Morphine Withdrawal Syndrome In Rats Research Articles

The Effects of Bupropion and Varenicline on Morphine Withdrawal Syndrome in Rats

Objective: Opioid dependence is a chronic and complex disorder characterized by relapse and remission. Chronic administration of morphine causes symptoms of physical and psychological dependence. The purpose of the present study was to investigate the effect of anti-addictive drugs such as bupropion and varenicline on morphine dependence and naloxone precipitated withdrawal syndrome in a rat model. Materials and Methods: To assess the physical dependence of morphine, Wistar albino rats were intraperitoneal (i.p.) administered increasing doses of morphine twice daily for 5 days, 4 hours after a single dose of morphine on day 6, and 15 minutes before subcutaneous (s.c.) naloxone (2 mg/kg, s.c.) administration to elicit withdrawal symptoms. Physical dependence was evaluated by giving intraperitoneal bupropion (5, 10 and 20 mg/kg, i.p.) and varenicline (0.5. 1 and 2 mg/kg, s.c) for 15 minutes. Results: The morphine-dependent rats had significantly more withdrawal symptoms than naive control rats. The results demonstrated administration of bupropion and varenicline during induction of morphine dependence attenuated the most of the severity of withdrawal symptoms. Co-administration of bupropion reduced withdrawal symptoms such as jumping, wet dog shaking, weight loss and total withdrawal symptoms. Co-administration of varenicline was found to be effective on withdrawal symptoms such as bupropion, but had no effect on weight loss. Conclusion: These outcomes provide preliminary data that bupropion and varenicline could be used as a candidate drugs to attenuate morphine withdrawal symptoms.

Protective effect of zinc sulfate and continuous/interval training on liver oxidative stress in morphine-withdrawal syndrome in rats

Introduction: In this study, the effect of zinc sulfate (ZS) supplement and eight-week continuous training (CT) and interval training (IT) on liver oxidative stress of morphine-dependent rats following withdrawal syndrome (WS) were evaluated. Methods: Seventy Wistar rats were randomly divided into seven groups: control rats, withdrawing rats (WS), withdrawing rats receiving 9mg/kg ZS orally (WS+Z), withdrawing rats under CT (WS+CT), withdrawing rats under IT (WS+IT), withdrawing rats under CT and receiving 9mg/kg zinc sulfate (WS+Z+CT), withdrawing rats under IT and receiving 9mg/kg zinc sulfate (WS+Z+IT). Animals were addicted by 0.4g/l morphine sulfate in 21 days. Animals in the training groups ran on a treadmill and received ZS 5 days/week for 8 weeks. At the end of the study, oxidative stress in liver tissue and liver enzymes were measured by spectrophotometric and ELISA methods. Results: ZS supplement, CT/IT led to decrease DNA damage and malondialdehyde in comparison with morphine group. Also, ZS, CT and IT significantly elevated levels in superoxide dismutase, catalase activity, total antioxidant capacity and thiol groups in the liver of rats in comparison with morphine group. Additionally, it is observed that ZS and CT/IT made a significant reduction in aspartate aminotransferase levels in comparison to the morphine group. Conclusion: CT/IT with ZS because of its antioxidant effects has the potential to be used for decreased withdrawal syndrome complications.

The blockade of GABAA receptors attenuates the inhibitory effect of orexin type 1 receptors antagonist on morphine withdrawal syndrome in rats

The aim of present study was to investigate the involvement of orexin-A neuropeptide in naloxone-induced morphine withdrawal syndrome via modulating neurons bearing GABAA receptors. The locus coeruleus (LC) is a sensitive site for expression of the somatic aspects of morphine withdrawal. Intra-LC microinjection of GABAA receptor agonist attenuates morphine withdrawal signs in rats. Here we studied the influence of LC orexin type 1 receptors blockade by SB-334867 in presence of bicuculline, a GABAA receptor antagonist, on naloxone-induced morphine withdrawal syndrome.Adult male Wistar rats, weighing 250–300g, were rendered dependent on morphine by subcutaneous (s.c.) injection of increasing morphine doses (6, 16, 26, 36, 46, 56 and 66mg/kg, 2ml/kg) at set intervals of 24h for 7 days. On 8th day, naloxone (3mg/kg, s.c.) was injected and the somatic signs of morphine withdrawal were evaluated. Intra-LC microinjections (0.2μl) of either bicuculline (15μM) or SB-334867 (3mM) or a combination of both chemicals were done immediately before naloxone injection. Intra-LC microinjection of bicuculline (15μM) had no significant effect on morphine withdrawal signs, whereas intra-LC microinjection of SB-334867 considerably attenuated morphine withdrawal signs. However, the effect of SB-334867 in attenuating naloxone-induced morphine withdrawal signs was blocked in presence of bicuculline. This finding, for the first time, indicated that orexin-A may participate in expression of naloxone-induced morphine withdrawal syndrome partly through decreasing the activity of neurons bearing GABAA receptors.

Acute Administration of Pioglitazone Attenuates Morphine Withdrawal Syndrome in Rat: A Novel Role of Pioglitazone

Long-term exposure to opiates such is morphine induces dependence. The purpose of the present study was to investigate the effects of the acute administration of pioglitazone, a selective agonist of peroxisome proliferator activated receptors gamma (PPAR-γ), on the morphine withdrawal syndrome in the rat. Male Wistar rats (200-250 g) were selected randomly and divided into 8 groups including 2 non-dependent groups and 6 morphine-dependent groups which were received additive doses of morphine subcutaneously at an interval of 12 h for 9 continuous days. On the ninth day, only the morning dose of morphine was injected and 2 h later, morphine withdrawal was precipitated by naloxone and then ten distinct withdrawal behaviors were recorded for 45 min. Pioglitazone (5, 10, 20 and 40 mg/kg) was gavaged 2 h before naloxone injection. It is worth noting that 1 h before the pioglitazone (40 mg/kg) gavage, GW-9662 (2 mg/kg), a selective PPAR-γ antagonist, was administrated in order to evaluate the possible role of the PPAR-γ. The results of this study showed that administration of pioglitazone (40 mg/kg) decreased all withdrawal signs and the statistical analysis indicated that pioglitazone could attenuate the total withdrawal scores significantly. Administration of GW-9662 had no significant effect on pioglitazone attenuation effect on morphine withdrawal symptoms.Taking together, it was concluded that acute oral administration of pioglitazone prevented naloxone-precipitated withdrawal symptoms and GW-9662 could not revert its effect on morphine withdrawal syndrome. It seems that pioglitazone suppresses morphine withdrawal syndrome through PPAR-γ independent mechanisms.

Repeated central administration of selegiline attenuated morphine physical dependence in rat

BackgroundLong-term exposure to opiates induces physical dependence; however, the neurobiological mechanisms of this phenomenon are not completely clear. The purpose of this study was to evaluate the effects of systemic and intracerebroventricular (icv) administration of selegiline (a selective inhibitor of monoamine oxidase B) on the morphine withdrawal syndrome in rats. MethodsTo this aim, adult male Sprague Dawley rats were selected randomly, and then growing doses of morphine were administered subcutaneously at an interval of 12h for nine days with the intention of inducing dependency. Nine days after, only the morning dose of morphine was administered, followed by systemic or central injection of saline or selegiline. Later, naloxone was injected after 30min and withdrawal signs recorded for a period of 60min. ResultsResults showed failure of systemic administration of selegiline in changing the withdrawal symptoms; nevertheless, icv injection attenuated the withdrawal signs significantly. ConclusionIn conclusion we found that central administration of selegiline attenuated morphine withdrawal symptoms

Suppression of acute morphine withdrawal syndrome by adenovirus-mediated β-endorphin in rats

Background: Endogenous β-endorphin (β-EP) in the central nervous system (CNS) is decreased upon opioid addiction. The current study examined whether exogenous β-EP, delivered using an adenoviral vector into the CNS could attenuate morphine withdrawal syndrome in rats. Methods: The model of opioid-dependent rats was set up by receiving subcutaneous injection of morphine using an escalating regimen for 6 days (5, 10, 20, 40, 50, 60 mg/kg, three times/day). The adenovirus mediated β-EP gene was constructed based on our previous work. The ilea of opioid-dependent rats were isolated and treated with the supernatant of Ad-NEP. The basic and naloxone-induced (4 μm/l) contractions of dependent ilea were recorded. The Ad-NEP was injected into the left lateral ventricle of the addition rats. The expression of the β-EP gene was verified by radioimmunoassay of the cerebrospinal fluid (CSF) and immunocytochemistry for β-EP. Withdrawal syndrome was evaluated after intraperitoneal injection of naloxone. Results: The contractions of dependent ilea were attenuated with supernatant containing β-EP expressed by Ad-NEP. Injection of the Ad-NEP resulted in significant increases in β-EP level in the CSF and β-EP-positive neurons. Rats receiving adenovirus carrying the β-EP gene had significantly less severe withdrawal symptoms upon naloxone challenge. Conclusions: Exogenous β-EP mediated by adenovirus could attenuate withdrawal syndrome in morphine-dependent rats.

The inhibitory effect of Hypericum perforatum extract on morphine withdrawal syndrome in rat and comparison with clonidine

The effects of Hypericum perforatum (St John's wort) on morphine withdrawal syndrome and comparison with clonidine have been investigated in morphine-dependent rats. Adult male Wistar rats were subjects. The frequencies of withdrawal behavioral signs (rearing, teeth chattering and jumping) induced by naloxone challenge were demonstrated in morphine dependent rats receiving Hypericum perforatum extract (HPE), saline or clonidine. The withdrawal behavioral manifestations in rats were inhibited significantly by chronic co-administration of Hypericum perforatum extract or clonidine with morphine. This study showed that clonidine was more effective than HPE at a dose of 0.4 mL/200 g and there was no significant statistical difference between the mean frequency of withdrawal signs of HPE at a dose of 0.8 mL/200 g compared with clonidine (0.2 mg/kg i.p.) but at a dose of 1.2 mL/200 g of HPE was significantly stronger than clonidine in attenuation of the morphine withdrawal syndrome.The findings suggest that HPE is capable of reducing the symptoms of opiate withdrawal and its effectiveness may be equivalent to clonidine in reducing the opiate withdrawal syndrome and may have human therapeutic potential.

P03-40 The effects of Locus coeruleus inactivation on I.V self administration of morphine and morphine withdrawal symptoms in rats

Biochemical, behavioral, and electrophysiologic studies indicate that activation of the noradrenergic cells in the Locus coeruleus (LC) play an important role in the symptoms of opiate withdrawal. There for in this study the effects of LC inactivation on self-administration of Morphine and on morphine withdrawal syndrome in rats has been investigated.Male rats (250-300gr) were anaesthetized and implanted with silastic catheters inserted in to the right jugular vein. after 5 days animals were fitted and the external end of the catheter was connected with a syringe-driven pump, then were placed in the self-administration apparatus that had two lever (active, passive) for 2 h every day. Active lever switched on the infusion pump for 10 sec, injecting. 1ml of saline or saline containing 5 mg/ml of morphine (training period was 10days). LC was inactivated by (1ul) lidocaein (%2) five min befor training.Animals were allowed to self administer morphine (1mg/kg per inf.) ten consecutive daily 2-h session. During all morphine self administration session lever pressing behavior was measured. Our results show that LC inactivation 5min before morphine self administration produced a significant decrease in the initiation of morphine self administration during all session. after the last test session morphine withdrawal symptom signs (MWS) precipitated by naloxone were measured. Our results show that most of MWS (but not all) were decreased by LC inactivation in comparison with morphine group.

Effect of testosterone on morphine withdrawal syndrome in rats

To determine whether testosterone is involved in morphine withdrawal syndrome (WS). In order to induce dependency, rats were treated with subcutaneous injection of morphine (days 1-2, 5 mg/kg; days 3-5, 7.5 mg/kg; days 6-8, 10 mg/kg), and after the last dose of morphine (day 8) WS was induced by intraperitoneal injection of naloxone (1 mg/kg). Wet dog shake (WDS), abdomen writhing (AW), and jumps (J) were recorded as indicators of WS. The severity of WDS, AW, and J in male rats was greater than that in females. Accordingly, in 4-week castrated and flutamide-treated (10 mg/kg/day for 8 days, i.p.) male rats, WDS, AW, and J were significantly decreased compared to male control rats. Testosterone replacement therapy (10 mg/kg/day for 8 days, i.m.) in 4-week castrated rats restored the severity of WDS, AW, and J behaviors to the level of non-castrated male rats, whereas testosterone potentiated the WDS behavior in non-castrated male rats. It can be concluded that testosterone might be effectively involved in morphine WS.

P.6.d.007 Evaluation of the role of 5-HT1A receptors in dorsal and median raphe nuclei on the morphine withdrawal syndrome in rat

P.6.d.007 Evaluation of the role of 5-HT1A receptors in dorsal and median raphe nuclei on the morphine withdrawal syndrome in rat

NMDA Receptor in Nucleus Accumbens is Implicated in Morphine Withdrawal in Rats

The purpose of the present study is to elucidate whether ketamine, a non-competitive antagonist of the NMDA receptor, can suppress the morphine withdrawal syndrome in rats at a dose without affecting motor functions and to identify its site of action in the central nervous system. Rats were made dependent on morphine by multiple injections of morphine hydrochloride for 5 days. They were then given ketamine at the following doses and routes of administration: (a) intraperitoneal (i.p.) injections (2-16 mg/kg), (b) intracerebroventricular (i.c.v.) injections (4-100 microg), and (c) intra-nucleus accumbens (NAc) or intra-amygdalar microinjections (0.4-10 microg). Naloxone HCl (1 mg/kg, i.p.) was administered 3 h after the last ketamine injection to precipitate withdrawal syndrome, which was scored within a period of 30 min. Results showed that some of the precipitated withdrawal signs were dose-dependently suppressed by repeated injections of ketamine at 8 and 16 mg/kg, i.p. or 100 microg, i.c.v. Dose-dependent suppression was observed by repeated microinjections (0.4-10 microg) of ketamine to NAc, but not to amygdala. These results indicate that the NMDA receptor antagonist ketamine has the ability to suppress morphine withdrawal syndrome in experimental settings without motor interference, and NAc could be the critical CNS site mediating such effect.

Influence of nociceptin(1-17) fragments and its tyrosine-substituted derivative on morphine-withdrawal signs in rats.

Our previous studies demonstrated that endogenous ligand of nociceptin (NOP) receptor, nociceptin(1-17) (also known as orphanin FQ), inhibits morphine-withdrawal syndrome measured as wet dog shakes in rats [Life Sci. 66 (2000) PL119]. This peptide is metabolized in the spinal cord, both in vitro and in vivo, to shorter fragments, including nociceptin(1-11) and nociceptin(1-6). These fragments, formed after cleavage by endogenous peptidase, are behaviorally active and modulate nociception in a bi-phasic process [Peptides 20 (1999) 239]. As these peptides induced transient naloxone-reversible analgesia in behavioral tests [Peptides 20 (1999) 239], in the present study we tested the influence of nociceptin(1-11) (10 and 20 microg) and nociceptin(1-6) (10, 20 and 40 microg) on the morphine-withdrawal syndrome in rats. Furthermore, the modified fragment of nociceptin(1-6) with an opioid-message domain achieved by replacement of Phe1 with Tyr was tested. Morphine-withdrawal syndrome was precipitated by the i.p. injection of naloxone hydrochloride (2 mg/kg), 72 h after implantation of morphine pellets. The wet-dog shakes were chosen for statistical analyses of the abstinence signs. The results show that nociceptin(1-11) and (1-6) attenuate this morphine-withdrawal symptom. The replacement of Phe1 with Tyr in nociceptin(1-6) fragment did not potentiate the influence of nociceptin(1-6) on wet dog shakes precipitated by naloxone in morphine-dependent rats.

Effects of harman and harmine on naloxone-precipitated withdrawal syndrome in morphine-dependent rats

The effects of the beta-carbolines, harman and harmine, on naloxone-precipitated withdrawal syndrome in morphine-dependent rats were investigated. Two morphine pellets containing 75 mg morphine base were implanted subcutaneously in the scapular area of adult male Wistar rats (200–250 g) under light ether anesthesia. Rats were then assigned to several groups (n = 12 for each group). Seventy-two hours after morphine implantation, harman (5 and 10 mg/kg), harmine (5 and 10 mg/kg) or saline was injected to rats intraperitoneally (ip). After 45 min, a morphine withdrawal syndrome was precipitated by naloxone (2 mg/kg, ip), and morphine withdrawal signs were observed and evaluated for 15 min. Harmine (5 and 10 mg/kg) attenuated significantly the intensity of all signs of morphine withdrawal except for jumping. While jumping behaviour appearing in morphine withdrawal was intensified by harman (5 and 10 mg/kg) treatment, harmine administration did not produce any significant change in the intensity of this sign. Harman attenuated significantly the intensity of wet dog shakes, writhing, defecation, tremor and ptosis. However, it produced no significant changes in the intensity of teeth chattering and diarrhea. Our results suggest that harman and harmine, β-carbolines, have some beneficial effects on naloxone-precipitated morphine withdrawal syndrome in rats. Findings from the present study also indicated that harmine was more effective than harman on morphine abstinence syndrome.

Possible involvement of the locus coeruleus in inhibition by prostanoid EP 3 receptor-selective agonists of morphine withdrawal syndrome in rats

We examined the mechanism of the inhibitory effect of prostanoid EP 3 receptor agonists on naloxone-precipitated withdrawal syndrome in morphine-dependent rats. Rats were rendered morphine dependent by subcutaneous (s.c.) implantation of two pellets containing 75 mg morphine for 5 days. Morphine withdrawal syndrome was precipitated by i.p. injection of naloxone (3 mg/kg). Intracerebroventricular (i.c.v.) administration of (±)-15α-hydroxy-9-oxo-16-phenoxy-17,18,19,20-tetranorprost-13- trans-enoic acid (M&B28,767: prostanoid EP 3 receptor agonist) or sulprostone (prostanoid EP 1/EP 3 receptor agonist) significantly suppressed many withdrawal signs. Northern blotting and in situ hybridization studies revealed that i.c.v. administration of M&B28,767 (1 pg/rat) attenuated the elevation of c- fos mRNA during naloxone-precipitated withdrawal in many brain regions, including the cerebral cortex, thalamus, hypothalamus and locus coeruleus. Double in situ hybridization analysis revealed that in the locus coeruleus most of the tyrosine hydroxylase mRNA-positive neurons expressed μ-opioid receptor mRNA and more than half of these neurons were positive for prostanoid EP 3 receptor mRNA. These results indicate that the suppression by prostanoid EP 3 receptor agonists of naloxone-precipitated morphine withdrawal syndrome can be attributed to the inhibition of neuronal activity in several brain regions, including the locus coeruleus, the largest source of central noradrenergic neurons.

Suppression of morphine withdrawal by electroacupuncture in rats: dynorphin and κ-opioid receptor implicated

Our previous work has demonstrated that 100-Hz electroacupuncture (EA) or 100-Hz transcutaneous electrical nerve stimulation (TENS) was very effective in ameliorating the morphine withdrawal syndrome in rats and humans. The mechanism was obscure. (1) Rats were made dependent on morphine by repeated morphine injections (5–140 mg/kg, s.c., twice a day) for eight days. They were then given 100-Hz EA for 30 min 24 h after the last injection of morphine. A marked increase in tail flick latency (TFL) was observed. This effect of 100-Hz EA could be blocked by naloxone (NX) at 20 mg/kg, but not at 1 mg/kg, suggesting that 100-Hz EA-induced analgesia observed in morphine-dependent rats is mediated by κ-opioid receptors. (2) A significant decrease of the concentration of dynorphin A (1–17) immunoreactivity (-ir) was observed in the spinal perfusate in morphine-dependent rats, that could be brought back to normal level by 100-Hz EA. (3) 100-Hz EA was very effective in suppressing NX-precipitated morphine withdrawal syndrome. This effect of EA could be prevented by intrathecal administration of nor-BNI (2.5 μg/20 μl), a κ-opioid receptor antagonist, or dynorphin A (1–13) antibodies (25 μg/20 μl) administered 10 min prior to EA. In conclusion, while the steady-state spinal dynorphin release is low in morphine-dependent rats, it can be activated by 100-Hz EA stimulation, which may be responsible for eliciting an analgesic effect and ameliorating morphine withdrawal syndrome, most probably via interacting with κ-opioid receptor at spinal level.

ICV administration of CRF blocker (CRF 9–41 ∂ helical) reduces morphine withdrawal in rats

1. 1. The effects of CRF 9–41 ∂ helical on morphine withdrawal signs in rats were studied 2. 2. Intracerebroventricular administration of CRF 9–41 ∂ helical 5 at 10 μg/kg reduced central and peripheral symptons of the withdrawal syndrome, such as ptosis, jumping, wet dog shakes and teeth chatering; other signs remained unchanged. The effect were not dose dependent. 3. 3. The hypothermi characteristic of the Withdrawal sindrome was reduced by CRF 9–41 ∂ helical. 4. 4. These results suggest that the hypothalamo pituitary adrenal(HPA) axis play an important role in the morphine withdrawal syndrome in rats.

Cholecystokinin modulates the aversive component of morphine withdrawal syndrome in rats

The conditioned place aversion paradigm was used to investigate the role of cholecystokinin in the aversive/dysphoric component of morphine abstinence. Several cholecystokinin ligands were chronically administered during the development of morphine dependence: the CCK A antagonist devazepide, the CCK B antagonists PD-134,308 and L-365,260, and the CCK B agonist BC 264. The CCK-B antagonists L-365,260 and PD-134,308 decreased and completely blocked (respectively) the place aversion induced by naloxone in morphine dependent animals whereas BC 264 and devazepide were inactive in this model. No effect was observed in non-dependent animals after chronic administration of these CCK-ligands. These results show a distinct role for CCK receptors in the regulation of the motivational component of morphine abstinence, probably related to their differential effects in the regulation of limbic dopaminergic neurons.

Ethopharmacological analysis of naloxone-precipitated morphine withdrawal syndrome in rats: a newly-developed “etho-score”

The intensity of opiate withdrawal syndrome in rats is usually quantified on the basis of selected physical signs or global scores. However, the selection criteria of signs and scores have not been subjected to an ethological discussion, hence they appear to be somewhat arbitrary. The objectives of this study were thus: i) to analyse the rat's behaviour during the naloxone-precipitated morphine withdrawal syndrome, ii) to evaluate the validity of classic methods, and iii) to design a new "etho-score". Ten rats were implanted with morphine pellets (75 mg x 2, SC), all receiving different naloxone doses following a within-subject design (0, 0.01, 0.05, 0.1, 0.5, 1 mg/kg SC). Twenty unexperienced rats and 20 with placebo pellets were injected with either saline or naloxone. Behaviour was videotaped and later analysed by computer-based ethological techniques. The ethogram encompassed 16 patterns displayed by rats during morphine withdrawal. Frequency, duration and latency of each pattern was measured, and a cluster analysis allowed discerning the structure of behaviour. Several physical signs and the Gellert-Holtzman score were also evaluated. The data revealed that writhing responses linearly changed in a dose-related fashion, and mastication was also enhanced after naloxone. Wet-dog shakes and jumping changed following an U-shaped curve. Significant changes in weight loss were found to be dose-dependent, and highly correlated to diarrhea. Learning effects were found to reliably affect exploration, writhing responses and some physical signs. The Gellert-Holtzman score was gradually enhanced after naloxone, being affected by learning as well. Naloxone affected lying and self-care responses in placebo rats. To sum up, the data indicated that: i) classic signs are useful, although most of them are disrupted by high naloxone or affected by learning effects, ii) the Gellert-Holtzman score was validated in this study, and iii) mastication and weight loss are good indicators of naloxone-precipitated morphine withdrawal, representing the basis of an "etho-score" which is herein proposed.

Comparative study of normotensive and hypertensive nitric oxide synthase inhibitors on morphine withdrawal syndrome in rats

The effects of the normotensive, mainly centrally active nitric oxide synthase (NOS) inhibitor 7-nitro indazole and the hypertensive drug N G-nitro- l-arginine, which blocks both the endothelial and the central NOS, have been examined on naloxone-precipitated withdrawal in morphine-dependent rats. Both drugs attenuated the same withdrawal signs (teeth-chattering, penile licking, diarrhoea, chewing, wet-dog shakes, grooming), while other signs remained unaffected (rearing, jumping, ptosis, rhinorrhoea, irritability on touch). These findings indicate that mainly central (but not endothelial) nitric oxide is involved in the expression of some opioid withdrawal symptoms.

The inhibitory effect of norharman on morphine withdrawal syndrome in rats: Comparison with ibogaine

Norharman (20 mg/kg, i.p.) and ibogaine (40 mg/kg, i.p.) significantly attenuated naloxone (4 mg/kg, i.p.)-precipitated withdrawal syndrome in morphine-dependent rats. Several withdrawal signs, such as teeth-chattering, chewing, penile licking and diarrhoea, were decreased by both norharman and ibogaine. In addition, norharman reduced also the withdrawal grooming and rearing. It is concluded that both norharman and ibogaine are inhibitors of withdrawal syndrome in morphine-dependent rats.