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Nicholas E Goeders - One of the best experts on this subject based on the ideXlab platform.

  • lack of effect of the combination of Metyrapone and oxazepam on brain dopamine
    Brain Research, 2019
    Co-Authors: Courtney M Keller, Nicholas E Goeders
    Abstract:

    Abstract The combination of Metyrapone and oxazepam (Met-Ox) has recently shown promise as a pharmacotherapy for cocaine use disorder. Metyrapone is available clinically and is typically used to diagnose adrenal insufficiency, while oxazepam is often prescribed to treat anxiety. The combination of low doses of Metyrapone and oxazepam has been shown to significantly attenuate cocaine self-administration and cue-reactivity in rats, as well as decrease the number of subjects that used cocaine in a pilot clinical trial. Previous studies in rats suggest that the combination of these two drugs may decrease drug-related behaviors by reducing corticosterone synthesis in the medial prefrontal cortex. Since corticosterone has been associated with increased brain dopamine, these reductions in central corticosterone produced by Met-Ox might be accompanied by a concomitant decrease in dopamine to thereby attenuate drug taking and seeking. Thus, these studies were designed to determine the effects of Met-Ox on dopamine in rats. In vivo microdialysis studies in the medial prefrontal cortex and nucleus accumbens revealed that Met-Ox produced no measurable effects on cocaine-induced increases in dopamine. Further, the combination of these two drugs produced no effect on dopamine in the absence of cocaine. Together, these studies demonstrate that Met-Ox does not exert its effects by altering dopamine, suggesting that it might be possible to treat cocaine use disorder without affecting dopamine, which would lead to reduced side effects and increased compliance.

  • the extra adrenal effects of Metyrapone and oxazepam on ongoing cocaine self administration
    Brain Research, 2014
    Co-Authors: Glenn F Guerin, Christopher D. Schmoutz, Nicholas E Goeders
    Abstract:

    Abstract Investigation of the role of stress in cocaine addiction has yielded an efficacious combination of Metyrapone and oxazepam, hypothesized to decrease relapse to cocaine use by reducing stress-induced craving. However, recent data suggest an extra-adrenal role for Metyrapone in mediating stress- and addiction-related behaviors. The interactions between the physiological stress response and cocaine self-administration were characterized in rodents utilizing surgical adrenalectomy and pharmacological treatment. Male Wistar rats were trained to self-administer cocaine (0.25 mg/kg/infusion) and food pellets under a concurrent alternating fixed-ratio schedule of reinforcement. Surgical removal of the adrenal glands resulted in a significant decrease in plasma corticosterone and a consequent increase in ACTH, as expected. However, adrenalectomy did not significantly affect ongoing cocaine self-administration. Pretreatment with Metyrapone, oxazepam and their combinations in intact rats resulted in a significant decrease in cocaine-reinforced responses. These same pharmacological treatments were still effective in reducing cocaine- and food-reinforced responding in adrenalectomized rats. The results of these experiments demonstrate that adrenally-derived steroids are not necessary to maintain cocaine-reinforced responding in cocaine-experienced rats. These results also demonstrate that Metyrapone may produce effects outside of the adrenal gland, presumably in the central nervous system, to affect cocaine-related behaviors.

  • the combination of Metyrapone and oxazepam for the treatment of cocaine and other drug addictions
    Advances in pharmacology (San Diego), 2014
    Co-Authors: Nicholas E Goeders, Glenn F Guerin, Christopher D. Schmoutz
    Abstract:

    Abstract Although scientists have been investigating the neurobiology of psychomotor stimulant reward for many decades, there is still no FDA-approved treatment for cocaine or methamphetamine abuse. Research in our laboratory has focused on the relationship between stress, the subsequent activation of the hypothalamic–pituitary–adrenal (HPA) axis, and psychomotor stimulant reinforcement for almost 30 years. This research has led to the development of a combination of low doses of the cortisol synthesis inhibitor, Metyrapone, and the benzodiazepine, oxazepam, as a potential pharmacological treatment for cocaine and other substance use disorders. In fact, we have conducted a pilot clinical trial that demonstrated that this combination can reduce cocaine craving and cocaine use. Our initial hypothesis underlying this effect was that the combination of Metyrapone and oxazepam reduced cocaine seeking and taking by decreasing activity within the HPA axis. Even so, doses of the Metyrapone and oxazepam combination that consistently reduced cocaine taking and seeking did not reliably alter plasma corticosterone (or cortisol in the pilot clinical trial). Furthermore, subsequent research has demonstrated that this drug combination is effective in adrenalectomized rats, suggesting that these effects must be mediated above the level of the adrenal gland. Our evolving hypothesis is that the combination of Metyrapone and oxazepam produces its effects by increasing the levels of neuroactive steroids, most notably tetrahydrodeoxycorticosterone, in the medial prefrontal cortex and amygdala. Additional research will be necessary to confirm this hypothesis and may lead to the development of improved and specific pharmacotherapies for the treatment of psychomotor stimulant use.

  • effects of the combination of Metyrapone and oxazepam on cocaine craving and cocaine taking a double blind randomized placebo controlled pilot study
    Journal of Psychopharmacology, 2012
    Co-Authors: Anita Kablinger, Marie A Lindner, Stephanie Casso, Franz Hefti, George Demuth, Barbara S Fox, Lindsay Mcnair, Bruce G Mccarthy, Nicholas E Goeders
    Abstract:

    Although cocaine dependence affects an estimated 1.6 million people in the USA, there are currently no medications approved for the treatment of this disorder. Experiments performed in animal models have demonstrated that inhibitors of the stress response effectively reduce intravenous cocaine self-administration. This exploratory, double-blind, placebo-controlled study was designed to assess the safety and efficacy of combinations of the cortisol synthesis inhibitor Metyrapone, and the benzodiazepine oxazepam, in 45 cocaine-dependent individuals. The subjects were randomized to a total daily dose of 500 mg Metyrapone/20 mg oxazepam (low dose), a total daily dose of 1500 mg Metyrapone/20 mg oxazepam (high dose), or placebo for 6 weeks of treatment. The outcome measures were a reduction in cocaine craving and associated cocaine use as determined by quantitative measurements of the cocaine metabolite benzoylecgonine (BE) in urine at all visits. Of the randomized subjects, 49% completed the study. The combination of Metyrapone and oxazepam was well tolerated and tended to reduce cocaine craving and cocaine use, with significant reductions at several time points when controlling for baseline scores. These data suggest that further assessments of the ability of the Metyrapone and oxazepam combination to support cocaine abstinence in cocaine-dependent subjects are warranted.

  • effects of the combination of Metyrapone and oxazepam on cocaine and food self administration in rats
    Pharmacology Biochemistry and Behavior, 2008
    Co-Authors: Nicholas E Goeders, Glenn F Guerin
    Abstract:

    For several years, our laboratory has investigated the role for the HPA axis in cocaine reinforcement. Two classes of drugs that we have studied include corticosterone synthesis inhibitors (e.g., Metyrapone) and benzodiazepine receptor agonists (e.g., oxazepam). In the experiments described in this manuscript, we tested the effects of various doses of Metyrapone and oxazepam against several doses of self-administered cocaine. Behavioral, endocrine and pharmacokinetic measures of the effects of the combination of Metyrapone and oxazepam on cocaine reward are presented. Combinations of Metyrapone and oxazepam at doses that produced no observable effects when administered separately significantly reduced cocaine self-administration without affecting food-maintained responding during the same sessions. Changes in pharmacokinetics or endocrine function do not appear to mediate these effects, suggesting a central mechanism of action. Therefore, although these drugs produce their effects through distinct mechanisms, an additive effect on cocaine self-administration is obtained when these drugs are administered together, suggesting that combinations of low doses of Metyrapone and oxazepam may be useful in reducing cocaine seeking with a reduced incidence of unwanted side effects and a decreased potential for abuse.

K Balasubramanian - One of the best experts on this subject based on the ideXlab platform.

  • differential response of leydig cells in expressing 11β hsd type i and cytochrome p450 aromatase in male rats subjected to corticosterone deficiency
    Molecular and Cellular Endocrinology, 2009
    Co-Authors: Chandrakesan Parthasarathy, Sambandam Yuvaraj, R Ilangovan, Panneerselvam Janani, P Kanagaraj, Muthusamy Balaganesh, Bhaskaran Natarajan, Sivanandane Sittadjody, K Balasubramanian
    Abstract:

    Abstract Emerging evidence suggests that the glucocorticoid and estradiol are important for Leydig cell steroidogenesis and are regulated via aromatase for estradiol production and 11β-HSD for oxidatively inactivating glucocorticoid. Although it is known that corticosterone deficiency impaired Leydig cell steroidogenesis, its effect on the expression of Leydig cell 11β-HSD type I and aromatase are yet to be recognized. Following Metyrapone-induced corticosterone deficiency, serum corticosterone and testosterone levels decrease, whereas serum estradiol remains unaltered. 11β-HSD type I mRNA and its activity was decreased by corticosterone deficiency, whereas the activity and mRNA of aromatase remains unaltered. Simultaneous administration of corticosterone prevented its deficiency-induced changes of 11β-HSD type I in Leydig cells. Our results show that Metyrapone-induced corticosterone deficiency impairs Leydig cell 11β-HSD enzyme activity and 11β-HSD type I mRNA expression, and the Leydig cells need to maintain their intracellular concentration of corticosterone for a normal function.

  • differential effect of corticosterone deficiency on the expression of lh prolactin and insulin receptors on rat leydig cells
    Molecular and Cellular Endocrinology, 2008
    Co-Authors: Chandrakesan Parthasarathy, K Balasubramanian
    Abstract:

    The adverse effects of glucocorticoid deficiency on the expression of genes encoding Leydig cell surface receptors and the response to LH/prolactin/insulin to produce testosterone production are yet to be recognized. Following Metyrapone-induced corticosterone deficiency, serum corticosterone, testosterone and insulin levels decrease, whereas serum prolactin exhibits a significant increase and serum LH remains unaltered. LH binding and LH receptor mRNA expression were not altered, but a significant decrease in PRL and insulin binding and in the mRNA expressions of their receptors were observed in corticosterone-deficient rats in vivo. Corticosterone deficiency significantly decreases the Leydig cellular basal as well as hormone-stimulated testosterone production in vitro. Simultaneous administration of corticosterone prevented its deficiency-induced changes in Leydig cells both in vivo and in vitro. Our results show that Metyrapone-induced corticosterone deficiency impairs Leydig cell insulin and prolactin receptors, and their mRNA expression and the response of Leydig cells to LH/PRL/insulin on testosterone production.

Thomas C Neylan - One of the best experts on this subject based on the ideXlab platform.

  • sleep and hypothalamic pituitary adrenal axis responses to Metyrapone in posttraumatic stress disorder
    Psychoneuroendocrinology, 2018
    Co-Authors: Sabra S Inslicht, Thomas J Metzler, Madhu N Rao, Anne Richards, Aoife Odonovan, Carolyn J Gibson, Tierney Baum, Thomas C Neylan
    Abstract:

    Disturbed sleep is a core feature of posttraumatic stress disorder (PTSD), characterized in part by decreased delta power sleep that may result from stress-related alterations in corticotropin releasing factor (CRF), hypothalamic pituitary adrenal axis (HPA) regulation and glucocorticoid signaling. Overnight HPA axis response mediating sleep disturbances in men and women with PTSD was examined using a Metyrapone challenge. Metyrapone blocks cortisol synthesis, removing negative feedback, and increases the release of hypothalamic CRF and pituitary adrenocorticotropic hormone (ACTH). Laboratory-based polysomnography was used to monitor the sleep of 66 medically healthy, medication-free men and pre-menopausal follicular phase women including 33 with chronic PTSD (16 women and 17 men) and 33 age- and sex-matched controls (14 women and 19 men) over 3 consecutive nights. Participants completed an overnight Metyrapone challenge after an adaptation and baseline night of sleep and ACTH was obtained by repeated blood sampling. Metyrapone resulted in a greater increase in ACTH and greater decreases in cortisol and delta spectral power sleep in PTSD subjects compared to controls, and a greater increase in ACTH in women compared to men. There was no sex difference in Metyrapone effects on delta power sleep, and no significant Metyrapone by PTSD by sex interactions with either ACTH or delta power sleep. Regression analyses indicated that a greater increase in ACTH response was associated with a greater decrease in delta power sleep response in PTSD subjects, but no such relationship was found in controls. The PTSD group difference was similar in men and women. These results suggest that stress-related alterations of the HPA axis in PTSD may contribute to sleep difficulties. Therapeutics that target the HPA axis may offer promise as a potential future treatment for PTSD and related sleep difficulties.

  • effects of Metyrapone on hypothalamic pituitary adrenal axis and sleep in women with post traumatic stress disorder
    Biological Psychiatry, 2007
    Co-Authors: Christian Otte, Maryann Lenoci, Thomas J Metzler, Rachel Yehuda, Charles R Marmar, Thomas C Neylan
    Abstract:

    Background Metyrapone blocks cortisol synthesis which results in removal of negative feedback, a stimulation of hypothalamic corticotropin releasing factor (CRF) and a reduction in delta sleep. We previously reported a diminished delta sleep and hypothalamic-pituitary-adrenal (HPA) response to Metyrapone in men with post-traumatic stress disorder (PTSD). In this study, we aimed to extend these findings to women. Methods Three nights of polysomnography were obtained in 17 women with PTSD and 16 controls. On day 3, Metyrapone was administered throughout the day up until bedtime. Plasma adrenocorticotropic hormone (ACTH), cortisol, and 11-deoxycortisol were obtained the morning following sleep recordings the day before and after Metyrapone administration. Results There were no significant between-group differences in hormone concentration and delta sleep at baseline. Relative to controls, women with PTSD had decreased ACTH and delta sleep responses to Metyrapone. Decline in delta sleep was associated with the magnitude of increase in ACTH across groups. Conclusions Similar to our previous findings in men, the ACTH and sleep electroencephalogram response to Metyrapone is attenuated in women with PTSD. These results are consistent with a model of downregulation of CRF receptors in an environment of chronically increased CRF activity or with enhanced negative feedback regulation in PTSD.

Chandrakesan Parthasarathy - One of the best experts on this subject based on the ideXlab platform.

  • differential response of leydig cells in expressing 11β hsd type i and cytochrome p450 aromatase in male rats subjected to corticosterone deficiency
    Molecular and Cellular Endocrinology, 2009
    Co-Authors: Chandrakesan Parthasarathy, Sambandam Yuvaraj, R Ilangovan, Panneerselvam Janani, P Kanagaraj, Muthusamy Balaganesh, Bhaskaran Natarajan, Sivanandane Sittadjody, K Balasubramanian
    Abstract:

    Abstract Emerging evidence suggests that the glucocorticoid and estradiol are important for Leydig cell steroidogenesis and are regulated via aromatase for estradiol production and 11β-HSD for oxidatively inactivating glucocorticoid. Although it is known that corticosterone deficiency impaired Leydig cell steroidogenesis, its effect on the expression of Leydig cell 11β-HSD type I and aromatase are yet to be recognized. Following Metyrapone-induced corticosterone deficiency, serum corticosterone and testosterone levels decrease, whereas serum estradiol remains unaltered. 11β-HSD type I mRNA and its activity was decreased by corticosterone deficiency, whereas the activity and mRNA of aromatase remains unaltered. Simultaneous administration of corticosterone prevented its deficiency-induced changes of 11β-HSD type I in Leydig cells. Our results show that Metyrapone-induced corticosterone deficiency impairs Leydig cell 11β-HSD enzyme activity and 11β-HSD type I mRNA expression, and the Leydig cells need to maintain their intracellular concentration of corticosterone for a normal function.

  • differential effect of corticosterone deficiency on the expression of lh prolactin and insulin receptors on rat leydig cells
    Molecular and Cellular Endocrinology, 2008
    Co-Authors: Chandrakesan Parthasarathy, K Balasubramanian
    Abstract:

    The adverse effects of glucocorticoid deficiency on the expression of genes encoding Leydig cell surface receptors and the response to LH/prolactin/insulin to produce testosterone production are yet to be recognized. Following Metyrapone-induced corticosterone deficiency, serum corticosterone, testosterone and insulin levels decrease, whereas serum prolactin exhibits a significant increase and serum LH remains unaltered. LH binding and LH receptor mRNA expression were not altered, but a significant decrease in PRL and insulin binding and in the mRNA expressions of their receptors were observed in corticosterone-deficient rats in vivo. Corticosterone deficiency significantly decreases the Leydig cellular basal as well as hormone-stimulated testosterone production in vitro. Simultaneous administration of corticosterone prevented its deficiency-induced changes in Leydig cells both in vivo and in vitro. Our results show that Metyrapone-induced corticosterone deficiency impairs Leydig cell insulin and prolactin receptors, and their mRNA expression and the response of Leydig cells to LH/PRL/insulin on testosterone production.

Glenn F Guerin - One of the best experts on this subject based on the ideXlab platform.

  • the extra adrenal effects of Metyrapone and oxazepam on ongoing cocaine self administration
    Brain Research, 2014
    Co-Authors: Glenn F Guerin, Christopher D. Schmoutz, Nicholas E Goeders
    Abstract:

    Abstract Investigation of the role of stress in cocaine addiction has yielded an efficacious combination of Metyrapone and oxazepam, hypothesized to decrease relapse to cocaine use by reducing stress-induced craving. However, recent data suggest an extra-adrenal role for Metyrapone in mediating stress- and addiction-related behaviors. The interactions between the physiological stress response and cocaine self-administration were characterized in rodents utilizing surgical adrenalectomy and pharmacological treatment. Male Wistar rats were trained to self-administer cocaine (0.25 mg/kg/infusion) and food pellets under a concurrent alternating fixed-ratio schedule of reinforcement. Surgical removal of the adrenal glands resulted in a significant decrease in plasma corticosterone and a consequent increase in ACTH, as expected. However, adrenalectomy did not significantly affect ongoing cocaine self-administration. Pretreatment with Metyrapone, oxazepam and their combinations in intact rats resulted in a significant decrease in cocaine-reinforced responses. These same pharmacological treatments were still effective in reducing cocaine- and food-reinforced responding in adrenalectomized rats. The results of these experiments demonstrate that adrenally-derived steroids are not necessary to maintain cocaine-reinforced responding in cocaine-experienced rats. These results also demonstrate that Metyrapone may produce effects outside of the adrenal gland, presumably in the central nervous system, to affect cocaine-related behaviors.

  • the combination of Metyrapone and oxazepam for the treatment of cocaine and other drug addictions
    Advances in pharmacology (San Diego), 2014
    Co-Authors: Nicholas E Goeders, Glenn F Guerin, Christopher D. Schmoutz
    Abstract:

    Abstract Although scientists have been investigating the neurobiology of psychomotor stimulant reward for many decades, there is still no FDA-approved treatment for cocaine or methamphetamine abuse. Research in our laboratory has focused on the relationship between stress, the subsequent activation of the hypothalamic–pituitary–adrenal (HPA) axis, and psychomotor stimulant reinforcement for almost 30 years. This research has led to the development of a combination of low doses of the cortisol synthesis inhibitor, Metyrapone, and the benzodiazepine, oxazepam, as a potential pharmacological treatment for cocaine and other substance use disorders. In fact, we have conducted a pilot clinical trial that demonstrated that this combination can reduce cocaine craving and cocaine use. Our initial hypothesis underlying this effect was that the combination of Metyrapone and oxazepam reduced cocaine seeking and taking by decreasing activity within the HPA axis. Even so, doses of the Metyrapone and oxazepam combination that consistently reduced cocaine taking and seeking did not reliably alter plasma corticosterone (or cortisol in the pilot clinical trial). Furthermore, subsequent research has demonstrated that this drug combination is effective in adrenalectomized rats, suggesting that these effects must be mediated above the level of the adrenal gland. Our evolving hypothesis is that the combination of Metyrapone and oxazepam produces its effects by increasing the levels of neuroactive steroids, most notably tetrahydrodeoxycorticosterone, in the medial prefrontal cortex and amygdala. Additional research will be necessary to confirm this hypothesis and may lead to the development of improved and specific pharmacotherapies for the treatment of psychomotor stimulant use.

  • effects of the combination of Metyrapone and oxazepam on cocaine and food self administration in rats
    Pharmacology Biochemistry and Behavior, 2008
    Co-Authors: Nicholas E Goeders, Glenn F Guerin
    Abstract:

    For several years, our laboratory has investigated the role for the HPA axis in cocaine reinforcement. Two classes of drugs that we have studied include corticosterone synthesis inhibitors (e.g., Metyrapone) and benzodiazepine receptor agonists (e.g., oxazepam). In the experiments described in this manuscript, we tested the effects of various doses of Metyrapone and oxazepam against several doses of self-administered cocaine. Behavioral, endocrine and pharmacokinetic measures of the effects of the combination of Metyrapone and oxazepam on cocaine reward are presented. Combinations of Metyrapone and oxazepam at doses that produced no observable effects when administered separately significantly reduced cocaine self-administration without affecting food-maintained responding during the same sessions. Changes in pharmacokinetics or endocrine function do not appear to mediate these effects, suggesting a central mechanism of action. Therefore, although these drugs produce their effects through distinct mechanisms, an additive effect on cocaine self-administration is obtained when these drugs are administered together, suggesting that combinations of low doses of Metyrapone and oxazepam may be useful in reducing cocaine seeking with a reduced incidence of unwanted side effects and a decreased potential for abuse.