Anxiogenic-Like Effects of Spontaneous and Naloxone-Precipitated Opiate Withdrawal in the Elevated Plus-Maze

Schulteis, Gery; Yackey, Michael; Risbrough, Victoria B.; Koob, George F.

doi:10.1016/s0091-3057(98)00034-3

Cited by 87 publications

(81 citation statements)

References 24 publications

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“…To our knowledge this is the first study which has confirmed this effect of naloxone-precipitated mild morphine withdrawal in the open field test in mice. In contrast to the data obtained in mice, morphine administration increased %OAT and %OAE in rats [32][33][34] and decreased these parameters during morphine withdrawal [21,35]. In line with literature, naloxone alone did not alter the behavior of mice in our experiments [22,36].…”

Section: Discussionsupporting

confidence: 88%

“…The apparatus was thoroughly cleaned with ethanol (96%) and water between mice. Mice were placed in the center of the maze facing toward an enclosed arm and behavioral activities were recorded for 10 min [21]. The following behavioral parameters were monitored: the time spent in open arms and the entries into open arms compared to the total time (%OAT) and entries (%OAE) and the total activity which was defined as the total number of crosses between any two arms.…”

Section: Elevated Plus Maze (Epm)mentioning

confidence: 99%

“…was given at 09.45 h. Naloxone treatment in a dose of 0.2 mg/kg, s.c. preceded behavioral assessment by 5 min. The behavioral changes were measured for 10 min 2 h after the final morphine treatment with EPM [21,23]. The treatment of specific groups is described below (Figs.…”

Section: The Effect Of Naloxone and Obestatin On Epm Behavior In Micementioning

confidence: 99%

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Obestatin prevents analgesic tolerance to morphine and reverses the effects of mild morphine withdrawal in mice

Lipták

Dochnal

Csabafi

et al. 2013

Regulatory Peptides

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Obestatin is a 23-amino acid gut-derived neuropeptide, encoded by the same gene with ghrelin. The goal of this study was to examine the effects of obestatin on the acute and chronic analgesic actions of morphine and on mild morphine withdrawal. Open-field (OF) and elevated plus maze (EPM) tests were used to assess mild morphine withdrawal-induced behavior changes and the heat-radiant tail-flick assay was used to investigate analgesic actions of morphine. CFLP male mice were treated twice a day with graded doses of morphine in EPM and OF experiments and once a day in tail-flick studies. Obestatin (1.5 μg/2 μl) was administrated once a day in all experiments. Furthermore, 0.2 mg/kg naloxone or saline was administered after the final injection of morphine at a dose of 20 mg/kg in EPM and OF. These behavioral parameters were monitored in the OF: the percentage of center ambulation time and distance; whereas in the EPM: the time spent in open arms and the entries into open arms compared to the total time (%OAT) and entries (%OAE). In the OF, obestatin significantly decreased the percentage of time spent in the center in mice undergoing naloxone-precipitated mild morphine withdrawal. EPM results were similar to open field, but obestatin had no significant effect on parameters mentioned above. Besides, obestatin maintained the analgesic effect of morphine 90 and 120 min after morphine injection in mice treated with morphine receiving obestatin compared to mice treated with morphine. In tolerance studies, obestatin diminished the analgesic tolerance to morphine on the 5th day. In this study we confirmed that obestatin reversed the effect of mild morphine withdrawal and enhances the analgesic effect of morphine. These data suggest that obestatin may have a role in opioid-induced analgesia and in behavioral responses induced by opioid withdrawal.

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Section: Discussionsupporting

confidence: 88%

Section: Elevated Plus Maze (Epm)mentioning

confidence: 99%

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Obestatin prevents analgesic tolerance to morphine and reverses the effects of mild morphine withdrawal in mice

Lipták

Dochnal

Csabafi

et al. 2013

Regulatory Peptides

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“…These results are consistent with the hypothesis that rats withdrawn from chronic, palatable diet cycling become vulnerable to the pharmacological effects of rimonabant. Indeed, spontaneous or precipitated withdrawal from many drugs of abuse can induce not only anorexia and body weight loss (Aceto et al, 2001;Koga and Inukai, 1981;Tsuda et al, 1998) (Supplementary ref 22-28), but also anxiety-like behavior (Basso et al, 1999;George et al, 2007;Rodriguez de Fonseca et al, 1997;Schulteis et al, 1998). Also noteworthy, is the apparent discrepancy between the systemic lowest effective doses in the food intake and anxiety-like behavior experiments, which is very likely determined by the additional contribution of peripheral mechanisms to the anorectic effects of rimonabant (Di Marzo and Matias, 2005).…”

Section: Discussionmentioning

confidence: 99%

Rimonabant Precipitates Anxiety in Rats Withdrawn from Palatable Food: Role of the Central Amygdala

Blasio

Iemolo

Sabino

et al. 2013

Neuropsychopharmacol

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The anti-obesity medication rimonabant, an antagonist of cannabinoid type-1 (CB 1 ) receptor, was withdrawn from the market because of adverse psychiatric side effects, including a negative affective state. We investigated whether rimonabant precipitates a negative emotional state in rats withdrawn from palatable food cycling. The effects of systemic administration of rimonabant on anxiety-like behavior, food intake, body weight, and adrenocortical activation were assessed in female rats during withdrawal from chronic palatable diet cycling. The levels of the endocannabinoids, anandamide and 2-arachidonoylglycerol (2-AG), and the CB 1 receptor mRNA and the protein in the central nucleus of the amygdala (CeA) were also investigated. Finally, the effects of microinfusion of rimonabant in the CeA on anxiety-like behavior, and food intake were assessed. Systemic administration of rimonabant precipitated anxiety-like behavior and anorexia of the regular chow diet in rats withdrawn from palatable diet cycling, independently from the degree of adrenocortical activation. These behavioral observations were accompanied by increased 2-AG, CB 1 receptor mRNA, and protein levels selectively in the CeA. Finally, rimonabant, microinfused directly into the CeA, precipitated anxiety-like behavior and anorexia. Our data show that (i) the 2-AG-CB 1 receptor system within the CeA is recruited during abstinence from palatable diet cycling as a compensatory mechanism to dampen anxiety, and (ii) rimonabant precipitates a negative emotional state by blocking the beneficial heightened 2-AG-CB 1 receptor signaling in this brain area. These findings help elucidate the link between compulsive eating and anxiety, and it will be valuable to develop better pharmacological treatments for eating disorders and obesity.

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“…A number of well-characterized behavioral measures of the negative affective consequences of withdrawal from chronic opioid treatment have been developed using rodents as subjects, and include antagonist-precipitated suppression of operant responding for food, conditioned place aversion (CPA), elevation of brain stimulation reward thresholds, and anxiogenic-like effects measured in the elevated plus maze or fear-potentiated startle paradigms (Fendt and Mucha, 2001;Gellert and Sparber, 1977;Higgins and Sellers, 1994;Koob et al, 1989;Schaefer and Michael, 1986;Schulteis et al, 1994Schulteis et al, , 1998Stinus et al, 1990). Two of these models, suppression of operant responding and CPA, serve as general measures of the aversive stimulus effects of opioid withdrawal, and to date these have been the most extensively applied models to the study of acute opioid dependence (Adams and Holtzman, 1990;Azar et al, 2003;Parker and Joshi, 1998;Schulteis et al, 1997Schulteis et al, , 1999Schulteis et al, , 2003Schulteis et al, , 2004Young, 1986).…”

Section: Introductionmentioning

confidence: 99%

Brain reward deficits accompany naloxone-precipitated withdrawal from acute opioid dependence

Liu

Schulteis

2004

Pharmacology Biochemistry and Behavior

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Single injections with morphine can induce a state of acute opioid dependence in humans and animals, typically measured as precipitated withdrawal when an antagonist such as naloxone is administered 4-24 h after morphine. Repeated treatment with morphine results in a progressive shift in potency of naloxone to produce such acute withdrawal signs. The current study examined alterations in brain reward thresholds after acute and repeated treatment with morphine (5.6 mg/kg) using a discrete-trial current-intensity brain-stimulation reward procedure. Rats with stimulation electrodes aimed at the medial forebrain bundle at the level of the lateral hypothalamus were tested in twice daily sessions separated by 4 h. Separate groups of rats received treatment with morphine immediately after the first daily test session, and one of several doses of naloxone (0.10, 0.33, 1.0 mg/kg) 4 h later and immediately before the second session; these morphine and naloxone treatments were repeated for four consecutive days (Morphine-Repeat NAL). Additional groups examined the independent contribution of repeated morphine or repeated naloxone. One control group (Morphine-Vehicle) received morphine on all four treatment days, but vehicle before the second test session. A second group (Morphine-Single NAL) also received morphine on all four treatment days, but received 1.0 mg/kg only once after the final morphine pretreatment. A final control group received no morphine at all but received the 1.0-mg/kg dose of naloxone four times (Vehicle-Repeat NAL) before the second daily test session. Repeated naloxone alone (Vehicle-Repeat NAL) produced no changes in brain reward thresholds. Repeated morphine alone (Morphine-Vehicle) failed to alter reward thresholds measured 4 h postmorphine, but produced a slight increase in thresholds in the test sessions that occurred before morphine treatment on Days 3 and 4 (and hence 23.5 h after the previous day's morphine injection). This suggested the development of a modest spontaneous withdrawal-induced reward deficit measurable at 23.5 but not 4 h postmorphine. Naloxone dose-dependently increased brain reward thresholds 4 h after a single morphine pretreatment, with a further shift to the left in the naloxone dose-effect function resulting from repeated morphine and naloxone administration (Morphine-Repeat NAL). However, when the highest dose of naloxone was tested only after the final morphine pretreatment (Morphine-Single NAL), its potency was no different than when administered after the first morphine pretreatment. The results indicate that neuroadaptation within brain reward circuitry results in significant reward deficits after a single morphine pretreatment, and this deficit increases rapidly with repeated morphine and naloxone-induced withdrawal experience. D

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Anxiogenic-Like Effects of Spontaneous and Naloxone-Precipitated Opiate Withdrawal in the Elevated Plus-Maze

Cited by 87 publications

References 24 publications

Obestatin prevents analgesic tolerance to morphine and reverses the effects of mild morphine withdrawal in mice

Obestatin prevents analgesic tolerance to morphine and reverses the effects of mild morphine withdrawal in mice

Rimonabant Precipitates Anxiety in Rats Withdrawn from Palatable Food: Role of the Central Amygdala

Brain reward deficits accompany naloxone-precipitated withdrawal from acute opioid dependence

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