Doses Of Naltrexone Research Articles

A placebo-controlled trial of memantine as an adjunct to injectable extended-release naltrexone for opioid dependence

There is preclinical support for using NMDA receptor glutamatergic antagonists to aid in naltrexone-based treatment of opioid dependence. We hypothesized that adding memantine will improve efficacy of extended-release (XR) naltrexone to prevent relapse. In this double blind study opioid-dependent participants (N=82) underwent inpatient detoxification and naltrexone induction. During naltrexone initiation participants were randomized to receive memantine 40mg or placebo and continued treatment for 12-weeks with XR naltrexone and relapse-prevention therapy. Sixty eight percent of participants completed detoxification and received the first dose of XR naltrexone. Rates of trial completion were significantly greater in participants receiving placebo than memantine (70% vs. 43%, p<0.05). Severity of opioid withdrawal symptoms during the first 3 weeks of the trial appeared to be lower in the group receiving memantine (p=0.07). Adding memantine does not appear to increase the effectiveness of injectable XR naltrexone as a relapse prevention strategy in opioid dependence and may lead to an increase in treatment drop-out.

Conversation with Charles P. O'Brien

Conversation with <scp>C</scp>harles <scp>P</scp>. <scp>O</scp>'<scp>B</scp>rien

On the behavioural specificity of hypophagia induced in male rats by mCPP, naltrexone, and their combination

Serotonergic (5-hydroxytryptamine, 5-HT) and opioidergic mechanisms are intimately involved in appetite regulation. In view of recent evidence of positive anorectic interactions between opioid and various non-opioid substrates, our aim was to assess the behavioural specificity of anorectic responses to the opioid receptor antagonist naltrexone, the 5-HT2C/1B receptor agonist mCPP and their combination. Behavioural profiling techniques, including the behavioural satiety sequence (BSS), were used to examine acute drug effects in non-deprived male rats tested with palatable mash. Experiment 1 characterised the dose-response profile of mCPP (0.1-3.0 mg/kg), while experiment 2 assessed the effects of combined treatment with a sub-anorectic dose of mCPP (0.1 mg/kg) and one of two low doses of naltrexone (0.1 and 1.0 mg/kg). Experiment 1 confirmed the dose-dependent anorectic efficacy of mCPP, with robust effects on intake and feeding-related measures observed at 3.0 mg/kg. However, that dose was also associated with other behavioural alterations including increased grooming, reductions in locomotion and sniffing, and disruption of the BSS. In experiment 2, naltrexone dose-dependently reduced food intake and time spent feeding, effects accompanied by a behaviourally selective acceleration in the BSS. However, the addition of 0.1 mg/kg mCPP did not significantly alter the behavioural changes observed in response to either dose of naltrexone given alone. In contrast to recently reported positive anorectic interactions involving low-dose combinations of opioid receptor antagonists or mCPP with cannabinoid CB1 receptor antagonists, present results would not appear to provide any support for potentially clinically relevant anorectic interactions between opioid and 5-HT2C/1B receptor mechanisms.

Phase I study of injectable, depot naltrexone for the relapse prevention treatment of opioid dependence

We tested long-acting injectable depot naltrexone for its tolerability, pharmacokinetics, and safety in Phase I. The Phase I trial enrolled 36 healthy participants in two panels (A, B). In Panel A, 24 subjects were randomly assigned to the high-dosage group (400 mg naltrexone, n=6; placebo, n=6) or low-dosage group (200 mg naltrexone, n=6; placebo, n=6). In Panel B, 12 subjects were randomized to take six doses of monthly injectable naltrexone (400 mg) or placebo. After a single injection of naltrexone 200 and 400 mg, means (SD) of naltrexone plasma concentrations were .57 (.28) ng/ml and 1.5 (.8) ng/ml 30 days post-injection. There was no effect of accumulation after multiple dosing. Eleven of 30 subjects (36.67%) who were administered injectable depot naltrexone reported a total of 12 adverse events (AEs). Seven of these 11 AEs were coded as possibly related with study medication. All treatment-related AEs were mild in severity. No serious treatment-related AEs occurred. This long-acting formulation of injectable depot naltrexone is well tolerated, results in constant plasma concentration of naltrexone for at least 1 month. The tolerability and safety of long-acting injectable depot naltrexone are good.

Divergent short- and long-term effects of acute stress in object recognition memory are mediated by endogenous opioid system activation

Acute stress induces short-term object recognition memory impairment and elicits endogenous opioid system activation. The aim of this study was thus to evaluate whether opiate system activation mediates the acute stress-induced object recognition memory changes. Adult male Wistar rats were trained in an object recognition task designed to test both short- and long-term memory. Subjects were randomly assigned to receive an intraperitoneal injection of saline, 1mg/kg naltrexone or 3mg/kg naltrexone, four and a half hours before the sample trial. Five minutes after the injection, half the subjects were submitted to movement restraint during four hours while the other half remained in their home cages. Non-stressed subjects receiving saline (control) performed adequately during the short-term memory test, while stressed subjects receiving saline displayed impaired performance. Naltrexone prevented such deleterious effect, in spite of the fact that it had no intrinsic effect on short-term object recognition memory. Stressed subjects receiving saline and non-stressed subjects receiving naltrexone performed adequately during the long-term memory test; however, control subjects as well as stressed subjects receiving a high dose of naltrexone performed poorly. Control subjects’ dissociated performance during both memory tests suggests that the short-term memory test induced a retroactive interference effect mediated through light opioid system activation; such effect was prevented either by low dose naltrexone administration or by strongly activating the opioid system through acute stress. Both short-term memory retrieval impairment and long-term memory improvement observed in stressed subjects may have been mediated through strong opioid system activation, since they were prevented by high dose naltrexone administration. Therefore, the activation of the opioid system plays a dual modulating role in object recognition memory.

The mesolimbic system participates in the naltrexone-induced reversal of sexual exhaustion: Opposite effects of intra-VTA naltrexone administration on copulation of sexually experienced and sexually exhausted male rats

Male rats allowed to copulate until reaching sexual exhaustion exhibit a long-lasting sexual behavior inhibition (around 72h) that can be reversed by systemic opioid receptor antagonist administration. Copulation activates the mesolimbic dopaminergic system (MLS) and promotes endogenous opioid release. In addition, endogenous opioids, acting at the ventral tegmental area (VTA), modulate the activity of the MLS. We hypothesized that endogenous opioids participate in the sexual exhaustion phenomenon by interacting with VTA opioid receptors and consequently, its reversal by opioid antagonists could be exerted at those receptors. In this study we determined the effects of intra-VTA infusion of different doses of the non-specific opioid receptor antagonist naltrexone (0.1–1.0μg/rat) on the already established sexual behavior inhibition of sexually exhausted male rats. To elucidate the possible involvement of VTA δ-opioid receptors in the naltrexone-mediated reversal of sexual exhaustion, the effects of different doses of the selective δ-opioid receptor antagonist, naltrindole (0.03–1.0μg/rat) were also tested. Results showed that intra-VTA injection of 0.3μg naltrexone reversed the sexual inhibition of sexually exhausted rats, evidenced by an increased percentage of animals capable of showing two successive ejaculations. Intra-VTA infused naltrindole did not reverse sexual exhaustion at any dose. It is concluded that the MLS is involved in the reversal of sexual exhaustion induced by systemic naltrexone, and that μ-, but not δ-opioid receptors participate in this effect. Intra-VTA naltrexone infusion to sexually experienced male rats had an inhibitory effect on sexual activity. The opposite effects of intra-VTA naltrexone on male rat sexual behavior expression of sexually experienced and sexually exhausted rats is discussed

Combining naltrexone and prazosin in a single oral medication decreases alcohol drinking more effectively than does either drug alone.

Naltrexone (NTX) is underutilized in clinical treatment settings because its efficacy is modest, and it is not effective for all alcoholics and, when it is effective, a significant number of alcoholics fail to maintain initial treatment gains and subsequently relapse to heavy drinking. This has slowed acceptance of NTX by the treatment community, and there is a clear need for additional treatments for alcoholism and alcohol use disorders. Given that NTX and prazosin can each reduce alcohol drinking in rats selectively bred for alcohol preference and high voluntary alcohol drinking (alcohol-preferring "P" rats), we tested whether a combination of NTX + prazosin is more effective in decreasing alcohol drinking than is either drug alone. P rats were given access to a 15% (v/v) alcohol solution for 2 hours daily. Rats were fed NTX and prazosin, alone or in combination, prior to onset of the daily 2-hour alcohol access period for 4 weeks and the effect of drug treatment on alcohol and water intake was assessed. During the first week of treatment, neither a low dose of NTX, nor prazosin, was effective in decreasing alcohol intake when each drug was administered alone, but combining the 2 drugs in a single medication significantly reduced alcohol intake. The combination was as effective as was a higher dose of NTX. Using a low dose of NTX in combination with prazosin may reduce the potential for undesirable side effects early in treatment which, in turn, may improve patient compliance and result in a more successful outcome when NTX is used for treating alcoholism and alcohol use disorders. Combining low-dose NTX and prazosin in a single medication may be more useful than is either drug alone for treating both inpatient and outpatient alcoholics and heavy drinkers early in the treatment process.

Naltrexone treatment for opioid dependence: Does its effectiveness depend on testing the blockade?

BackgroundFDA approval of long-acting injectable naltrexone (Vivitrol) for opioid dependence highlights the relevance of understanding mechanisms of antagonist treatment. Principles of learning suggest an antagonist works through extinguishing drug-seeking behavior, as episodes of drug use (“testing the blockade”) fail to produce reinforcement.We hypothesized that opiate use would moderate the effect of naltrexone, specifically, that opiate-positive urines precede dropout in the placebo group, but not in the active-medication groups. MethodsAn 8-week, double-blind, placebo-controlled trial (N=57), compared the efficacy of low (192mg) and high (384mg) doses of a long-acting injectable naltrexone (Depotrex) with placebo (Comer et al., 2006). A Cox proportional hazard model was fit, modeling time-to-dropout as a function of treatment assignment and urine toxicology during treatment. ResultsInteraction of opiate urines with treatment group was significant. Opiate-positive urines predicted dropout on placebo and low-dose, but less so on high-dose naltrexone, where positive urines were more likely followed by sustained abstinence. Among patients with no opiate-positive urines, retention was higher in both low- and high-dose naltrexone conditions, compared to placebo. ConclusionsFindings confirm that injection naltrexone produces extinction of drug-seeking behavior after episodes of opiate use. Adequate dosage appears important, as low-dose naltrexone resembled the placebo group; opiate positive urines were likely to be followed by dropout from treatment. The observation of high treatment retention among naltrexone-treated patients who do not test the blockade, suggests naltrexone may also exert direct effects on opiate-taking behavior that do not depend on extinction, perhaps by attenuating craving or normalizing dysregulated hedonic or neuroendocrine systems.

Investigating the safety and efficacy of naltrexone for anti-psychotic induced weight gain in severe mental illness: study protocol of a double-blind, randomized, placebo-controlled trial

BackgroundObesity is a growing health problem leading to high rates of mortality and morbidity in patients with severe mental illness (SMI). The increased rate of obesity is largely attributed to antipsychotic use. The effect of antipsychotic medications on H1 and 5HT2 receptors has been associated with weight gain, but there is also a substantial amount of evidence showing that D2 receptor blockade may be responsible for weight gain by interacting with the dopamine-opioid system. Unfortunately, current available medications for weight loss have limited efficacy in this population. Naltrexone, an opioid receptor antagonist, may be a promising agent to reduce antipsychotic induced weight gain by decreasing food cravings. We aim to investigate the safety and efficacy of two doses of naltrexone (25 mg & 50 mg) versus placebo for weight and health risk reduction in overweight and obese individuals (BMI ≥ 28) with SMI, who gained weight while being treated with antipsychotics.Methods and designOne hundred and forty four patients will be recruited throughout the greater New Haven area. The participants will be randomized to naltrexone 25 mg/day, naltrexone 50 mg/day, or placebo in a 1:1:1 ratio. Participants will be on the study medication for 52 weeks, and assessed weekly for the first 4 weeks and bi-weekly thereafter. The primary outcome measurements are weight reduction and percentage achieving clinically significant weight loss (5% of total body weight). Waist circumference, body mass index, serum lipid profile, fasting glucose, and glycosylated hemoglobin are the secondary outcome measures. The effect of naltrexone on other outcome measurements such as schizophrenia symptoms, depression, dietary consumption, quality of life, cognitive functioning, physical activity, metabolism/inflammation markers, serum leptin, ghrelin, peptide YY, adinopectin, high sensitivity CRP, interleukin 6, interleukin-1B, interleukin-18, and tumor necrosis factor alpha (TNF-α) will be evaluated. The data will be analyzed by applying linear mixed effect models.DiscussionThis is the first large scale study investigating the safety and efficacy of naltrexone in antipsychotic induced weight gain; and hopefully, this may lead to a novel pharmacological option for management of this major health problem.Trial registrationThis trial is registered in http://www.clinicaltrials.gov as NCT01866098

Withdrawal syndrome caused by naltrexone in opioid abusers

Naltrexone is a competitive opioid receptor antagonist acting at the µ- and k-opioid receptors that blocks the euphoric effects of exogenous administered opioids. When used in opioid-dependent patients, naltrexone can cause acute and severe withdrawal symptoms. This was a cross-sectional study conducted from December 2007 to March 2008 and consisted of patients who had used naltrexone accidentally or deliberately and were referred to Loghman-Hakim Poison Hospital, Tehran, Iran. All symptoms and signs were assessed and the relationship between the dose of naltrexone, opioid dependence, and outcome was evaluated. In 132 patients referred to our hospital, the most frequently reported symptoms and signs occurring in more than 10% of patients were agitation (96.2%), altered level of consciousness (38.6%), nausea (28%), vomiting (27.3%), abdominal pain (24.2%), diarrhea (16.7%), bone and muscle pain (15.9%), tachycardia (12.9%), and dilated pupils (11.4%). Being the most prominent symptom, the agitation was the most difficult aspect of withdrawal to manage. Except for agitation, no relationship was found between the presence of these symptoms and the dose of naltrexone used. Outcome of the patients (classified as complete recovery, partial recovery, death, and no follow-up) was related to the substance of addiction (p<0.05) but not to the naltrexone dose. Emergency physicians should be aware of the potential for severe agitation from naltrexone-precipitated hyperacute withdrawal and its appropriate management. Opioid-dependent patients who wish to continue withdrawal and abstinence must be encouraged to visit trained physicians and be warned about misuse of naltrexone.

The interaction of adenosine and morphine on pentylenetetrazole-induced seizure threshold in mice

Adenosine agonists or low doses of morphine exert anti-convulsant effects in different models of seizures. On the other hand, a tight interaction has been reported between morphine and adenosine in various paradigms. This study investigated the effect of the interaction of adenosine and morphine on seizure susceptibility in the intravenous mouse model of pentylenetetrazole (PTZ)-induced clonic seizures. The researchers used acute systemic administration of morphine, N6-cyclohexyladenosine (CHA) (a selective A1 receptor agonist), naltrexone (an opioid receptor antagonist) and 8-Cyclopentyl-1,3-dimethylxanthine (8-CPT) (a selective A1 receptor antagonist). Acute administration of morphine (0.25, 0.5 and 1 mg/kg) or CHA (0.25, 0.5, 1, 2 and 4 mg/kg) raised the threshold of seizures induced by PTZ. Non-effective dose of 8-CPT (2 mg/kg) inhibited the anticonvulsant effects of CHA (0.5 and 1 mg/kg). Combination of sub-effective doses of morphine (0.125 mg/kg) and CHA (0.125 mg/kg) increased clonic seizure latency showing the additive effect of morphine and CHA. The enhanced latency induced by combination of low doses of morphine and CHA completely reversed by 8-CPT (2 mg/kg) or naltrexone (1 mg/kg). Moreover, 8-CPT (2 mg/kg) inhibited anticonvulsant effects of morphine (0.25 and 0.5 mg/kg) and naltrexone (1 mg/kg) inhibited anticonvulsant effects of CHA (0.25, 0.5 and 1 mg/kg). Combination of low doses of 8-CPT (1 mg/kg) and naltrexone (0.5 mg/kg) inhibited the anticonvulsant effect of CHA (0.5 and 1 mg/kg). In conclusion, adenosine and morphine exhibit an additive effect on the enhancement of the pentylenetetrazole-induced seizure threshold in mice, probably through A1 or μ receptors.

Effects of neonatal visceral pain on morphine tolerance, dependence, and withdrawal in rats

Changes in brain opioid systems have been demonstrated in response to neonatal visceral pain (NVP), but few studies have examined the impact of these changes on opioid pharmacology. In these studies, we examined the effects of NVP on the development of tolerance, dependence, and expression of withdrawal effects of morphine in the rat. Experimental rats were subjected to a colorectal distension procedure on postnatal days 4, 6, and 8 to induce NVP, while control rats were not exposed to the NVP procedure. All rats were gradually shaped to a terminal FR20 schedule reinforced by food presentation. Once responding was stable and reliable, saline was injected subcutaneously (SC) before behavioral sessions, and morphine was administered (SC) immediately after behavioral sessions. Morphine doses were increased one quarter‐log every 7 days, from 1.0 mg/kg, to a final dose of 30 mg/kg, upon which rats were maintained for the duration of the experiment. Various doses of the opioid antagonist naltrexone (NTX) were sometimes administered 10 min before behavioral sessions to precipitate withdrawal. For both groups of rats, NTX dose‐dependently suppressed response rates, indicative of a precipitated withdrawal effect on food‐maintained responding. However, NTX induced more pronounced rate suppression in NVP rats at all tested doses. These findings demonstrate that the changes in brain opioid systems elicited by NVP have persistent pharmacological consequences into adulthood, are consistent with our previous studies suggesting that NVP increases sensitivity to abuse‐related effects of opioids across development, and extend our characterization of this vulnerable phenotype to include an increased susceptibility to antagonist‐precipitated withdrawal. These studies supported by the UAMS Center for Translational Neuroscience (RR020146) and the UAMS Translational Research Institute (RR029884).

Resistance to depression through interference of opioid and nitrergic systems in bile-duct ligated mice

This study was done to investigate the effects of opioid and nitrergic systems on depression in an experimental model of cholestasis in mice, since elevated levels of these substances are seen in cholestatic subjects. Bile duct ligated (BDL) and sham-operated mice were forced to swim individually and the immobility time in the last 4min of the 6min test was evaluated to determine the effects of cholestasis on depression. To assess the possible involvement of endogenous opioids and nitric oxide (NO), effective and sub-effective doses of naltrexone an antagonist of opioid receptors, and N-nitro-l-arginine methyl ester (L-NAME) a non-specific NO synthase inhibitor, were administrated acutely and chronically to BDL and Sham-operated mice and then their immobility time was measured in forced swimming test (FST). The immobility time significantly decreased after bile-duct ligation. Naltrexone and L-NAME significantly reversed antidepressant like effect of cholestasis. Co-administration of sub-effective doses of naltrexone and L-NAME also reversed antidepressant effect in FST in chronic administration. But acute drug administration did not reverse the anti-depressant effect of cholestasis. We have shown that elevated levels of endogenous opioids and NO in cholestatic mice induce an anti depressant like effect, causing a reduction in the mice immobility time in FST. And the study also showed the predominant effect of opioid system and NO modulation of that in anti-depressant like effect of cholestasis.

Involvement of μ-opioid receptors in antinociceptive action of botulinum toxin type A

Botulinum toxin A (BTX-A) is approved for treatment of chronic migraine and has been investigated in various other painful conditions. Recent evidence demonstrated retrograde axonal transport and suggested the involvement of CNS in antinociceptive effect of BTX-A. However, the mechanism of BTX-A central antinociceptive action is unknown. In this study we investigated the potential role of opioid receptors in BTX-A's antinociceptive activity.In formalin-induced inflammatory pain we assessed the effect of opioid antagonists on antinociceptive activity of BTX-A. Naltrexone was injected subcutaneously (0.02–2 mg/kg) or intrathecally (0.07 μg/10 μl–350 μg/10 μl), while selective μ-antagonist naloxonazine was administered intraperitoneally (5 mg/kg) prior to nociceptive testing. The influence of naltrexone (2 mg/kg s.c.) on BTX-A antinociceptive activity was examined additionally in an experimental neuropathy induced by partial sciatic nerve transection. To investigate the effects of naltrexone and BTX-A on neuronal activation in spinal cord, c-Fos expression was immunohistochemically examined in a model of formalin-induced pain.Antinociceptive effects of BTX-A in formalin and sciatic nerve transection-induced pain were prevented by non-selective opioid antagonist naltrexone. Similarly, BTX-A-induced pain reduction was abolished by low dose of intrathecal naltrexone and by selective μ-antagonist naloxonazine. BTX-A-induced decrease in dorsal horn c-Fos expression was prevented by naltrexone.Prevention of BTX-A effects on pain and c-Fos expression by opioid antagonists suggest that the central antinociceptive action of BTX-A might be associated with the activity of endogenous opioid system (involving μ-opioid receptor). These results provide first insights into the mechanism of BTX-A’s central antinociceptive activity.

The effect of naltrexone on the perception and distress in tinnitus: an open-label pilot study

Tinnitus is a perceived sensation of sound without actual acoustic stimulation. Currently there are no standardized drug therapies for the treatment of tinnitus patients. A potential novel treatment for chronic tinnitus is naltrexone. Tinnitus can be considered an auditory phantom phenomenon similar to phantom pain. Naltrexone acts predominantly on μ-opioid receptors which are present in multiple areas of the brain, including the thalamus, dorsal part of the anterior cingulate, insula, amygdala, nucleus accumbens, and ventromedial to orbitofrontal cortex. These areas overlap with the areas involved in tinnitus-related distress. The aim of the present study is to investigate three doses of naltrexone, namely 5, 12.5, and 50 mg and determine their influence on tinnitus complaints. We conducted a 4-week single-center, open-label treatment study. 86 patients received the drug treatment, while 30 patients received no treatment. Overall tinnitus distress was significantly reduced for the drug treatment group, while for the waiting control group this was not the case. No significant effect could be obtained for tinnitus intensity. A closer look at the data indicates that this effect is mainly generated due to a significant difference in the 50 mg drug treatment group for tinnitus distress. our results indicate that naltrexone might have an effect on tinnitus distress and more particularly higher doses of naltrexone.

Effectiveness of Naltrexone in the Prevention of Delayed Respiratory Arrest in Opioid-Naive Methadone-Intoxicated Patients

Acute methadone toxicity is a major public health concern in Iran. Methadone-intoxicated patients are in a great risk of recurrent or delayed respiratory arrest despite the prescription of initial doses of naloxone. This study aimed to evaluate the effectiveness of oral naltrexone in the management of acute methadone overdose in opioid-naive patients and check if it could be a substitute of continuous infusion of naloxone in maintaining adequate ventilation. In a randomized, double-blind, placebo-controlled study, a total of 54 opioid-naive patients with acute methadone toxicity were enrolled. The patients received either oral naltrexone or placebo capsules after awakening by naloxone. All patients underwent close monitoring of respiration. Frequency of respiratory depression or arrest, need for another dose of naloxone, duration of hospital stay, and adverse outcomes compared between the two groups. The incidence of respiratory depression was significantly less in those who had received naltrexone. Our results show that single oral dose of naltrexone is quite efficient in the prevention of recurrent or delayed respiratory arrest in opioid-naive methadone-intoxicated patients. It can shorten the duration of hospitalization and, as a consequence, decreased the risk of complications. Further studies are warranted before the generalization of this approach to other patient populations.

Opioidergic and dopaminergic manipulation of gambling tendencies: a preliminary study in male recreational gamblers.

Gambling is characterized by cognitive distortions in the processing of chance and skill that are exacerbated in pathological gambling. Opioid and dopamine dysregulation is implicated in pathological gambling, but it is unclear whether these neurotransmitters modulate gambling distortions. The objective of the current study was to assess the effects of the opioid receptor antagonist naltrexone and the dopamine D2 receptor antagonist haloperidol on gambling behavior. Male recreational gamblers (n = 62) were assigned to receive single oral doses of naltrexone 50 mg, haloperidol 2 mg or placebo, in a parallel-groups design. At 2.5 h post-dosing, participants completed a slot machine task to elicit monetary wins, “near-misses,” and a manipulation of personal choice, and a roulette game to elicit two biases in sequential processing, the gambler's fallacy and the hot hand belief. Psychophysiological responses (electrodermal activity and heart rate) were taken during the slot machine task, and plasma prolactin increase was assessed. The tasks successfully induced the gambling effects of interest. Some of these effects differed across treatment groups, although the direction of effect was not in line with our predictions. Differences were driven by the naltrexone group, which displayed a greater physiological response to wins, and marginally higher confidence ratings on winning streaks. Prolactin levels increased in the naltrexone group, but did not differ between haloperidol and placebo, implying that naltrexone but not haloperidol may have been functionally active at these doses. Our results support opioid modulation of cognition during gambling-like tasks, but did not support the more specific hypothesis that naltrexone may act to ameliorate cognitive distortions.

P13 Resistance to depression through interference of opioid and nitrergic systems in bile-duct ligated (BDL) mice

<h3>Objective</h3> Endogenous opioids and nitric oxide (NO) are signalling molecules that play important roles in depressive disorders. Elevated levels of these substances are seen in cholestasis subjects. This study was undertaken to investigate the effect of opioid and nitrergic systems on depression in an experimental model of cholestasis. <h3>Method</h3> Bile duct ligated (BDL) and sham-operated mice were forced to swim individually and the immobility time of the last 4 min was evaluated to determine the effect of cholestasis on depression. To assess the possible involvement of endogenous opioids and NO, an antagonist of opioids receptors, naltrexone (20 mg/kg, i.p.), and a non-specific NOS inhibitor, N-nitro-l-arginine methyl ester (L-NAME, 20 mg/kg, i.p.), and sub-effective doses of both of them (3 mg/kg, i.p.) were administrated acutely, one hour before forced swimming test (FST). And chronically, both for 5 and 7 days after operation, to BDL and Sham-operated mice and then were tested by FST. <h3>Results</h3> The immobility time significantly decreased after bile duct ligation. naltrexone and L-NAME significantly reversed antidepressant like effect of cholestasis in both 5 and 7 days groups .Co-administration of sub-effective doses of naltrexone and L-NAME also reversed antidepressant effect in FST in chronic administration, and significant difference was observed in immobility times between all 5 and 7 days groups. But acute drug administration did not reverse the anti-depressant effect of cholestasis. <h3>Conclusion</h3> We have shown for the first time that elevated levels of endogenous opioids and nitric oxide (NO) due to bile-duct ligation in mice induce an antidepressant like effect, causing a reduction in mice immobility time in FST. The effect was reversed with blockage of nitrergic and opioid systems. And also study showed the predominant effect of opioid system and NO modulation of that in anti-depressant like effect of cholestasis.

Cocaine reverses the naltrexone-induced reduction in operant ethanol self-administration: The effects on immediate-early gene expression in the rat prefrontal cortex

Naltrexone is a clinically approved medication for alcoholism. We aimed to investigate the effectiveness of naltrexone co-administered with cocaine and the association of these substances with immediate-early gene expression in the rat prefrontal cortex. We used chronic operant ethanol self-administration and oral treatments prescribed for alcoholism and available in pharmacies to maximise the predictive validity in humans. We performed real-time PCR analysis to determine gene expression levels in the prefrontal cortex. Only the highest dose of naltrexone (1, 3, and 10 mg/kg, p.o.) reduced the response to ethanol. Cocaine increased ethanol self-administration in a dose-dependent manner (2.5, 10, 20 mg/kg, i.p.) and reversed the naltrexone-induced reduction. Naltrexone failed to prevent the cocaine-induced increase in locomotor activity observed in these animals. Chronic self-administration of ethanol reduced the expression of the C-fos gene 4- to 12-fold and increased expression of the COX-2 (up to 4-fold) and Homer1a genes in the rat prefrontal cortex. Chronic ethanol self-administration is prevented by naltrexone, but cocaine fully reverses this effect. This result suggests that cocaine may overcome naltrexone's effectiveness as a treatment for alcoholism. The ethanol-induced reduction in C-fos gene expression in the prefrontal cortex reveals an abnormal activity of these neurons, which may be relevant in the compulsive consumption of ethanol, the control of reward-related areas and the behavioural phenotype of ethanol addiction.

A ‘MIRACLE CURE’ MISUNDERSTOOD

Keith Humphreys' inclusion of ‘ultra-rapid opiate detoxification’[1], among discredited ‘miracle cures’ for addiction, needs several important qualifications. The basic theory (using opiate antagonists to make withdrawal shorter, more successful and less unpleasant) was validated in several randomized controlled trials (RCTs) by respected academics in the 1970s and 1980s, all using oral sedation as well as specific antiwithdrawal drugs such as clonidine, to reduce discomfort. Using general anaesthesia (GA) or intravenous sedation (IVS) was a logical development, especially for patients who were difficult to sedate orally. Loimer and his entirely academic colleagues in Vienna were the first to use anaesthesia and regarded the procedure as merely making planned opiate withdrawal easier and more certain. Antagonist-precipitated withdrawal is now combined invariably with initiating oral or implanted naltrexone (NTX). RCTs show that supervised NTX is an effective adjunct to abstinence-based programmes [2] (as supervised disulfiram is in alcoholism), and that NTX implants/depot-injections are more effective than oral NTX or placebo implants. A ‘rapid’ opiate detoxification (ROD) is simply one in which a full dose of NTX (or an implant) is given within 24 hours of starting [3] and can be performed under oral sedation, IVS or GA. ‘Ultra-rapid opiate detox’ (UROD) is no quicker than other rapid methods but was trademarked by the CITA company, who promoted UROD irresponsibly as a miracle cure [4]. They also criticized agonist maintenance. In Britain, ROD acquired a bad reputation when a UROD patient died in unsupervised and thus still mysterious circumstances in a CITA clinic. However, in several other centres, using a variety of rapid or accelerated techniques, hundreds or even thousands of patients have had ROD followed by depot NTX with little detoxification morbidity, no deaths and 3-year outcomes that can compare with agonist maintenance. The Stapleford Centre is a private clinic and provides both agonist- and antagonist-based treatments for opiate dependence. It does not currently conduct rapid detoxifications.