Defective ACTH response to stress in previously stressed rats: dependence on glucocorticoid status. (25/2102)

The effect of previous exposure to stress on the pituitary-adrenal response to a further stress was characterized in rats with different glucocorticoid status: sham-operated rats (Sham), adrenalectomized (ADX) rats, and ADX rats supplemented with a low corticosterone (B) dose in the drinking saline (ADX + B). Previous exposure of Sham rats to 1 h of immobilization (Imo) reduced, 2 h later, the ACTH response to a second severe stressor (Imo) but not to a less severe stressor (tail shock). In ADX rats, previous Imo totally suppressed the ACTH response to Imo or to shock. In ADX + B rats the response to shock was blocked and that to Imo tended to be lower. These changes were not explained by depletion of adenohypophysial ACTH stores. After previous Imo, reduced response to corticotropin-releasing factor was observed in Sham and ADX + B, but not in ADX, rats. Taken together, the present results suggest that the reduced ACTH response of previously stressed rats to a second severe stress is observed in the presence and absence of glucocorticoids, but the main site at which such inhibition occurs might be critically dependent on the glucocorticoid status.  (+info)

A comparison of brain angiotensin II receptors during lactation and diestrus of the estrous cycle in the rat. (26/2102)

During lactation there are many dramatic alterations in the hypothalamic-pituitary (HP) axis, as well as an increased demand for food and water. The renin-angiotensin system (RAS) is one of the major mediators of the HP axis. This study examined the receptors for ANG II in the rat brain during lactation and diestrus. Compared with diestrus, lactating rats had significant decreases in ANG II receptor binding in several forebrain regions, most notably in the arcuate nucleus/median eminence, dorsomedial hypothalamic nucleus (DMH), and lateral hypothalamic area (LHA). In contrast, there was an increase in ANG II receptor binding in the preoptic area during lactation. These significant changes in ANG II binding in the brain during lactation support the hypothesis that changes in the RAS may contribute to the dramatic changes in the HP axis during lactation. In addition, the significant reduction in ANG II binding in the DMH and LHA may be indicative of a role in the regulation of food intake, a function only recently associated with the RAS.  (+info)

Altered anxiety and weight gain in corticotropin-releasing hormone-binding protein-deficient mice. (27/2102)

Corticotropin-releasing hormone (CRH) is widely recognized as the primary mediator of the neuroendocrine and behavioral responses to stress, including stress-induced anxiety. The biological activity of CRH and other mammalian CRH-like peptides, such as urocortin, may be modulated by CRH-binding protein (CRH-BP). To assess directly the CRH-BP function, we created a mouse model of CRH-BP deficiency by gene targeting. Basal adrenocorticotropic hormone and corticosterone levels are unchanged in the CRH-BP-deficient mice, and the animals demonstrate a normal increase in adrenocorticotropic hormone and corticosterone after restraint stress. In contrast, adult male CRH-BP-deficient mice show significantly reduced body weight when compared with wild-type controls. CRH-BP-deficient mice also exhibit a significant increase in anxiogenic-like behavior as assessed by the elevated plus maze and defensive withdrawal tests. The increased anorectic and anxiogenic-like behavior most likely is caused by increased "free" CRH and/or urocortin levels in the brain of CRH-BP-deficient animals, suggesting an important role for CRH-BP in maintaining appropriate levels of these peptides in the central nervous system.  (+info)

Neonatal handling induces anovulatory estrous cycles in rats. (28/2102)

Since previous work has shown that stimulation early in life decreases sexual receptiveness as measured by the female lordosis quotient, we suggested that neonatal handling could affect the function of the hypothalamus-pituitary-gonadal axis. The effects of neonatal handling on the estrous cycle and ovulation were analyzed in adult rats. Two groups of animals were studied: intact (no manipulation, N = 10) and handled (N = 11). Pups were either handled daily for 1 min during the first 10 days of life or left undisturbed. At the age of 90 days, a vaginal smear was collected daily at 9:00 a.m. and analyzed for 29 days; at 9:00 a.m. on the day of estrus, animals were anesthetized with thiopental (40 mg/kg, ip), the ovaries were removed and the oviduct was dissected and squashed between 2 glass slides. The number of oocytes of both oviductal ampullae was counted under the microscope. The average numbers for each phase of the cycle (diestrus I, diestrus II, proestrus and estrus) during the period analyzed were compared between the two groups. There were no significant differences between intact and handled females during any of the phases. However, the number of handled females that showed anovulatory cycles (8 out of 11) was significantly higher than in the intact group (none out of 10). Neonatal stimulation may affect not only the hypothalamus-pituitary-adrenal axis, as previously demonstrated, but also the hypothalamus-pituitary-gonadal axis in female rats.  (+info)

Strenuous resistive breathing induces proinflammatory cytokines and stimulates the HPA axis in humans. (29/2102)

Interleukin-1beta (IL-1beta) and interleukin-6 (IL-6), powerful stimulants of the hypothalamic-pituitary-adrenal (HPA) axis, increase in response to whole body exercise. Strenuous inspiratory resistive breathing (IRB), a form of clinically relevant "exercise" for the respiratory muscles, produces beta-endorphin through a largely unknown mechanism. We investigated (in 11 healthy humans) whether strenuous IRB produces proinflammatory cytokines and beta-endorphin in parallel with stimulation of the HPA axis, assessed by concurrent measurement of ACTH. Subjects underwent either severe [at 75% of maximal inspiratory pressure (P(m) (max))] or moderate (at 35% of P(m) (max)) IRB. Plasma cytokines, beta-endorphin, and ACTH were measured at rest (point R), at the point at which the resistive load could not be sustained (point F), and at exhaustion [15 min later (point E)]. During severe IRB, IL-1beta increased from 0.83 +/- 0.12 pg/ml at point R to 1.88 +/- 0. 53 and 4.06 +/- 1.27 pg/ml at points F and E, respectively (P < 0. 01). IL-6 increased from 5.30 +/- 1.02 to 10.33 +/- 2.14 and 11.66 +/- 2.29 pg/ml at points F and E, respectively (P = 0.02). ACTH and beta-endorphin fluctuated from 20.87 +/- 5.49 and 25.03 +/- 3.97 pg/ml at point R to 22.97 +/- 4.41 and 26.32 +/- 3.93 pg/ml, respectively, at point F and increased to 46.96 +/- 8.55 and 40.32 +/- 5.94 pg/ml, respectively, at point E (P < 0.01, point E vs. point F). There was a positive correlation between the IL-6 at point F and the ACTH and beta-endorphin at point E (r = 0.88 and 0.94, respectively; P < 0.01) as well as between the increase in IL-6 (between points R and F) and the increases in ACTH and beta-endorphin (between points F and E, r = 0.91 and 0.92, respectively; P < 0.01). Moderate IRB did not produce any change. We conclude that severe IRB produces proinflammatory cytokines and stimulates the HPA axis in humans secondary to the production of cytokines (especially IL-6).  (+info)

Trait markers for alcoholism: clinical utility. (30/2102)

Because alcoholism is a multi-factorial psychiatric disorder, with both psychosocial and biochemical/genetic factors leading to its manifestation in any one individual, the presence of biochemical/genetic factors alone may not lead to the manifestation of the disorder. There are numerous difficulties associated with identification of a trait abnormality in a disorder that requires suitable socio-cultural permissiveness with distinct behavioural characteristics to manifest a disorder that may not require that predisposing trait abnormality in order to develop. Numerous studies have been performed in the past to potentially identify a biochemical or genetic trait abnormality in alcoholism, and not all of them have addressed significant methodological flaws in this type of research. This review addresses some of the difficulties inherent in this research, and aims for a comprehensive review of the highlights of the search for a clinically useful trait abnormality. Some series of investigations hold promise that a trait marker for a particular subset of alcoholics may be developed, e.g. severe alcoholism and the dopamine D2 receptor gene; the level of reaction to alcoholism in family history-positive alcoholics; beta-endorphin abnormalities in specific family groups of alcoholics; reduced P3 wave event-related potentials as markers and predictors of development of substance abuse in predisposed youths; reduced growth hormone response to apomorphine as a predictor of relapse to alcoholism in early abstinence; abnormal adenylyl cyclase activity in certain defined subgroups of alcoholics; and abnormal platelet monoamine oxidase levels in subjects with a behavioural predisposition to addictive disorders. The review concludes that while there has not yet been an identification of a comprehensive trait marker for alcoholism, there is hope for identification subgroups of alcoholics with consistent biological markers within that subgroup that may well prove fruitful over time. It will then be up to a future generation of clinicians to take that information and develop prevention programmes that can incorporate this information to help the predisposed individual avoid alcohol problems.  (+info)

A single exposure to amphetamine is sufficient to induce long-term behavioral, neuroendocrine, and neurochemical sensitization in rats. (31/2102)

Repeated treatment with psychostimulant drugs causes long-lasting behavioral sensitization and associated neuroadaptations. Although sensitization induced by a single psychostimulant exposure has also been reported, information on the behavioral and neurochemical consequences of a single psychostimulant exposure is sparse. Therefore, to evaluate whether behavioral sensitization evoked by single and repeated psychostimulant pretreatment regimens represent the same neurobiological phenomenon, the time-dependent expression of behavioral, neurochemical, and neuroendocrine sensitization after a single exposure to amphetamine was investigated in rats. A single exposure to amphetamine (5 mg/kg, i.p.) caused context-independent sensitization of the locomotor effects of amphetamine, which intensified over time. Thus, sensitization to amphetamine was marginal at 3 d after treatment and more evident after 1 week, whereas 3 weeks after treatment, profound sensitization, as well as cross-sensitization, to cocaine was observed. Amphetamine pretreatment caused an increase in the electrically evoked release of [(3)H]dopamine from nucleus accumbens, caudate putamen, and medial prefrontal cortex slices and of [(14)C]acetylcholine from accumbens and caudate slices. The hyperreactivity of dopaminergic nerve terminals appeared to parallel the development of locomotor sensitization, i.e., whereas hyperreactivity of accumbens dopaminergic terminals increased between 3 d and 3 weeks after treatment, the hyperreactivity of medial prefrontal dopaminergic terminals decreased. Pre-exposure to amphetamine also sensitized the hypothalamus-pituitary-adrenal axis response to amphetamine at 1 and 3 weeks, but not at 3 d after treatment. Because these data closely resemble those reported previously for repeated amphetamine pretreatment, it is concluded that a single exposure to amphetamine is sufficient to induce long-term behavioral, neurochemical, and neuroendocrine sensitization in rats.  (+info)

Hypothalamic-pituitary-adrenal activity and pro-opiomelanocortin mRNA levels in the hypothalamus and pituitary of the rat are differentially modulated by acute intermittent morphine with or without water restriction stress. (32/2102)

Acute administration of morphine stimulates the secretion of hypothalamic-pituitary-adrenal (HPA) hormones, ACTH, beta-endorphin and corticosterone in the rat. In this study we investigated the effects of repeated multiple-dose morphine on HPA activity under two different conditions: without or with water restriction stress. Rats received six intermittent injections of morphine (6.25 mg/kg per injection, s.c.) every 2 h and were killed 30 min after the last injection. The results were as follows. (1) Morphine significantly elevated plasma ACTH and corticosterone levels; water restriction also significantly increased ACTH secretion, but with no significant increase of plasma corticosterone levels. In contrast, rats treated with morphine under the water restriction condition failed to show any increases of either ACTH or corticosterone levels. (2) Morphine did not change pro-opiomelanocortin (POMC) mRNA levels in the anterior pituitary; whereas water restriction significantly increased the POMC mRNA levels. The water restriction-induced increases of POMC mRNA in the anterior pituitary were absent in the rats which received morphine. (3) Morphine significantly increased POMC mRNA levels in the hypothalamus; water restriction had no effect. The morphine-induced increases in POMC mRNA in the hypothalamus were absent in the rat under the water restriction condition. These findings, that the effects of morphine on HPA activation or POMC mRNA expression depend on the presence of stress, suggest a counter-regulatory role of opiates on a stress response and opioid gene expression.  (+info)