Inhibition of corticosterone synthesis by Metyrapone decreases cocaine-induced locomotion and relapse of cocaine self-administration
ABSTRACT Several studies have recently shown that basal and stress-induced secretion of corticosterone may enhance vulnerability to drugs of abuse. In this report, we studied the effects of metyrapone, an inhibitor of the synthesis of corticosterone, on cocaine-induced locomotion and on the relapse of cocaine self-administration. Locomotor response to cocaine was studied because psychomotor effects of drugs have been shown to be related to their reinforcing properties. Self-administration was studied in the relapse phase since blockade of relapse is central to the therapy of addiction. Before these behavioral tests, rats in different experimental groups were injected subcutaneously with either metyrapone (100 mg/kg) or vehicle, twice a day for 8 days. Metyrapone treatment reduced cocaine-induced locomotor activity and relapse of cocaine self-administration, without inducing a nonspecific disruption of motor or food-directed behaviors. Under these experimental conditions, the metyrapone treatment totally blocked stress-induced corticosterone secretion but did not modify basal corticosterone levels. These results confirm the involvement of glucocorticoids in the pathophysiological mechanisms underlying vulnerability to drug abuse, and may have implications for the development of new therapeutic strategies of drug addiction.
- SourceAvailable from: Edythe D London
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- "If the finding that higher evening/night-time cortisol levels are associated with increased vulnerability for smoking and/or development of nicotine dependence is replicated, it will have clinical implications for developing more specific interventions. For example, metyrapone, an inhibitor of corticosteroid synthesis, and antagonists of the corticotropinreleasing hormone (CRH) reduce self-administration of nicotine and other addictive drugs in animals (Bruijnzeel et al., 2007; Fahlke et al., 1994; Piazza et al., 1994; Zislis et al., 2007). Anti-glucocorticoid agents and CRH antagonists might have anti-depressant properties, and have been tested in humans for the treatment of depression and other psychiatric disorders (Gallagher et al., 2008; Holsboer and Ising, 2008; Seymour et al., 2003). "
ABSTRACT: Although tobacco smoking, which has been linked to depression, is a major public health problem, little is known about the neurobiological factors that confer vulnerability to smoking in youngsters and the effects of adolescent smoking on the course of depression. This study examined whether hypothalamic-pituitary-adrenal (HPA) activity and stressful life experiences are related to smoking behavior in depressed and non-depressed adolescents, and whether smoking predicts a worsening course of depression. Smoking history and stressful experiences were assessed in 151 adolescents (48 with no personal or family history of psychiatric disorder, 48 with no psychiatric history, but at high risk for depression by virtue of parental depression, and 55 with current major depressive disorder). Evening salivary cortisol and nocturnal urinary-free cortisol were measured for three consecutive evenings. The participants were then followed at regular intervals for up to 5 years to assess smoking history, clinical course of depression and stressful experiences during the follow-up period. Increased evening/night-time cortisol levels were associated with both initiation and persistence of smoking during follow-up. Stressful life experiences further increased the risk for smoking in depressed as well as non-depressed youth. Smoking was also associated with a higher frequency of depressive episodes during follow-up. A model that included stressful experiences and cortisol levels reduced the contribution of smoking per se to depression. High evening/night-time cortisol level appears to be a vulnerability marker for smoking in adolescents, with stressful experiences further increasing the risk for smoking in vulnerable youth. High evening/night-time cortisol levels and stressful experiences accounted, at least partially, for the association between depressive illness and smoking behavior.Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 09/2009; 34(13):2721-32. DOI:10.1038/npp.2009.112 · 7.83 Impact Factor
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- "Likewise, administering alcohol or cocaine to rats significantly lowers plasma ACTH and corticosteroid responses to stress or CRH challenges (Rivier & Vale, 1988; Goeders, 1997) which is consistent with a self-medication hypothesis. Conversely, modulating corticosteroid secretion or CRH antagonism attenuates the reinforcing effects of psychomotor stimulants, and alleviates some of the affective symptoms that emerge during withdrawal from drug taking (Piazza et al., 1994; Fahlke et al., 1994; Heinrichs et al., 1995; Zobel et al., 2000). "
ABSTRACT: The impact of ostensibly aversive social stresses on triggering, amplifying and prolonging intensely rewarding drug taking is an apparent contradiction in need of resolution. Social stress encompasses various types of significant life events ranging from maternal separation stress, brief episodes of social confrontations in adolescence and adulthood, to continuous subordination stress, each with its own behavioral and physiological profile. The neural circuit comprising the VTA-accumbens-PFC-amygdala is activated by brief episodes of social stress, which is critical for the DA-mediated behavioral sensitization and increased stimulant consumption. A second neural circuit comprising the raphe-PFC-hippocampus is activated by continuous subordination stress and other types of uncontrollable stress. In terms of the development of therapeutics, brief maternal separation stress has proven useful in characterizing compounds acting on subtypes of GABA, glutamate, serotonin and opioid receptors with anxiolytic potential. While large increases in alcohol and cocaine intake during adulthood have been seen after prolonged maternal separation experiences during the first two weeks of rodent life, these effects may be modulated by additional yet to be identified factors. Brief episodes of defeat stress can engender behavioral sensitization that is relevant to escalated and prolonged self-administration of stimulants and possibly opioids, whereas continuous subordination stress leads to anhedonia-like effects. Understanding the intracellular cascade of events for the transition from episodic to continuous social stress in infancy and adulthood may provide insight into the modulation of basic reward processes that are critical for addictive and affective disorders.Pharmacology [?] Therapeutics 09/2008; 120(2):102-28. DOI:10.1016/j.pharmthera.2008.07.006 · 7.75 Impact Factor
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- "The notion that novelty can act as a stressor stems from its ability to activate the hypothalamo–pituitary–adrenal (HPA) axis and increase plasma corticosterone levels in the rat (Friedman and Ader 1967; Hennessy et al. 1977; Badiani et al. 1995c, 1998), an effect that does not necessarily habituate after repeated exposures (Hennessy 1991). There is some evidence suggesting that the HPA axis is implicated in cocaine self-administration (Piazza et al. 1994; Goeders and Guerin 1996). Therefore, the possible contribution of the HPA axis to the effects of environmental " novelty " described here deserves to be investigated (although we have shown that the modulatory effect of " novelty " on amphetamine sensitization is not blocked by the surgical removal of the adrenal glands; Badiani et al. 1995c). "
ABSTRACT: Previous studies have shown that environmental context can powerfully modulate the induction of psychomotor sensitization to cocaine in the rat. Rats that receive repeated administrations of cocaine in association with environmental novelty exhibit greater psychomotor sensitization than animals that receive the same treatments in their home cages. The goal of the present study was to investigate whether environmental context can exert its modulatory influence also on cocaine self-administration. Independent groups of rats with intravenous catheters were given the possibility to self-administer different doses of cocaine (0.0, 0.2, 0.4, and 0.8 mg/kg per infusion) under two environmental conditions. Some animals were housed in the self-administration cages (home groups), whereas other rats were transported to the self-administration cages only for the test sessions (novelty groups). Environmental "novelty" facilitated the acquisition of cocaine self-administration at the doses of 0.2 and 0.4 mg/kg per infusion. When rats were given access to a higher dose of cocaine (0.8 mg/kg per infusion), there were no significant group differences in drug taking. Environmental context had no effect on the self-administration of the vehicle. Thus, it appears that environmental "novelty" produced a shift to the left in the dose-effect curve for cocaine self-administration. Furthermore, "novelty" enhanced the motivation of the rats to work for cocaine, as indicated by the results of a progressive ratio procedure. The present findings demonstrate for the first time that the environment surrounding drug taking can alter both the intake of and motivation for cocaine.Psychopharmacology 07/2007; 192(3):397-406. DOI:10.1007/s00213-007-0717-z · 3.99 Impact Factor