterization of the mouse DAX-1 gene reveals evolutionary conservation of a unique amino-terminal motif and widespread expression in mouse tissue.

The human genetic disorder adrenal hypoplasia congenita with hypogonadotropic hypogonadism results from mutations in the recently isolated DAX-1 gene, a member of the nuclear hormone receptor superfamily. To study the role of DAX-1 in adrenal development and activation of the hypothalamic pituitary-gonadal axis, animal model systems will be essential. Here, we report the isolation and characterization of the mouse DAX-1 gene and its tissue-specific pattern of expression. The mouse DAX-1 gene codes for a 472-amino acid protein, with 75% overall nucleotide sequence homology to its human homolog. The 3.5 amino-terminal repeats of a unique motif with probable DNA-binding activity have been conserved between mouse and human, although highest conservation in the DAX-1 peptide exists in the carboxy-terminal ligand-binding domain. The DAX-1 gene remains X-linked in the mouse, consistent with its potential role in sex determination. We have developed a sensitive reverse transcription-PCR assay that detects DAX-1 messenger RNA in the central nervous system, pituitary, lung, heart, spleen, kidney, and thymus in addition to the adrenal and testis DAX-1 expression noted for the human DAX-1 gene. Future studies using mouse models of altered DAX-1 expression will be critical in defining the role of this factor in tissue- and development-specific gene regulation.

Natural and cellular immune responses in flinders sensitive and resistant line rats

Major depression is associated with impairments in natural and cellular immune responses. This study characterized baseline natural and cellular immune function in the Flinders Sensitive Line (FSL) genetic animal model of depression and in Flinders Resistant Line (FRL) controls. Splenic natural cytotoxicity per natural killer (NK) cell was significantly lower in the FSL rats, suggesting that NK cells are less activated at rest in the FSL rats than in the FRL controls. Neither lymphocyte proliferative responses nor interleukin-2 production differed between the two strains. Resting baseline concentrations of plasma adrenocorticotropic hormone and corticosterone were similar between the FSL and FRL rats, indicating that hypothalamo-pituitary adrenal axis activation did not mediate immunological differences. FSL rats show abnormalities in natural immunity similar to those found in clinically depressed human beings, indicating that this animal model may be useful in understanding the neural and neuroendocrine mechanisms associated with immune alterations in depression.

Characterization of the mouse DAX-1 gene reveals evolutionary conservation of a unique amino-terminal motif and widespread expression in mouse tissue

The human genetic disorder adrenal hypoplasia congenita with hypogonadotropic hypogonadism results from mutations in the recently isolated DAX-1 gene, a member of the nuclear hormone receptor superfamily. To study the role of DAX-1 in adrenal development and activation of the hypothalamic pituitary-gonadal axis, animal model systems will be essential. Here, we report the isolation and characterization of the mouse DAX-1 gene and its tissue-specific pattern of expression. The mouse DAX-1 gene codes for a 472-amino acid protein, with 75% overall nucleotide sequence homology to its human homolog. The 3.5 amino-terminal repeats of a unique motif with probable DNA-binding activity have been conserved between mouse and human, although highest conservation in the DAX-1 peptide exists in the carboxy-terminal ligand-binding domain. The DAX-1 gene remains X-linked in the mouse, consistent with its potential role in sex determination. We have developed a sensitive reverse transcription-PCR assay that detects DAX-1 messenger RNA in the central nervous system, pituitary, lung, heart, spleen, kidney, and thymus in addition to the adrenal and testis DAX-1 expression noted for the human DAX-1 gene. Future studies using mouse models of altered DAX-1 expression will be critical in defining the role of this factor in tissue- and development-specific gene regulation.

Effects of Fetal Alcohol Exposure on Fever, Sickness Behavior, and Pituitary–Adrenal Activation Induced by Interleukin-1β in Young Adult Rats

Exposure to alcoholin uterocan lead to long-lasting impairments of immune functions and to decreased resistance to infectious agents. We have previously reported that fetal alcohol-exposed rats show markedly decreased lipopolysaccharide-induced fever and suggested that fetal alcohol exposure (FAE) impairs the communication between the immune and the nervous systems. The present study examined the effects of interleukin-1β (IL-1) on body temperature, motor activity, ingestive behavior, and pituitary–adrenal activation in fetal alcohol-exposed and control rats. Transmitters for continuous biotelemetric recording of body temperature and motor activity were implanted ip in normal (N) adult rats, offspring of dams fed a liquid diet supplemented with ethanol (E), and pair-fed control offspring (P). In one experiment, rats were injected with either IL-1 (2 μg/kg, ip) or saline at the beginning of the light period. IL-1 produced a marked increase in body temperature, which was significantly lower in E rats than in N and P rats. In a second experiment, rats were administered either IL-1 (10 μg/kg, ip) or saline at the beginning of the dark period. IL-1 produced an initial transient hypothermia followed by a longer-lasting hyperthermia. During the hyperthermic phase, fever in the E rats was lower than in the P rats, but comparable to fever in the N rats. IL-1 significantly reduced motor activity, during both the hypothermic and hyperthermic phases. This effect was similar in all prenatal treatment groups. IL-1 also suppressed 24-h food consumption in N and P rats and water consumption in P rats, but it did not produce significant anorexia and adypsia in E rats. A third experiment demonstrated that IL-1 (2 μg/kg, ip) significantly increased ACTH and corticosterone release in all prenatal treatment groups. IL-1-induced corticosterone secretion was attenuated in P offspring, compared to both E and N rats. Together, these findings indicate that exposure to ethanolin uteroproduces impairments in mechanisms that mediate the effects of IL-1 on body temperature (particularly during the light period) and ingestive behavior, but not on motor activity and pituitary–adrenal activation. In view of the adaptive role of IL-1-induced fever and anorexia, these impairments may contribute to the decreased resistance to infections observed in animals and humans following FAE.

Regulation of neuronal birth, migration and death in the rat dentate gyrus.

The granule cell population of the rat dentate gyrus forms over an extended period which begins during gestation and continues into adulthood. During the embryonic period, the postnatal period and in adulthood, granule cells proliferate, migrate and degenerate. We have found that granule cell production is dependent on the levels of circulating adrenal steroids and NMDA receptor-mediated excitatory input throughout life. In general, increases in adrenal steroid levels or NMDA receptor activation diminish the rate of cell proliferation whereas decreases in adrenal steroid levels or NMDA receptor activation increase the rate of cell production. This paper describes the regulation of granule cell proliferation, migration and survival by adrenal steroids and excitatory input and presents evidence that these factors may affect dentate gyrus-mediated behaviors.

Significance of adrenal corticosteroid secretion for the food restriction-induced enhancement of alcohol drinking in the rat

Male Wistar rats with continuous access to 6% ethanol solution and water in their home cages were subjected to food restriction (FR). Reduction of body weight to 80% of normal was associated with a significant increase in ethanol drinking. It is known that the stress of FR gives rise to increased corticosterone secretion, and in line with these findings it was found that the weight of the thymus (whose size is inversely related to corticosterone levels) was reduced to 55% of normal in the present FR rats. Two subsequent experiments indicated that this adrenal activation contributed to the FR-induced enhancement of alcohol drinking. Firstly, adrenalectomized rats showed no evidence of enhanced alcohol drinking during food restriction, suggesting that adrenal corticosterone hypersecretion contributes to the enhanced ethanol consumption during FR. Secondly, treatment of FR rats with the enzyme inhibitor cyanoketone, which blocks stress-induced but not basal corticosterone secretion, at least partly prevented the FR-induced increase in ethanol drinking. These results add further evidence that sustained exposure to corticosterone facilitates ethanol consumption in the rat.

Acute infusions of cocaine result in time- and dose-dependent effects on lymphocyte responses and corticosterone secretion in rats

In the present study, we investigated the effect of intravenously (i.v.) administered cocaine on mitogen-induced lymphocyte proliferation and NK cytolytic activity in rats implanted with indwelling jugular cannula. To assess whether the effects of cocaine were accompanied by adrenal gland activation, plasma corticosterone concentrations were also determined. It was found that the i.v. infusion of cocaine resulted in both a time- and dose-dependent decrease in both blood and splenic Con-A-stimulated lymphocyte proliferative responses. Within 60 minutes, blood responses were maximally inhibited by more than 60% with 5 mg/kg cocaine. By 4 h, the suppression of blood lymphocyte responses was no longer significant. In contrast to these findings, there were no significant effects observed with splenic lymphocyte responses until 4 h after drug administration. At this time, cocaine at doses of 5 and 10 mg/kg inhibited splenic proliferative responses by 50 and 75%, respectively. These effects appeared to be selective, since no concurrent decreases in NK cell activity were observed with 5 mg/kg at either 2 or 4 h. Within 30 min, plasma corticosterone concentrations were maximally increased by 10-fold with 5 and 10 mg/kg doses of cocaine. At lower doses of cocaine (1 mg/kg), neither changes in lymphocyte proliferative responses, NK cytolytic activity nor plasma corticosterone levels were apparent. This study demonstrates that a single i.v. infusion of cocaine results in a selective dose- and time-dependent immunosuppression which is preceded by transient increases in circulating levels of corticosterone.