Central nitric oxide regulation of the hypothalamic-pituitary-adrenocortical axis in adult male rats

The presence of nitric oxide (NO) synthase (NOS) in hypothalamic structures which control the activity of the pituitary-adrenocortical axis suggests that NO might be involved in the central regulation of ACTH secretion. We have studied the involvement of NO in the activity of the hypopothalamic-pituitary-adrenocortical (HPA) axis in intact and adrenalectomized rats. The acute effects (4 h) of two NOS inhibitors (HP-228 and NMMA), injected into the left lateral cerebral ventricle of freely moving male rats, on hypothalamic CRH and pituitary proopiomelacortin (POMC) mRNA levels as well as ACTH plasma levels were evaluated. In intact rats, HP-228, but not NMMA, induced an increase in CRH mRNA levels, while in adrenalectomized animals, both NOS inhibitors were effective in increasing CRH mRNA. In intact and adrenalectomized rats, both NOS inhibitors induced an increase in anterior pituitary POMC mRNA levels. Plasma ACTH levels were significantly elevated from 30 min to 2 h following the administration of either HP-228 or NMMA. In adrenalectomized animals, both NOS inhibitors produced a much striking increase of plasma ACTH levels which were still significantly increased at the longest time-interval studied. These results suggest that the central NO system exerts a tonic negative influence on the activity of the HPA axis in the presence or absence of circulating glucocorticoids.     

Effect of hypothalamic norepinephrine depletion on median eminence CRF-41 content and serum ACTH in control and adrenalectomized rats.

In this study we examined the role of the noradrenergic innervation of the hypothalamus on the adrenalectomy-induced changes in median eminence (ME) CRF-41 and serum ACTH. 6-Hydroxydopamine (6-OHDA), the catecholaminergic neurotoxin, or vehicle was injected into the ventral noradrenergic bundle of male rats. One week later animals underwent adrenalectomy or sham operation and were sacrificed 18 or 120 h later. In sham-operated rats 6-OHDA did not affect ME CRF-41 content or serum ACTH. In vehicle-injected adrenalectomized rats ACTH was increased approximately 3-fold at 18 h and almost 6-fold at 120 h. At 18 h CRF-41 content was markedly depleted (reduced approximately 20-fold) but by 120 h CRF-41 content had partially recovered and was about 70% of control animals. In adrenalectomized animals, 6-OHDA lesions caused a complete inhibition of the increase in serum ACTH both at 18 h and at 120 h. Pretreatment with 6-OHDA partially attenuated the drastic reduction in ME CRF-41 content following adrenalectomy at 18 h. However, at 120 h, the neurotoxin prevented the recovery of CRF-41 following adrenalectomy. These results suggest that intact norepinephrine innervation to the hypothalamus is necessary for the increased production of ACTH following adrenalectomy and that its interruption interferes with both the adrenalectomy-induced ME CRF-41 reduction and subsequent recovery.     

The suprachiasmatic nuclei stimulate evening ACTH secretion in the rat

The effect of bilateral lesions of the suprachiasmatic nuclei (SCN) on the circadian rhythm in ACTH was studied in rats that were adrenalectomized and implanted with a subcutaneous corticosterone (B) pellet. Rats wee chronically cannulated to allow for repeated blood sampling. In rats with B pellets, bilateral lesions of the SCN eliminated the circadian rise in plasma ACTH seen in sham-lesioned animals. This is consistent with the idea that the SCN stimulate ACTH secretion in the evening.     

A temporal study of post-adrenalectomy increase in ACTH secretion in the rat: effect of various hypothalamic deafferentations

Adult male rats, intact (N) or with complete (CHD), anterior (AHD), or posterior (PHD) hypothalamic deafferentations were bilaterally adrenalectomized. At 3, 6, 12 and 20 days post-adrenalectomy they were decapitated and trunk blood was collected for ACTH determinations. In N rats, ACTH markedly elevated up to 850 pg/ml. A similar ACTH response was found in PHD rats but the values were lower by approximately 20%. In contrast, in either AHD or CHD rats, ACTH responses were markedly attenuated and reached a plateau of about 350 pg/ml. These data suggest that: (1) neural inputs entering the medio-basal hypothalamus (MBH) from both the caudal and rostral directions are important for obtaining maximal ACTH responses following adrenalectomy; (2) at least part of this ACTH response is mediated by sites inside the MBH or in the pituitary.     

Effect of Corticosterone and Adrenalectomy on NMDA-Induced Cholinergic Cell Death in Rat Magnocellular Nucleus Basalis

The present study demonstrates the effects of adrenalectomy and subcutaneously administered corticosterone on N-methyl-d-aspartate-induced neurodegeneration in the cholinergic magnocellular basal nucleus of the rat. NMDA was unilaterally injected into the nucleus basalis at different plasma corticosterone concentrations in adrenalectomized rats, in adrenalectomized animals with subcutaneously implanted cholesterol-corticosterone pellets containing 25% or 100% corticosterone, and in sham-adrenalectomized controls. The neurotoxic impact of the NMDA injection in the various experimental groups was assessed by the loss of cholinergic fibers stained with acetylcholinesterase histochemistry in the parietal neocortex. Reactive cortical astrocytes as a result of the treatments were detected by glial fibrillary acidic protein immunohistochemistry. Measurements of the densities of astrocytes and cholinergic fibers at the injected side of the brain were carried out by image analysis.     

Receptor specificity of a glucocorticoid- and stress-induced hippocampal protein

Following treatment of rats with a subcutaneous injection of 5 mg of corticosterone, hippocampal slices in vitro show increased labeling from 35S-methionine of a protein with an apparent molecular weight (Mr) of 35,000. Increased protein labeling is seen in response to corticosterone, dexamethasone, and aldosterone, steroids that associate with glucocorticoid receptors. Little or no response occurs after administration of progesterone or estradiol. Because the injected dose of steroids is high and responses to an injection of this magnitude may be pharmacological, several experiments have been done to determine whether stimuli that increase endogenous levels of corticosterone have the same effect on labeling of the 35,000 Mr protein. One hour after various stresses (immobilization, cold, ether, and sham-injection), when plasma levels of corticosterone are elevated, labeling of the 35,000 Mr protein is increased. Injection of ACTH also stimulates the synthesis of this protein in intact animals in a manner analogous to that seen with corticosterone injections. In addition, a dose-response curve for corticosterone with adrenalectomized rats shows that synthesis of the protein is maximally increased when the injected dosage causes serum levels of corticosterone to increase to the levels seen during stress. The increase in labeling of the 35,000 Mr protein in adrenalectomized animals is only half as great as that observed in intact animals. Injections of the type II glucocorticoid (GR) receptor agonist, RU 28362, into adrenalectomized rats differentially stimulates the synthesis of the 35,000 Mr protein compared with the mineralocorticoid aldosterone, which has a higher affinity for the type I (CR) receptor.(ABSTRACT TRUNCATED AT 250 WORDS)     

Corticotropin-Releasing Factor But Not Urocortin Is Involved in Adrenalectomy-Induced Adrenocorticotropin Release

Urocortin, a new corticotropin-releasing factor (CRF)-related peptide, has been reported to have the ability to bind to CRF receptors and to stimulate adrenocorticotropin (ACTH) secretion from the rat anterior pituitary in vivo and in vitro . In this study, we examined the effect of intravenous administration of urocortin-antiserum to investigate the role of endogenous urocortin on ACTH secretion from rat anterior pituitary after adrenalectomy. Male Sprague-Dawley rats, which were maintained in a conscious and undisturbed condition, were administered non-immunized rabbit serum (NRS), CRF-antiserum or urocortin-antiserum at a volume of 1  ml/kg b.w. 15  min before the injection of secretagogues. Synthetic rat urocortin (2  μg/kg B.W.) increased plasma ACTH concentrations by about sixfold the basal concentration. The pretreatment with urocortin-antiserum but not CRF-antiserum abolished the urocortin-induced increase in plasma ACTH concentrations. In adrenalectomized rats, plasma ACTH concentrations were markedly increased at basal conditions, and rapidly reduced after the administration of CRF-antiserum. By contrast, administration of urocortin-antiserum did not alter ACTH secretion induced by adrenalectomy. Our results suggest that endogenous urocortin is unlikely to be involved in ACTH release in adrenalectomized rats.     

Neuroendocrine and metabolic responses induced by interleukin-1

We have previously demonstrated that Interleukin-1 (IL-1), a cytokine mainly produced by activated monocytes, stimulates the pituitary-adrenal axis and affects glucose homeostasis. Comparative studies revealed that a beta form of recombinant human IL-1, similar to the mature peptide secreted naturally, is more powerful than other preparations of this monokine in stimulating adrenocorticotrophic hormone (ACTH) and corticosterone output. Another monokine, tumor necrosis factor (TNF), does not share with IL-1 the capacity to induce such effects. In extending our studies to rats, we showed that increased ACTH and blood corticosterone levels are also induced by IL-1 in this species. Another in vivo activity of IL-1 relates to its capacity to induce a reduction in blood glucose levels. Our studies strongly suggest that, as opposed to other effects elicited by IL-1, blockade of prostaglandin synthesis does not affect the capacity of IL-1 to stimulate insulin output and produce hypoglycemia. Administration of IL-1 to adrenalectomized mice, which are defective in counterregulatory mechanisms of glucose homeostasis, resulted in marked hypoglycemia. In contrast to the response observed in normal mice, in adrenalectomized animals this effect was paralleled by decreased blood insulin levels. IL-1 was also injected into alloxan-diabetic mice. A marked reduction in blood glucose levels occurred in these animals. This effect was already noticeable 1 hr after injection. After 2 hr and for at least another 6 hr, glucose levels of alloxan-treated mice injected with IL-1 remained within the normal range.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of adrenalectomy and corticosterone replacement on the hypothalamic-pituitary response to neural stimuli

In this study we examined whether circulating glucocorticoids (GC) have a permissive facilitatory role in the hypothalamo-pituitary-adrenal (HPA) axis responses to neural or metabolic stimuli. In control sham operated rats the exposure to photic or acoustic neural stimuli and to either cytoglucopenia induced by 2-deoxyglucose (2-DG) or to hypoglycemia induced by insulin caused a significant 5-fold increase in serum ACTH as compared to basal non-stress levels. In adrenalectomized (Adex) rats tested under basal conditions at 4, 7 and 14 days post-Adex, serum ACTH gradually increased in a time-dependent manner, Also, at 4 days post-Adex the median eminence (ME) content of CRH-41 was markedly depleted but gradually recovered to control levels at 7 and 14 days post-Adex. The serum ACTH responses to both photic and acoustic stimuli tested at the same time points were completely inhibited. In contrast, administration of either insulin or 2-DG caused a marked increase in serum ACTH levels. In Adex rats, implanted with low corticosterone (CS) pellets which produced basal serum levels of CS, ME CRH-41 levels and serum ACTH were similar to control sham operated animals. Exposure to both neural stimuli resulted in a significant depletion in CRH-41 ME content and in a rise in serum ACTH as in the respective controls. On the other hand in rats implanted with high CS pellets which produced stress typical CS serum levels, the ME CRH-41 and serum ACTH responses to both stimuli were markedly inhibited. These results suggest that (1) the HPA axis responses to neural stimuli but not to metabolic stimuli require the presence of circulating GC (2), the lack of ACTH response to neural stimuli in Adex rats may not be related to the low CRH-41 ME content.     

Effects of adrenalectomy and corticosterone replacement on the hypothalamic–pituitary response to neural stimuli

In this study we examined whether circulating glucocorticoids (GC) have a permissive facilitatory role in the hypothalamo–pituitary–adrenal (HPA) axis responses to neural or metabolic stimuli. In control sham operated rats the exposure to photic or acoustic neural stimuli and to either cytoglucopenia induced by 2-deoxyglucose (2-DG) or to hypoglycemia induced by insulin caused a significant 5-fold increase in serum ACTH as compared to basal non-stress levels. In adrenalectomized (Adex) rats tested under basal conditions at 4, 7 and 14 days post-Adex, serum ACTH gradually increased in a time-dependent manner, Also, at 4 days post-Adex the median eminence (ME) content of CRH-41 was markedly depleted but gradually recovered to control levels at 7 and 14 days post-Adex. The serum ACTH responses to both photic and acoustic stimuli tested at the same time points were completely inhibited. In contrast, administration of either insulin or 2-DG caused a marked increase in serum ACTH levels. In Adex rats, implanted with low corticosterone (CS) pellets which produced basal serum levels of CS, ME CRH-41 levels and serum ACTH were similar to control sham operated animals. Exposure to both neural stimuli resulted in a significant depletion in CRH-41 ME content and in a rise in serum ACTH as in the respective controls. On the other hand in rats implanted with high CS pellets which produced stress typical CS serum levels, the ME CRH-41 and serum ACTH responses to both stimuli were markedly inhibited. These results suggest that (1) the HPA axis responses to neural stimuli but not to metabolic stimuli require the presence of circulating GC (2), the lack of ACTH response to neural stimuli in Adex rats may not be related to the low CRH-41 ME content.     

Blockade of the anxiolytic-like action of ipsapirone and buspirone, but not that of 8-OH-DPAT, by adrenalectomy in male rats.

The effect of the 5-HT1A agonists ipsapirone (5 mg/kg), buspirone (5 mg/kg) and 8-OH-DPAT (0.5 mg/kg) on experimental anxiety was examined in sham-operated, adrenalectomized and adrenally demedullated male rats. The animal model of anxiety used was the defensive burying test. At the doses selected, all 5-HT1A compounds produced an anxiolytic-like action by reducing the burying behavior in both sham-operated and demedullated rats. However, in adrenalectomized subjects, while 8-OH-DPAT still reduced burying behavior, ipsapirone and buspirone lost their action. Data suggest that adrenocortical secretions play a role in the anxiolytic-like actions of buspirone and ipsapirone, but not in those of 8-OH-DPAT. Buspirone and ipsapirone also produced a reduction in burying behavior latency in sham-operated animals that was not observed in adrenalectomized or adrenally demedullated rats. These data suggest that adrenaline may be participating in the action of these compounds on the burying behavior latency. Present findings support possible direct relationships between the stimulation of 5-HT1A receptors and adrenal secretions.     

Behavioral sensitization to amphetamine is dependent on corticosteroid receptor activation

Thirty rats received 3 amphetamine injections (1.5 mg/kg, s.c.) 6 days apart and the locomotor response was measured. One day before the second injection they were adrenalectomized or sham operated. Corticosteroid replacement treatments (500 μg/kg, s.c.) were given every evening. Sham adrenalectomized animals exhibited behavioral sensitization to successive injections of amphetamine, which was prevented by adrenalectomy. Treatment with corticosterone or deoxycorticosterone did not reverse the effect of adrenalectomy, whereas dexamethasone completely restored and even potentiated sensitization to amphetamine. These results demonstrate that corticosteroids are necessary for sensitization of the dopaminergic system to occur and that they most probably act through the type II (or glucocorticoid) receptor subtype.     

Dopamine-β-Hydroxylase Activity is Necessary for Hypothalamo-Pituitary-Adrenal (HPA) Responses to Ether, and Stress-Induced Facilitation of Subsequent HPA Responses to Acute Ether Emerges as HPA Responses are Inhibited by Increasing Corticosterone (B)

To determine a role of norepinephrine (NE) in stress-induced HPA function, young male rats were treated with diethyldithiocarbamide (DDC) which inhibits dopamine-β-hydroxylase, the enzyme that synthesizes NE from dopamine (DA). DDC injected 5 h prior to ether stress stimulated ACTH and corticosterone (B) during this time, and there was no further HPA response to ether. To control for elevated B feedback in DDC effects on HPA responses to ether, rats were adrenalectomized (Adx) and replaced with no (0% B), moderate (40% B) and high (80% B) levels of steroid 5 d prior to DDC or saline with ether stress 5 h later; Sham-Adx rats were included. In Adx rats increasing B inhibited thymus weight, median eminence CRF content, pituitary and plasma ACTH. In saline-treated rats, ether 5 h later caused increased CRF content and plasma ACTH in Sham-Adx and Adx, 0%B, increased ACTH in Adx, 40%B, and no response in Adx, 80% B. B treatment did not alter catecholamine content, and DDC treatment reduced NE content in the paraventricular nuclei by 50–60% in all groups. 5 h after DDC, pituitary ACTH was decreased in all rats with B and plasma ACTH was increased in sham-Adx and Adx, 40%B; thus DDC caused significant, prolonged stress which should facilitate subsequent HPA responses to acute stress. There was no HPA response to ether in Sham-Adx, Adx, 0% or 40% B groups, but there was a marked ACTH response to ether in the Adx, 80%B group treated with DDC. We conclude that: 1) the HPA response to ether stress is probably mediated by catecholamines; 2) DDC does not stimulate responses in the HPA axis in the absence of B; and, 3) facilitation of HPA responses to acute stress depends on increased steady-state B signals. Facilitated responses are probably not mediated by catecholamines. The consequence of facilitation is that under conditions of chronic stress and elevated B concentrations, as in depression or anorexia nervosa in man, or adjuvent-induced arthritis in rats, the HPA axis is continually responsive to new stimuli.     

Supersensitive endocrine response to physostigmine in dopamine-depleted rats: a model of depression?

Depressed patients exhibit an abnormal "supersensitive" increase in the plasma concentration of several pituitary hormones following intravenous injection of the acetyl cholinesterase inhibitor physostigmine (PHY). In the present study, we examined the effects of PHY treatments on the plasma concentrations of prolactin (PRL) and adrenocorticotrophic hormone (ACTH) in the rat. Physostigmine (0-0.6 mg/kg, s.c.) produced a dose-dependent increase in PRL and ACTH immunoreactivity in unoperated animals. Neurotoxin-induced depletion of brain dopamine (DA) or norepinephrine (NE) did not significantly alter baseline plasma PRL or ACTH values. Following depletion of brain DA, but not NE, animals exhibited a "supersensitive" increase in plasma ACTH values, which was evidenced by a sixfold left shift in the dose-response properties of PHY. These results suggest that there are intriguing parallels between the abnormal endocrine response to PHY demonstrated by depressed patients and that demonstrated by rats following depletion of central nervous system (CNS) DA levels.     

Effect of adrenalectomy and dexamethasone treatment on prolactin secretion of lactating rats

The contribution of corticosteroids to the control of prolactin secretion in lactating rats was investigated. The prolactin response to domperidone (20 microg/kg b.w., i.v.), a dopamine receptor antagonist and to domperidone plus formalin stress was tested in adrenalectomized and/or dexamethasone-treated continuously nursing rats. Animals were adrenalectomized on the 3rd day of lactation and tested on the 7th day of lactation. Dexamethasone was injected s.c. 24 h before testing (400 microg/kg b.w.) and on the day of testing (200 microg/kg b.w.). Domperidone caused a significant rise in plasma prolactin levels. The prolactin response to domperidone was twice as high in solely adrenalectomized dams and in solely dexamethasone-treated rats compared to controls. In adrenalectomized animals treated with dexamethasone, the prolactin response to domperidone was like in controls. Formalin injection to either adrenalectomized plus domperidone-treated animals or to animals injected with dexamethasone plus domperidone, resulted in a statistically significant depletion of plasma prolactin. In controls and in adrenalectomized animals receiving dexamethasone and domperidone, the prolactin response to formalin was very similar, i.e., plasma prolactin levels did not change after the administration of formalin. The present findings suggest that in lactating rats, corticosteroids are involved in the prolactin response to domperidone and to formalin stress.     

Marked dissociation between hypothalamic-pituitary-adrenal activation and long-term behavioral effects in rats exposed to immobilization or cat odor

Exposure of rodents to cats or certain cat odors results in long-term behavioral effects reminiscent of enhanced anxiety that have been considered to model post-traumatic stress disorder. However, other severe stressors such as tail-shock or immobilization in wooden boards (IMO) appear to induce shorter lasting changes in anxiety. In addition, there are controversial results regarding the effects of urine/feces odors. In the present work, we studied in two experiments the relationship between the degree of stress experienced by the animals during exposure to IMO, urine odors or fur odors (as assessed by hypothalamic-pituitary-adrenal activation and plasma glucose) and the short- and long-term behavioral consequences. In the first experiment, rats were individually exposed for 15min to a novel environment (white large cages) containing either clean cat litter (controls) or litter soiled by cats (urine odors). Half of the rats in each condition were left to freely explore the environment whereas the others were subjected to immobilization (IMO) within the cages. Although ACTH, corticosterone and glucose responses to IMO were much stronger than those to the white cages with clean litter or urine odors (which did not differ from each other), no effect of treatments on anxiety-like behavior in the elevated plus-maze (EPM) were found one week later. However, previous IMO exposure did cause sensitization of the ACTH response to the EPM. In the second experiment, the response to white large cages containing either no odor (controls), litter soiled by cats (urine odor) or a cloth impregnated with cat odor (fur odor) was compared. Urine and fur odors elicited similar ACTH and corticosterone responses that were higher than those of controls, but plasma glucose levels were slightly higher in rats exposed to fur odor. When compared to controls, activity was only diminished in the novel cages containing fur odor. Similarly, fur odor-exposed rats, but not those exposed to urine odor, showed signs of enhanced anxiety in the EPM seven days later, although the ACTH response to the EPM was similar in the three groups. The present data demonstrate: (a) a marked dissociation between the degree of ACTH, corticosterone and glucose responses to stressors and their long-term anxiety-like effects; (b) that the type of cat odor is critical in determining the short-term and long-term physiological and behavioral consequences of exposure; and (c) that plasma ACTH released during brief exposure to the EPM does not appear to reflect anxiety-like behavior.     

The influence of capsaicin sensitive neurons on stress-induced release of ACTH

Changes in the plasma levels of ACTH in response to cold exposure or restraint stress were measured in adult rats which had been pretreated with capsaicin or vehicle as neonates. There was no difference in basal ACTH levels between capsaicin and vehicle pretreated animals. Following restraint stress, ACTH levels rose similarly in vehicle and capsaicin pretreated rats, indicating that the pituitary-adrenal system is not impaired by capsaicin pretreatment. However, following cold exposure ACTH levels rose only in control animals whereas no change was observed in capsaicin pretreated animals. It is concluded that capsaicin-sensitive afferent neurons participate in the cold stress-induced increase of plasma ACTH levels.     

Chromaffin cell function and structure is impaired in corticotropin-releasing hormone receptor type 1-null mice

Corticotropin-releasing hormone (CRH) is both a main regulator of the hypothalamic-pituitary-adrenocortical axis and the autonomic nervous system. CRH receptor type 1 (CRHR1)-deficient mice demonstrate alterations in behavior, impaired stress responses with adrenocortical insufficiency and aberrant neuroendocrine development, but the adrenal medulla has not been analyzed in these animals. Therefore we studied the production of adrenal catecholamines, expression of the enzyme responsible for catecholamine biosynthesis neuropeptides and the ultrastructure of chromaffin cells in CRHR1 null mice. In addition we examined whether treatment of CRHR1 null mice with adrenocorticotropic hormone (ACTH) could restore function of the adrenal medulla. CRHR1 null mice received saline or ACTH, and wild-type or heterozygous mice injected with saline served as controls. Adrenal epinephrine levels in saline-treated CRHR1 null mice were 44% those of controls (P<0.001), and the phenylethanolamine N-methyltransferase (PNMT) mRNA levels in CRHR1 null mice were only 25% of controls (P <0.001). ACTH treatment increased epinephrine and PNMT mRNA level in CRHR1 null mice but failed to restore them to normal levels. Proenkephalin mRNA in both saline- and ACTH-treated CRHR1 null mice were higher than in control animals (215.8% P <0.05, 268.9% P <0.01) whereas expression of neuropeptide Y and chromogranin B did not differ. On the ultrastructural level, chromaffin cells in saline-treated CRHR1 null mice exhibited a marked depletion in epinephrine-storing secretory granules that was not completely normalized by ACTH-treatment. In conclusion, CRHR1 is required for a normal chromaffin cell structure and function and deletion of this gene is associated with a significant impairment of epinephrine biosynthesis.     

Modification of malathion induced neurochemical changes by adrenalectomy in rats

The neurochemical changes induced by malathion, an organophosphate compound, were determined in rats. Maximal changes were found in the brain 2 h after the administration of malathion in a dose of 500 mg/kg ip. The activities of cholinesterase and succinic dehydrogenase were reduced whereas those of glycogen phosphorylase, phosphoglucomutase, and hexokinase were increased; the lactate content of brain was also increased. In malathion treated adrenalectomized animals, changes in the activities of cerebral cholinesterase and succinic dehydrogenase were still present; other changes were, however, abolished by adrenalectomy. Activities of certain enzymes, glucose-6-phosphatase, glucose-6-phosphate dehydrogenase, and lactate dehydrogenase were not significantly altered by malathion in normal or adrenalectomized animals. The results indicate that cerebral cholinergic mechanism in malathion treated animals was not modified by adrenalectomy which, however, abolished or reduced changes in the activities of certain glycolytic and glycogenolytic enzymes that are involved in the utilization or metabolism of glucose. The brain lactate content in malathion treated adrenalectomized animals was, also, not significantly different from the control values, suggesting the modification of induced changes by adrenalectomy.