Anti-addictive Properties Research Articles

Iboga compounds reverse the behavioural disinhibiting and corticosterone effects of acute methamphetamine: Implications for their antiaddictive properties

This study investigated the effects of pretreatment with the putative antiaddictive compound, ibogaine (IBO), and its synthetic derivative, 18-methoxycoronaridine (18-MC), on the changes in behaviour in an elevated plus maze and the changes in corticosterone (CORT) produced by a low dose of methamphetamine (METH). In the elevated plus maze, the acute administration of METH (0.1 mg/kg ip, −20 min) produced an increase in both the number and the duration of open arm entries relative to saline (SAL)-treated controls. No effect of METH administration was observed on the total number of arm entries. These data indicated that METH alone produced either anxiolysis or behavioural disinhibition in this paradigm. More consistent with the latter possibility, the open arm behaviour of METH controls was associated with an increase in plasma levels of CORT, supporting a facilitatory role for CORT in this METH-induced effect. Pretreatment with both IBO and 18-MC (40 mg/kg ip, 19 h earlier) antagonized the behavioural disinhibiting effects of acute METH without altering locomotor activity. In addition, both iboga agents antagonized the increase in CORT produced by METH. These data provide insight into yet another potential mechanism through which iboga compounds may exert their antiaddictive effects, a reversal of the behavioural disinhibiting properties of stimulant drugs. Furthermore, these data indicate that this reversal is related to effects of iboga compounds on the stimulation of neuroendocrine systems by stimulant drugs.

Ibogaine alters synaptosomal and glial glutamate release and uptake.

Ibogaine has aroused expectations as a potentially innovative medication for drug addiction. It has been proposed that antagonism of the NMDA receptor by ibogaine may be one of the mechanisms underlying its antiaddictive properties; glutamate has also been implicated in ibogaine-induced neurotoxicity. We here report the effects of ibogaine on [3H]glutamate release and uptake in cortical and cerebellar synaptosomes, as well as in cortical astrocyte cultures, from mice and rats. Ibogaine (2-1000 microM) had no effects on glutamate uptake or release by rat synaptosomes. However, ibogaine (500-1000 microM) significantly inhibited the glutamate uptake and stimulated the release of glutamate by cortical (but not cerebellar) synaptosomes of mice. In addition, ibogaine (1000 microM) nearly abolished glutamate uptake by cortical astrocyte cultures from rats and mice. The data provide direct evidence of glutamate involvement in ibogaine-induced neurotoxicity.

Chapter 3 Ibogaine as a glutamate antagonist: Relevance to its putative antiaddictive properties

The chapter presents a discussion on ibogaine as a glutamate antagonist. The chapter presents an overview data demonstrating that pharmacologically relevant concentrations of ibogaine produce a blockade of N methyl-D-aspartate (NMDA) receptors and relates the relevance of these findings to its antiaddictive properties. If the neurochemical and electrophysiological studies with ibogaine are pharmacologically meaningful, then like other NMDA antagonists, ibogaine should protect against NMDA receptor-mediated neurotoxicity. The chapter presents in vitro data that provide compelling evidence on ibogaine acting as an NMDA antagonist. Glycine is a coagonist at NMDA receptors. Because of the presence of specific transporters that appear colocalized with NMDA receptors, it is unlikely that these strychnine-insensitive glycine sites are saturated under physiological conditions. Like other NMDA antagonists, memantine (a lowaffinity, uncompetitive NMDA antagonist) blocks the expression of morphine withdrawal in mice.

Chapter 7 Changes in gene expression and signal transduction following ibogaine treatment

Publisher Summary The chapter presents a study on the changes in gene expression and signal transduction following ibogaine treatment. Drug addiction may not be mediated by one neurochemical pathway and brain structure, but by a complex interaction of programs of gene expression with specific signal transduction pathways and environmental factors. The putative antiaddictive effect of ibogaine may result from the restoration of altered or disrupted programs of central and peripheral neuroadaptative processes involving programmed genes and their associated signaling mechanisms. One new hypothesis being explored is that both the peripheral and central actions of abused substances contribute to drug addiction. One new hypothesis being explored is that both the peripheral and central actions of abused substances contribute to drug addiction. Treatment with cocaine influences the regulation of certain genes in the brain, as indicated by the activation and inhibition of the expression sequence tags (ESTs) that have been isolated. The cAMP-responsive element binding protein (CREB), the first CRE-binding factor to be characterized ( 5 ), is a transcription factor of general importance in both neuronal and other cells. CREB phosphorylation on Ser-133 promotes the activation of genes with an upstream CRE element. If anxiety or stress is a factor in drug dependency, then the anti-addictive property of ibogaine in vivo may be associated with modifying the CNS neurotransmission that may be involved in anxiety.

Chapter 4 Drug discrimination studies with ibogaine

The results of the studies described here support the hypothesis that ibogaine produces its effects via selective interactions with multiple receptors. It appears that 5-HT2A, 5-HT2C, and sigma 2 receptors are involved in mediating the stimulus effects of ibogaine. In addition, opiate receptors may also be involved. In contrast, sigma 1, PCP/MK-801, 5-HT3, and 5-HT1A receptors do not appear to play a major role. Ibogaine's hallucinogenic effects may be explained by its interactions with 5-HT2A and 5-HT2C receptors, while its putative antiaddictive properties may result from its interactions with sigma 2 and opiate receptors. Alternatively, the possibility that ibogaine's hallucinogenic properties underlie its antiaddictive effects, as previously suggested (34), would support a role for 5-HT2 receptors in mediating the reported therapeutic effects of ibogaine. Certainly many questions remain regarding ibogaine's mechanism of action. Although drug discrimination will be useful for answering some of those questions, the true potential of this technique is realized whin it is combined with other techniques. The next few years promise to be fruitful with respect to our understanding of this agent. Reasons supporting this belief include advances in the study of sigma receptors, interest in ibogaine's effects on second messenger systems, and the development of ibogaine congeners such as 18-methoxycoronaridine (35). In conclusion, the aforementioned studies should serve to guide further endeavors. Pertinent questions have been generated: What is the role of sigma receptors in the effects of ibogaine, especially with regard to addiction? How does ibogaine affect opiate neurotransmission? What effects, if any, do the Harmala alkaloids have on addiction phenomena? What is the mechanism of action of harmaline? Can 10-hydroxyibogamine serve as a discriminative stimulus and, if so, what receptor interactions mediate its stimulus effects? Does the ibogaine-trained stimulus generalize to novel agents, including 18-methoxycoronaridine?

Differential effects of ibogaine on behavioural and dopamine sensitization to cocaine

To investigate a possible basis for the proposed anti-addictive property of ibogaine, the effects of ibogaine (40 mg/kg, i.p., 19 h earlier) on the expression of sensitization induced by cocaine were investigated. Ibogaine pretreatment potentiated the increase in the stereotypic effects of a cocaine challenge (20 mg/kg) in both sensitized (5×15 mg/kg, i.p.) and acutely treated rats. However, while ibogaine pretreatment did not significantly alter the dopamine response in the nucleus accumbens to acute cocaine, it abolished the expression of cocaine-induced dopamine sensitization. This result demonstrates that ibogaine pretreatment can reverse one of the neuroadaptations produced by chronic cocaine administration, an effect that may contribute to its putative anti-addictive property.

Pharmacological comparison of the effect of ibogaine and 18-methoxycoronaridine on isolated smooth muscle from the rat and guinea-pig.

Ibogaine and 18-methoxycoronaridine are naturally occurring alkaloids reported to possess antiaddictive properties in several models of drug dependence. We have examined their effect at mu-opioid receptors regulating neurogenic contractions of several smooth muscle preparations and also against spontaneous contractions of the rat isolated portal vein. Ibogaine (pIC(50) 5.28) and 18-methoxycoronaridine (pIC(50) 5.05) caused a concentration-dependent inhibition of cholinergic contractions of the guinea-pig ileum which was not affected by the opioid receptor antagonist naloxone (1 microM). In the rat isolated vas deferens ibogaine and 18-methoxycoronaridine caused a concentration-dependent enhancement of purinergic contractions. Both agents (30 microM) caused a 3 - 5 fold rightward displacement of DAMGO-induced inhibition of purinergic contractions, but similar effects were observed for ibogaine against alpha(2)-adrenoceptor-mediated inhibition of neurogenic responses. In the guinea-pig isolated bladder both ibogaine (10 microM) and 18-methoxycoronaridine (10 microM) caused a 2 fold increase in the purinergic component of neurogenic contractions without significantly altering cholinergic contractions or responses to exogenous ATP. In contrast, ibogaine (1 - 30 microM), but not 18-methoxycoronaridine, caused a concentration-dependent enhancement of spontaneous contractions of the rat isolated portal vein. In summary, while ibogaine and 18-methoxycoronaridine modulated electrically-evoked contractions in the three preparations examined, we have no evidence for a selective interaction with pre-junctional mu-opioid receptors. The pronounced enhancement of purinergic contractions produced by both agents is a novel finding and worthy of further investigation.

Long-lasting ibogaine protection against NMDA-induced convulsions in mice.

Ibogaine, a putative antiaddictive drug, is remarkable in its apparent ability to downgrade withdrawal symptoms and drug craving for extended periods of time after a single dose. Ibogaine acts as a non-competitive NMDA receptor antagonist, while NMDA has been implicated in long lasting changes in neuronal function and in the physiological basis of drug addiction. The purpose of this study was to verify if persistent changes in NMDA receptors could be shown in vivo and in vitro after a single administration of ibogaine. The time course of ibogaine effects were examined on NMDA-induced seizures and [3H] MK-801 binding to cortical membranes in mice 30 min, 24, 48, and 72 h post treatment. Ibogaine (80 mg/kg, ip) was effective in inhibiting convulsions induced by NMDA at 24 and 72 hours post administration. Likewise, [3H] MK-801 binding was significantly decreased at 24 and 72 h post ibogaine. No significant differences from controls were found at 30 min or 48 h post ibogaine. This long lasting and complex pattern of modulation of NMDA receptors prompted by a single dose of ibogaine may be associated to its antiaddictive properties.

The effects of ibogaine on dopamine and serotonin transport in rat brain synaptosomes

Ibogaine has been shown to affect biogenic amine levels in selected brain regions. Because of the involvement of these neurotransmitters in drug addiction, the effects of ibogaine on biogenic amine transport may contribute to the potential anti-addictive properties of ibogaine in vivo. With rat brain synaptosomes as our experimental system, we measured the effects of ibogaine on the uptake and release of dopamine (DA) and serotonin (5-HT). Ibogaine competitively blocked both DA and 5-HT uptake with IC50 values of 20 μM at 75 nM 3H-DA and 2.6 μM at 10 nM 3H-5-HT. Ibogaine had no effect on K+-induced release of 3H-DA from preloaded synaptosomes, but 20 μM and 50 μM ibogaine inhibited roughly 40% and 60%, respectively, of the K+-induced release of 3H-5-HT from preloaded synaptosomes. In the absence of a depolarizing stimulus, ibogaine evoked a small release of 3H-DA but not 3H-5-HT. These relatively low-potency effects of ibogaine on DA and 5-HT uptake in synaptosomes are consistent with the low binding affinity of ibogaine that has been previously reported for DA and 5-HT transporters. Our results show that if ibogaine modulates DA and 5-HT levels in the brain by directly blocking their uptake, then a concentration of ibogaine in the micromolar range is required. Furthermore, if the anti-addictive effects of ibogaine require this concentration, then ibogaine likely exerts these effects through a combination of neurotransmitter pathways, because binding affinities and functional potencies of ibogaine in the micromolar range have been reported for a variety of neuronal receptors and transporters.

Acute iboga alkaloid effects on extracellular serotonin (5-HT) levels in nucleus accumbens and striatum in rats

The iboga alkaloid, ibogaine, its metabolite, noribogaine, and the congener, 18-methoxycoronaridine (18-MC) have all been claimed to have anti-addictive properties in animal models, but the mechanisms underlying these effects are unclear. Ibogaine and noribogaine were shown to have affinity for the serotonin transporter, and inhibition of serotonin reuptake has been proposed to be involved in their anti-addictive actions. It is not known yet if 18-MC also has this property. In vivo microdialysis and HPLC (microbore) were used to determine acute changes in extracellular serotonin levels in nucleus accumbens (NAC) and striatum (STR) after both i.p. (40 mg/kg for all drugs) and i.v. (1–10 mg/kg for ibogaine and noribogaine) drug administration in awake freely moving female Sprague–Dawley rats (250–275 g). After i.p. administration, ibogaine, noribogaine and 18-MC had very different effects on extracellular serotonin levels in both NAC and STR: ibogaine elicited large increases (up to 25-fold in NAC and 10- fold in STR), noribogaine produced moderate increases (up to 8-fold in NAC and 5-fold in STR), and 18-MC had no effect in either brain region. These and other data suggest that (1) the serotonergic system may not be an essential factor in the anti-addictive actions of these drugs; (2) ibogaine (or an unidentified metabolite) may release serotonin as well as inhibit its reuptake; (3) stimulation of the ascending serotonergic system may mediate ibogaine's hallucinogenic effect; and (4) 18-MC probably has no affinity for the serotonin transporter, and is unlikely to be a hallucinogen.

Alteration in Electroencephalogram and Monoamine Concentrations in Rat Brain following Ibogaine Treatment.

Ibogaine (IBO) is a psychoactive indole alkaloid that has antiaddictive properties. However, treatment with IBO may lead to neurotoxicity, since IBO and its metabolites interact persistently with many neurotransmitter systems. Here, we recorded cortical electroencephalogram (EEG) signals from rats anesthetized with isoflurane. The heart rate (HR) was monitored via electrocardiogram (EKG) electrodes. After the baseline EEG was recorded, rats received one intraperitoneal (i.p.) dose of 50 mg/kg IBO. EEG signals were recorded for 2 hr. Rats were then sacrificed and brains dissected into frontal cortex (FC), caudate nucleus (CN), hippocampus (HIP), and brain stem (BS). The level of dopamine (DA), serotonin (5-HT), and their metabolites were determined by high-performance liquid chromatography with electrochemical detection (HPLC-ECD). Compared with baseline, a decrease in HR immediately after IBO injection and a decrease in δ, θ, α, and β power spectra frequency bands (1-4, 4-8, 8-13, 13-32Hz) during the first 30 min after IBO administration was observed. EEG recovered within the next 15 min. In CN, the level of DA decreased and DA turnover rate increased significantly. The levels of 5-HT increased in FC. The pattern of EKG and EEG response to IBO may be due to multiple receptor interactions of IBO.

In Vivo Ibogaine Blockade and In Vitro PKC Action of Cocainea.

Ibogaine may have antiaddiction potential against alcohol, psychostimulant and opiate abuse, but its mechanism of action is unclear. Ibogaine, however, has been demonstrated in numerous studies to have effects in multiple central nervous system (CNS) neurotransmitters systems. We are using in vitro and in vivo systems to study the effects of cocaine and whether these effects can be blocked by ibogaine. For the In Vivo studies, we first determined the acute and subacute effects of ibogaine (1-5.0 mg/kg) in mice using the plus-maze test. Acutely increasing doses of ibogaine produced a reduced aversion to the open arms. The subacute administration provoked a variable response which was characterized by fluctuations in aversive and antiaversive behavior of the animals to the open arms of the plus-maze during the 14-day treatment period. A separate group of mice received 1.0 mg/kg cocaine for 14 days, and upon abrupt cessation from cocaine treatment, ibogaine 2.5 mg/kg was administered to a subgroup of these mice. Ibogaine reversed the withdrawal aversions produced by the abrupt cessation from cocaine administration. For the in vitro studies, the expression and activity of protein kinase C (PKC) isoforms and Ca2+ levels were examined following the incubation of PC 12 cells with cocaine. This is because PKC plays a key role in a number of cellular and neuronal functions. We report that cocaine disrupts signal transduction in PC 12 cells by altering the expression and activity of PKC isoforms and Ca2+ levels. The data obtained suggest (1) that the PC 12 cells may be useful in studying the neurobiology of abused drugs, like cocaine in vitro, (2) that if anxiety is a factor in drug dependency, then the antiaddictive property of ibogaine In Vivo may be associated with modifying the CNS neurotransmission that may be involved in anxiety. It remains to be determined whether the signaling involving PKC is important in the antiaddictive properties of ibogaine.

Medication Development of Ibogaine as a Pharmacotherapy for Drug Dependencea.

The potential for deriving new psychotherapeutic medications from natural sources has led to renewed interest in rain forest plants as a source of lead compounds for the development of antiaddiction medications. Ibogaine is an indole alkaloid found in the roots of Tabernanthe iboga (Apocynaceae family), a rain forest shrub that is native to equatorial Africa. Ibogaine is used by indigenous peoples in low doses to combat fatigue, hunger and in higher doses as a sacrament in religious rituals. Members of American and European addict self-help groups have claimed that ibogaine promotes long-term drug abstinence from addictive substances, including psychostimulants and cocaine. Anecdotal reports attest that a single dose of ibogaine eliminates withdrawal symptoms and reduces drug cravings for extended periods of time. The purported antiaddictive properties of ibogaine require rigorous validation in humans. We have initiated a rising tolerance study using single administration to assess the safety of ibogaine for the treatment of cocaine dependency. The primary objectives of the study are to determine safety, pharmacokinetics and dose effects, and to identify relevant parameters of efficacy in cocaine-dependent patients. Pharmacokinetic and pharmacodynamic characteristics of ibogaine in humans are assessed by analyzing the concentration-time data of ibogaine and its desmethyl metabolite (noribogaine) from the Phase I trial, and by conducting in vitro experiments to elucidate the specific disposition processes involved in the metabolism of both parent drug and metabolite. The development of clinical safety studies of ibogaine in humans will help to determine whether there is a rationale for conducting efficacy trials in the future.

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.

Ibogaine: a potent noncompetitive blocker of ganglionic/neuronal nicotinic receptors.

Ibogaine noncompetitively blocked (IC50 approximately 20 nM) 22NaCl influx through ganglionic-type nicotinic receptor channels of rat pheochromocytoma PC12 cells. The major metabolite O-des-methylibogaine was 75-fold less active, and O-t-butyl-O-des-methylibogaine was 20-fold less active. Ibogaine was relatively weak as a blocker (IC50 approximately 2000 nM) of the neuromuscular-type nicotinic receptor channels in human medulloblastoma TE671 cells. The blockade of nicotinic responses by ibogaine was only partially reversible in PC12 cells. In vivo, ibogaine at 10 mg/kg completely blocked epibatidine-elicited antinociception in mice, a response that is mediated by central nicotinic receptor channels. There was no significant blockade of the epibatidine response at 24 hr after the administration of 40 mg/kg ibogaine. The blockade of nicotinic channels could contribute to the antiaddictive properties of ibogaine.

Facilitation of memory retrieval by the "anti-addictive" alkaloid, ibogaine.

Anecdotal observations in humans indicate that indole alkaloid ibogaine may have anti-addictive properties. It has been suggested that the therapeutic action of ibogaine may depend upon facilitated access to the past experiences, purportedly influencing the initiation of drug addiction. To determine if ibogaine may facilitate memory retrieval, rats were trained in the Morris maze spatial navigation task. It has been found that ibogaine (0.25 or 2.5 mg/kg) or O-desmethyl-ibogaine (2.5 mg/kg) but not t-Butyl ibogaine, administered just before the test trial, facilitated spatial memory retrieval compared to rats receiving placebo treatment. It is concluded that although previously described NMDA receptor antagonistic properties of ibogaine may represent a locus for at least some of its actions, other mechanisms, involving facilitation of memory retrieval may be of importance for its anti-addictive effects.

Neuroendocrine and neurochemical effects of acute ibogaine administration: a time course evaluation

Ibogaine (IBO) is an indole alkaloid that is reported to facilitate drug abstinence in substance abusers. Despite considerable investigation, the mechanism of IBO action in vivo and its suitability as a treatment for drug addiction remains unclear. The present study was designed to evaluate the time-course effects of acute IBO on neuroendocrine and neurochemical indices. Adult male rats were treated with i.p. saline or 50 mg/kg IBO and sacrificed 15, 30, 60, 120 min and 24 h later. Trunk blood was collected for hormone measures and brains were dissected for neurochemical analyses. IBO produced a rapid elevation in plasma prolactin that declined to control levels by 60 min. Corticosterone levels increased 15 min after drug administration, continued to increase for 120 min, but returned to control levels 24 h after dosing. IBO decreased dopamine (DA) concentrations in the striatum and frontal cortex at 30, 60 and 120 min after injection while DA metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), were elevated over the same time period. 24 h after IBO, DOPAC concentrations in striatum and HVA levels in the frontal cortex were below control values. Serotonin (5-HT) and its metabolite 5-hydroxyindole acetic acid (5-HIAA) were decreased at 60 min after IBO administration only in the striatum. These data indicate that a single injection of IBO produces a spectrum of effects that includes: (1) elevation of plasma prolactin and corticosterone, (2) short- and long-term effects on DA neurotransmission, and (3) modest, transient effects of 5-HT neurotransmission. The effects of IBO reported herein may have relevance to the anti-addictive properties of this drug, and this proposal warrants further investigation.

Structurally modified ibogaine analogs exhibit differing affinities for NMDA receptors

Based on both preclinical findings and anecdotal evidence in man, the psychoactive indole alkaloid ibogaine has been suggested to have anti-addictive properties. Previous studies indicate that blockade of NMDA receptors may mediate at least some of the putative anti-addictive actions of ibogaine. The potencies of a series of ibogaine analogs to inhibit (+)-[3- 3H]5-methyl-10,11-dihydro-5 H-dibenzo[a,d]cyclohepten-5,10-imine ([ 3H]MK-801) binding to NMDA receptors were examined. This series of analogs included the putative ibogaine metabolite O-desmethylibogaine, its metabolism resistant analog O-t-butyl- O-desmethylibogaine, the iboga alkaloids (±)-ibogamine, (±)-coronaridine, tabernanthine, harmaline, and the indolotropanes endo-3-(1-methylindol-2-yl)-8-methyl-8-azabicyclo[3.2.1]octane (RS 075194-190), exo-3-(1-methylindol-2-yl)-8-methyl-8-azabicyclo[3.2.1]octane (RS 075237-190) and endo-3-(indol-2-yl)-8-methyl-8-azabicyclo[3.2.1]octane (RS 025989-190). Among these compounds, ibogaine was the most potent inhibitor of [ 3H]MK-801 binding ( K i = ∼ 1.2 μM), whilst the compounds with the greatest structural similarity to ibogaine, O-desmethylibogaine and O-t-butyl- O-desmethylibogaine were less potent ( K i = ∼ 5.5 and 179.0 μM, respectively). In morphine-dependent mice, ibogaine, but not O-desmethylibogaine or O-t-butyl- O-desmethylibogaine, attenuated naloxone precipitated withdrawal jumping. These findings are consistent with the hypothesis that inhibition of the expression of morphine dependence by ibogaine is related to its NMDA receptor antagonist properties.

Effects of ibogaine, and cocaine and morphine after ibogaine, on ventral tegmental dopamine neurons

Ibogaine, an indole containing alkaloid, has been shown to reduce the rate of injection of morphine and cocaine in self-administration protocols. Since morphine- and cocaine-induced modulation of dopamine release is impulse dependent and essential for their reinforcing effects, disruption of dopamine neuronal activity by ibogaine could explain its purported ‘antiaddictive’ properties. Therefore, the present study was designed to determine: (1) the acute effects of ibogaine on the activity of VTA dopamine neurons, and (2) whether ibogaine pretreatment causes a persistent modification of the dopamine neuronal response to morphine and cocaine. Extracellular recordings in anesthetized animals found that intravenous ibogaine markedly excited VTA dopamine neuronal firing. However, ibogaine pretreatment (6–8 hr and 19 hr before) failed to alter either the spontaneous activity of VTA neurons, or the response of these dopamine neurons to morphine or cocaine. Thus, ibogaine's excitatory effect on VTA neurons is not longlasting nor does it persistently alter cocaine- or morphine-induced changes in dopamine neuron impulse activity. Therefore, other mechanisms must be explored to account for the proposed antiaddictive properties of ibogaine.

Ibogaine block of the NMDA receptor: In vitro and in vivo studies

Ibogaine is an hallucinogenic indole alkaloid claimed to have anti-addictive properties. Although its mechanism of action is unknown, binding studies have indicated that the drug may interact with N-methyl- d-aspartate (NMDA) receptors. We further investigated the nature of the interaction between ibogaine and NMDA receptors in voltage clamp and binding studies, and sought to confirm that the drug has NMDA receptor blocking activity in vivo. In whole-cell recordings from cultured rat hippocampal neurons, ibogaine caused a slow, concentration-dependent block of NMDA-induced currents (IC 50, 3.1 μM at −60 mV). In contrast, ibogaine failed to affect either kainate- or γ-aminobutyric acid-evoked currents. The blockade of NMDA currents was use- and voltage-dependent, and the long lasting ibogaine block could be occluded by co-application of Mg 2+. Ibogaine also inhibited equilibrium [ 3H]dizocilpine binding to NMDA receptors in rat forebrain membranes (IC 50, 3.2 μM). We conclude that ibogaine is an open channel NMDA receptor antagonist. Administration of ibogaine to mice resulted in complete protection in the maximal electroshock test (ED 50, 31 mg/kg, i.p.) and partial protection against NMDA-induced lethality, confirming that ibogaine can block NMDA receptors in vivo.