Ibogaine-like effects of noribogaine in rats

Ibogaine is a naturally occurring alkaloid that has been claimed to be effective in treating addiction to opioids and stimulants; a single dose is claimed to be effective for 6 months. Analogously, studies in rats have demonstrated prolonged (one or more days) effects of ibogaine on morphine and cocaine self-administration even though ibogaine is mostly eliminated from the body in several hours. These observations have suggested that a metabolite may mediate some of the effects of ibogaine. Recently, noribogaine was identified as a metabolite of ibogaine. Accordingly, the present study sought to determine, in rats, whether noribogaine had pharmacological effects mimicking those of ibogaine. Noribogaine (40 mg/kg) was found to decrease morphine and cocaine self-administration, reduce the locomotor stimulant effect of morphine, and decrease extracellular levels of dopamine in the nucleus accumbens and striatum. All of these effects were similar to effects previously observed with ibogaine (40 mg/kg); however, noribogaine did not induce any ibogaine-like tremors. The results suggest that noribogaine may be a mediator of ibogaine's putative anti-addictive effects.     

Attenuation of alcohol consumption by a novel nontoxic ibogaine analogue (18-methoxycoronaridine) in alcohol-preferring rats

We previously reported that single administration of ibogaine, an indol alkaloid with antiaddictive properties, dose dependently reduced alcohol intake in three strains of alcohol-preferring rats. The present study examined the effect of different doses of a newly developed nontoxic ibogaine analogue, 18-methoxycoronaridine (18-MC), on alcohol intake. Selectively bred alcohol-preferring rats received a single intraperitoneal injection of vehicle or 5, 20 and 40 mg/kg of 18-MC at 9:30 AM, and their consumption of alcohol, water and food was measured for 24 h. Our results demonstrate that a single injection of 18-MC significantly and dose dependently attenuated alcohol consumption and preference and commensurately increased water intake. Only the highest dose of 18-MC significantly decreased food intake. Although the true mechanism of action of 18-MC in suppressing alcohol intake is not yet fully understood, it may, like ibogaine, exert its attenuating effects on alcohol consumption by modulating neurotransmitters believed to be involved in the regulation of alcohol intake.     

Modelling migration: the clock-and-compass model can explain the distribution of ringing recoveries

The present study was carried out to investigate the relative involvement of spinal opioid receptors in the development of physical dependence on intrathecal (i.t.) butorphanol in comparison with i.t. morphine. Dependence was induced by continuous i.t. infusion of butorphanol (52 nmol/h) and morphine (26 nmol/h) for 4 days in male Sprague-Dawley rats. Naloxone, CTOP, naltrindole, and nor-binaltorphimine (nor-BNI) were administered i.t. to precipitate behavioral signs of withdrawal. Administration of i.t. naloxone produced a significantly greater increase in the profile of withdrawal signs in i.t. morphine dependence than that in i.t. butorphanol dependence. An i.t. nor-BNI challenge elicits behavioral signs of withdrawal only in rats dependent on i.t. butorphanol, but not in rats dependent on i.t. morphine. CTOP administered i.t. precipitated withdrawal signs in i.t. morphine dependence that were greater than that in i.t. butorphanol dependence. An i.t. treatment with naltrindole produced equivalent signs of withdrawal in both i.t. butorphanol- and morphine-dependent rats. These results suggest that continuous i.t. butorphanol results in the development of less physical dependence than that of i.t. morphine. Spinal kappa- rather than delta- and mu-opioid receptors play a major role in the development of i.t. butorphanol dependence, whereas spinal mu-opioid receptors play a more important role than delta-opioid receptors in i.t. morphine dependence.     

Effect of yohimbine on the development of morphine dependence in the rat: lack of involvement of cortical beta-adrenoceptor modifications

The alpha-2 receptor antagonist yohimbine has been previously shown to prevent the development of morphine dependence in a rat behavioral model. This study was directed to clarify the mechanism of this interaction, which is presently unknown. Since upregulation of cortical beta-adrenoceptors has been suggested to be involved in morphine withdrawal, we have tested the possible correlation between receptor density and withdrawal behaviors in the presence of yohimbine. Sprague-Dawley male rats received a s.c. suspension of morphine (300 mg/kg) or the vehicle. Animals received saline or yohimbine (4 mg/kg, IP) 24, 28, 48 and 52 h after morphine and finally naloxone (1 mg/kg i.p) at 72 h; the subsequent signs of withdrawal (mainly wet-dog shakes and escape attempts) were recorded and the cerebral cortex dissected to study [3H]-CGP 12177 binding. Morphine-treated animals displayed a marked withdrawal behavior together with beta-adrenoceptor upregulation; nevertheless, these effects were not correlated. As expected, yohimbine prevented morphine withdrawal behavior but did not reverse the beta-adrenoceptor upregulation induced by the opiate. These results confirm previous evidence against the involvement of beta-adrenoceptor upregulation on morphine withdrawal behaviors and also permit to discard beta-adrenoceptor regulation as the neurochemical basis of the antiwithdrawal effect of yohimbine. The possible contribution of some other neurochemical effects of yohimbine are discussed to explain the inhibition of morphine dependence by that drug.     

Drug dependence study on vigabatrin in rhesus monkeys and rats

The dependence potential of vigabatrin (gamma-vinyl GABA; R(-)/S(+)-4-amino-5-hexenoic acid, CAS 60643-86-9, MDL 71,754) was assessed in rhesus monkeys and rats. In the test of cross physical dependence potential, morphine- and barbital-dependent monkeys were both withdrawn from the respective drugs and the ability of vigabatrin to suppress the withdrawal signs was assessed. In morphine-dependent monkeys, subcutaneous doses of vigabatrin at 256 and 1000 mg/kg did not suppress withdrawal signs while subcutaneous doses of codeine phosphate at 4 and 8 mg/kg clearly suppressed the withdrawal signs. In barbital-dependent monkeys, subcutaneous and intravenous dose of vigabatrin, both at 1000 mg/kg, did not suppress the withdrawal signs, while intragastric doses of diazepam at 8 and 16 mg/kg clearly suppressed them. Thus, while the cross-physical dependence potential of codeine/morphine and of diazepam/barbital was clearly observable, vigabatrin appeared to have no such potential. In the test of physical dependence-producing potential with the drug-admixed food method in rats, vigabatrin and diazepam were given to rats mixed with food for 28 days in an increasing dosage schedule, followed by feeding a drug-free diet to observe withdrawal signs for 7 days. Upon withdrawal, no decrease in food intake or body weight was observed in the vigabatrin-treated groups, and the gross condition of the animals did not differ from that in the control group. In contrast, food intake and body weight decreased markedly in the diazepam group, and most rats showed hyperreactivity to external stimuli. Thus, while the physical dependence-producing potential of diazepam was clearly demonstrated, such potential was not shown with vigabatrin. In the test of reinforcing effect, 4 monkeys were allowed to self-administer pentobarbital at 1 mg/kg/infusion, or vigabatrin at 16, 32, and 64 mg/kg/infusion, intravenously through an indwelling catheter. Each drug was preceded and followed by saline self-administration for at least 7 days. Active self-administration of pentobarbital was observed in all monkeys tested, while the self-administration rate of vigabatrin did not differ from saline. Thus, while the reinforcing effect of pentobarbital was clearly observed, such effect was not observable with vigabatrin. Based on these results, it was considered that vigabatrin was devoid of dependence potential.     

Prior morphine exposure enhances ibogaine antagonism of morphine-induced dopamine release in rats

The present study examines the effect of prior morphine exposure on ibogaine antagonism of morphine-induced dopamine release. Female Sprague-Dawley rats were pretreated once a day for 2 days with morphine (20 mg/kg, i.p.) or saline and given a low dose of ibogaine (10 mg/kg, i.p.) or saline 5 hr after the last morphine or saline injection. Nineteen hours later, rats (awake and freely moving) were challenged with morphine (5 mg/kg, i.p.), and dopamine and its metabolites were monitored in the striatum and nucleus accumbens using in vivo microdialysis. Neither saline pretreatment, morphine pretreatment, nor ibogaine alone altered morphine-induced increases in extracellular dopamine and dopamine metabolites in either structure. However, when morphine pretreatment was combined with ibogaine, the morphine-induced elevation of dopamine, but not of metabolites, was completely blocked. These data suggest that prior morphine exposure enhances an opioid antagonist action of ibogaine on dopaminergic systems and that prior drug exposure may be a clinically significant determinant of ibogaine efficacy and/or potency in the treatment of opioid addiction.     

Effect of ibogaine on the development of tolerance to the analgesic effect of morphine.

The results of 3 experiments demonstrated that (a) 20 mg/kg ibogaine (but not 10 mg/kg), administered 30 min before morphine, attenuates the development of tolerance to the analgesic effect of morphine in rats; (b) this 20 mg/kg dose of ibogaine, if administered 5 hr before morphine, has no effect on tolerance development; and (c) a high dose of ibogaine (40 mg/kg), administered 24 hr before morphine, does not affect analgesic tolerance (despite reports that this dose of ibogaine, administered 1 day before morphine, modulates the neurochemical and reinforcing effect of the opiate, see P. Popik, R. T. Layer, & P. Skolnick, 1995). The findings are discussed in the context of suggestions that ibogaine be evaluated as a treatment for opiate dependence, and recent research indicating that ibogaine is an N-methyl-{D}-aspartate antagonist. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Na+,K+-ATPase activity in cultured bovine retinal pigment epithelium

Ibogaine (Endabuse) is a psychoactive indole alkaloid found in the West African shrub, Tabernanthe iboga. This drug interrupts cocaine and amphetamine abuse and has been proposed for treatment of addiction to these stimulants. However, the mechanism of action that explains its pharmacological properties is unclear. Since previous studies demonstrated differential effects of psychotomimetic drugs (cocaine and methamphetamine) on neuropeptides such as neurotensin (NT), the present study was designed to determine: (1) the effects of ibogaine on striatal, nigral, cortical, and accumbens neurotensin-like immunoreactivity (NTLI); (2) the effects of selective dopamine antagonists on ibogaine-induced changes in NT concentrations in these brain areas; and (3) the effects of ibogaine pretreatment on cocaine-induced changes in striatal, nigral, cortical and accumbens NTLI content. Ibogaine treatments profoundly affected NT systems by increasing striatal, nigral, and accumbens NTLI content 12 h after the last drug administration. In contrast, NTLI concentrations were not significantly increased in the frontal cortex after ibogaine treatment. The ibogaine-induced increases in NTLI in striatum, nucleus accumbens and substantia nigra were blocked by coadministration of the selective D1 receptor antagonist, SCH 23390. The D2 receptor antagonist, eticlopride, blocked the ibogaine-induced increase in nigral NTLI, but not in striatum and nucleus accumbens. Ibogaine pretreatment significantly blocked the striatal and nigral increases of NTLI resulting from a single cocaine administration. Whereas many of the responses by NT systems to ibogaine resembled those which occur after cocaine, there were also some important differences. These data suggest that NT may contribute to an interaction between ibogaine and the DA system and may participate in the pharmacological actions of this drug.     

Ibogaine and a total alkaloidal extract of Voacanga africana modulate neuronal excitability and synaptic transmission in the rat parabrachial nucleus in vitro

Ibogaine is a natural alkaloid of Voacanga africana that is effective in the treatment of withdrawal symptoms and craving in drug addicts. As the synaptic and cellular basis of ibogaine's actions are not well understood, this study tested the hypothesis that ibogaine and Voacanga africana extract modulate neuronal excitability and synaptic transmission in the parabrachial nucleus using the nystatin perforated patch-recording technique. Ibogaine and Voacanga africana extract dose dependently, reversibly, and consistently attenuate evoked excitatory synaptic currents recorded in parabrachial neurons. The ED50 of ibogaine's effect is 5 microM, while that of Voacanga africana extract is 170 micrograms/ml. At higher concentrations, ibogaine and Voacanga africana extract induce inward currents or depolarization that are accompanied by increases in evoked and spontaneous firing rate. The depolarization or inward current is also accompanied by an increase in input resistance and reverses polarity around 0 mV. The depolarization and synaptic depression were blocked by the dopamine receptor antagonist haloperidol. These results indicate that ibogaine and Voacanga africana extract 1) depolarize parabrachial neurons with increased excitability and firing rate; 2) depress non-NMDA receptor-mediated fast synaptic transmission; 3) involve dopamine receptor activation in their actions. These results further reveal that the Voacanga africana extract has one-hundredth the activity of ibogaine in depressing synaptic responses. Thus, ibogaine and Voacanga africana extract may produce their central effects by altering dopaminergic and glutamatergic processes.     

Attenuation of punishing effects of morphine and amphetamine by chronic prior treatment.

In a previous study L. Parker et al (see record 1973-20548-001) found that the gustatory aversion normally produced by morphine did not occur when rats were first made dependent on the drug. Their explanation of this phenomenon was that dependent, withdrawn animals are in an "unnatural need state" such that a taste stimulus paired with morphine will become preferred by pairing with a beneficial need-replenishing event. This explanation was examined in the present 2 experiments with a total of 180 male Wistar rats. In Exp I the Parker et al results were supported in a conceptually similar experiment. In Exp II it was shown that analogous results could be produced with amphetamine, a drug upon which physicial dependence has not been unequivocally demonstrated and for which the regulation of self-administration does not follow the morphine pattern. Since the evidence for a "need" artificially induced by amphetamine withdrawal was not strong, the hypothesis that these data reflect preference for a substance associated with need reduction may be questioned. Of the various explanations for the phenomenon, only one involving the concept of drug tolerance has no arguments against it. (16 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Opioid receptors altered binding nature in guinea-pig brain following the development of morphine dependence

Morphine is well known to produce tolerance and dependence. The mechanisms for these phenomena are not clearly understood and there are a number of conflicting reports that chronic morphine administration decreases, increases, or leaves unchanged the number of opioid binding sites. We examined the potency of MScontin (oral controlled-release preparation of morphine) to induce morphine dependence and also determined the change of mu, delta and kappa opioid receptor types in brain homogenates obtained from morphine-dependent guinea-pigs. 1. Guinea-pigs were implanted subcutaneously with MScontin (300 mg.kg-1) and naloxone was employed to precipitate jumping behavior of withdrawal symptoms at various times. The highest degree of physical dependence was observed on the 2nd day after implantation. Therefore, this period was chosen to investigate opioid receptor binding assay. 2. Two days after implantation, the binding of 3H-DAGO (mu agonist), 3H-DPDPE (delta agonist) and 3H-U69593 (kappa agonist) to brain membranes prepared from morphine dependent and control guinea-pigs was determined. Scatchard plot of the saturation binding data revealed an increase in Bmax values (maximum specific binding) and no change in the Kd values (equilibrium dissociation constants) of 3H-opioid ligand bindings obtained from morphine-dependent animals as compared to controls. These results indicate that brain mu, delta and kappa opioid receptors are up-regulated in morphine dependent guinea-pigs.     

Effects of administration of phentonium bromide on opioid withdrawal syndrome in rats

This study has tested whether phentonium bromide, a quaternary ammonium anti-muscarinic agent, could reverse the signs of precipitated opioid withdrawal. Rats were treated with either saline or morphine for 4 days, after which half the rats received naloxone and half saline. Each animal also received one of four doses of phentonium bromide (0, 1, 3 and 9 mg kg(-1), i.p.). Administration of phentonium bromide in rats receiving naloxone after chronic morphine treatment reduced the intensity of withdrawal signs such as increased defecation or micturition, salivation and wet-dog shakes, and elevated the nociceptive threshold values. The effects of administration of phentonium bromide might result from its anti-muscarinic activity interfering peripherally with the mechanisms involved in the regulation of the withdrawal symptoms. The use of this drug is thus suggested as a possible means of controlling some of the signs observed during the acute phase of opioid withdrawal in heroin addicts.     

Ibogaine attenuates morphine-induced conditioned place preference.

Ibogaine, a putative anticraving drug in humans, reduces the ability of a single injection of morphine to produce a place preference in rats (Rattus norvegicus). The attenuation of morphine's effect is seen even if ibogaine is administered 24 hr before the opiate. However, after the 4th morphine conditioning trial, ibogaine no longer modified morphine reward. Ibogaine alone is neither reinforcing nor aversive, and ibogaine does not affect place aversions produced by naloxone or lithium chloride. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

An intraventricular infusion model for inducing morphine dependence in rats: Quantitative assessment of precipitated withdrawal.

Describes an experimental model of morphine dependence in which male Sprague-Dawley rats were made dependent upon morphine by intraventricular infusion. Morphine dependence was quantified by a series of withdrawal signs that were induced by the intraperitoneal administration of the morphine antagonist naloxone (5 mg/kg). The infusion of different concentrations of morphine resulted in the production of physical dependence, the severity of which was directly correlated with the concentration of morphine infused. A weak to moderate degree of dependence characterized by such withdrawal signs as teeth chattering, whole-body shakes, and vocalization was produced by infusions of morphine less than 5 μg/hr. A strong degree of physical dependence characterized by additional dominant withdrawal signs such as jumping and launching was produced by the infusion of 50 μg/hr morphine. The morphine pellet model that most closely approximated this degree of dependence was a 3-pellet model in which a single 75-mg morphine pellet was implanted at 48-hr intervals. Abstinence precipitated by removal of the morphine-containing osmotic minipumps was characterized primarily by teeth chattering and whole-body shakes that persisted for at least 48 hrs. (38 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Inhibitory effect of agmatine on naloxone-precipitated abstinence syndrome in morphine dependent rats

Effects of agmatine, which is an endogenous polyamine metabolite formed by decarboxylation of L-arginine, were investigated on the morphine abstinence syndrome in rats. Two pellets containing 75 mg morphine base (total 150 mg) were implanted subcutaneously on the back of rats. Seventy-two hours after morphine implantation, agmatine sulphate (20, 30 and 40 mg/kg) or saline was injected intraperitoneally. Forty-five min later, naloxone (2 mg/kg) was injected intraperitoneally to induce precipitated withdrawal. Immediately after naloxone injection, rats were observed for 15 min, and abstinence syndrome signs, which included jumping, wet dog shake, writhing, defecation, ptosis, teeth chattering and diarrhea were counted or rated. Agmatine attenuated all of the signs of the morphine abstinence syndrome dose dependently and significantly. Our results suggest that agmatine prevents naloxone-precipitated abstinence syndrome in morphine dependent rats; thus, this drug may be beneficial in the treatment of opioid dependence.     

Physical dependence produced by dihydroetorphine in mice

Using various administration schedules, the physical dependence produced by dihydroetorphine (DHE) was compared with that of morphine in mice. Physical dependence, evaluated by naloxone-precipitated withdrawal signs, did not develop following daily treatment with DHE (10, 20, 100 and 1000 micrograms/kg, i.p. or 30, 100 and 1000 ng/mouse, i.c.v.) for 6 d. However, 5 repeated injections of DHE (10 micrograms/kg, i.p.) at 1 or 2 h intervals did produce physical dependence and the dependent state disappeared after 2 h. Accordingly, it was demonstrated that a sufficient degree of antinociceptive activity needed to be maintained, longer than several hours, for the development of physical dependence on DHE and that the duration of the dependent state was very short. In the single dose suppression test, a single dose of DHE completely suppressed the natural withdrawal signs that appeared following abstinence in morphine-dependent animals without reappearance of significant withdrawal signs, indicating the suitability of DHE as a substitute for morphine. The characteristic properties of DHE, the extremely potent antinociceptive effect and minimal dependence, indicate the separation of the antinociceptive effect from dependence, and suggest that it may be possible to develop a novel drug which may be safely used in clinical situations.     

Oxytocin and addiction: a review

Neuropeptides affect adaptive central nervous system processes related to opiate ethanol and cocaine addiction. Oxytocin (OXT), a neurohypophyseal neuropeptide synthesized in the brain and released at the posterior pituitary, also is released in the central nervous system (CNS). OXT acts within the CNS and has been shown to inhibit the development of tolerance to morphine, and to attenuate various symptoms of morphine withdrawal in mice. In rats, intravenous self-administration of heroin was potently decreased by OXT treatment. In relation to cocaine abuse, OXT dose-dependently decreased cocaine-induced hyperlocomotion and stereotyped grooming behavior. Following chronic cocaine treatment, the behavioral tolerance to the sniffing-inducing effect of cocaine was markedly inhibited by OXT. Behavioral sensitization to cocaine, on the other hand, was facilitated by OXT. OXT receptors in the CNS--mainly those located in limbic and basal forebrain structures--are responsible for mediating various effects of OXT in the opiate- and cocaine-addicted organism. Dopaminergic neurotransmission--primarily in basal forebrain structures--is another important biochemical mediator of the central nervous system effects of OXT. Tolerance to ethanol (e.g. hypothermia-inducing effect of ethanol) also was inhibited by OXT.     

Results of systematic speech sound monitoring in children with cleft palate

Two potent inhibitors of nitric oxide synthase (NOS), namely, NG-nitro-L-arginine (NNA) and NG-monomethyl-L-arginine (NMMA) were administered intracerebroventricularly (i.c.v.) in morphine-dependent mice to investigate their effects on abrupt withdrawal and naltrexone-precipitated abstinence signs. Male Swiss-Webster mice were rendered dependent on morphine by subcutaneous implantation of a morphine pellet containing 75 mg of morphine base. Mice implanted with placebo pellets served as controls. NMMA or NNA administered i.c.v. had minimal effects on body weight loss and hypothermia that occur during abrupt withdrawal of morphine. When administered i.c.v., both NNA or NMMA (0.1, 1 and 10 micrograms/mouse) dose-dependently inhibited naltrexone-induced stereotyped jumping behavior in mice. I.c.v. administration of NMMA also attenuated withdrawal induced fecal pellet formation. This effect, however, was not dose-dependent. In conclusion, these results suggest that brain NO plays an important role in the expression of behavioral signs of morphine withdrawal syndrome. In addition, these results support the idea that NOS inhibitors may be potentially useful in the treatment of opioid withdrawal syndrome.     

The effects of cholinergic compounds on the development of morphine tolerance, dependence and increased naloxone potency in mice

The effects of chronic treatment with morphine and cholinergic compounds on the development of morphine tolerance, physical dependence and increased naloxone potency were studied. Using the abdominal constriction method, it was shown that morphine tolerance was apparent after s.c. administration of morphine 20.0 mg/kg three times a day for four days. It was found that, in animals which showed a low degree of morphine tolerance, the naloxone potency was similar to that determined in mice which had been pretreated with only a single dose of morphine which causes no measurable tolerance. Thus, the development of increased naloxone potency and tolerance to morphine do not parallel each other. In addition, while atropine inhibited, and anti-cholinesterase drugs enhanced, the development of increased naloxone potency caused by morphine treatment they had no or little effect on the development of morphine tolerance. Furthermore, chronic treatment with cholinergic agonists reduced, while muscarinic antagonist enhanced, the development of physical dependence on morphine as assessed by withdrawal jumping and body weight loss. It is concluded that the increased potency of naloxone in antagonising the antinociceptive effect of morphine can be dissociated from the development of tolerance to, and physical dependence on, morphine in mice.     

Opioid withdrawal activates MAP kinase in locus coeruleus neurons in morphine-dependent rats in vivo

Opioid dependence is widely believed to result from neuroadaptations in specific brain regions. However, the precise molecular mechanisms underlying these adaptations are not yet clear. Our aim was to explore the role of mitogen-activated protein kinase (MAPK) in mu opioid receptor signalling in vivo. Using anti-phospho MAPK antibodies, activated MAPK was detected in cortical neurons (layers II/III), median eminence, amygdaloid and hypothalamic nuclei in untreated animals. Dense nuclear and cytoplasmic staining was observed resulting in full visualization of processes in these cells. Chronic, but not acute, administration of morphine greatly diminished this staining pattern while mu opioid receptor levels and levels of MAP kinase as detected with a phosphorylation state-independent antibody were unchanged. When opioid withdrawal was precipitated with naloxone a dramatic increase in MAP kinase phosphorylation was observed in somata and fibres of locus coeruleus, solitary tract and hypothalamic neurons. Thus, the differential activation state of MAPK could have important implications for understanding the mechanisms underlying opioid tolerance and dependence.