Anti-addictive Properties Research Articles

Effect of ibogaine on cocaine-induced efflux of [ 3H]dopamine and [ 3H]serotonin from mouse striatum

Ibogaine, an indole alkaloid with proposed antiaddictive properties, has structural similarity to serotonin and has been shown to have affinity to the k-opioid binding site. In addition to the dopamine system, the serotonin system is a major target for cocaine action and the opioid system can affect the serotonin system. Therefore, the present study examined the effect of ibogaine on cocaine-induced, electrically evoked efflux of [ 3H]dopamine and [ 3H]serotonin from striatal tissue incubated in vitro, and their modulation by the k-opioid system. Cocaine (10 −6 M) added in vitro increased the fractional efflux of both [ 3H]dopamine ( FRS 2 FRS 1 = 2.42 ± 0.36 ) and [ 3H]serotonin ( FRS 2 FRS 1 = 1.31 ± 0.06 ). Mice treated in vivo with ibogaine (40 mg/kg or 2 times 40 mg/kg, IP) and killed 2 or 18 h later still showed the cocaine-induced increase in [ 3H]dopamine, but [ 3H]serotonin efflux was not increased. The 5-HT 1B agonist CGS-12066A (10 −6 M, added in vitro) increased [ 3H]dopamine release, but did not alter cocaine-induced efflux of [ 3H]dopamine. CGS-12066A did not affect [ 3H]serotonin release, but the cocaine-induced increase in [ 3H]serotonin was inhibited. CGS-12066A (1 mg/kg, SC) potentiated cocaine (25 mg/kg, SC)-induced locomotor activity. Ibogaine pretreatment reduced both the cocaine and the CGS-12066A cocaine-induced increase in locomotor activity. The k-opioid agonist U-62066 (10 −6 M, added in vitro) reduced both [ 3H]dopamine and [ 3H]serotonin release. This inhibitory effect was blocked by in vivo administration of ibogaine. U-62066 did not alter cocaine-induced [ 3H]dopamine efflux, but reduced cocaine-induced [ 3H]serotonin efflux. In striatal tissue from ibogaine-pretreated mice, U-62066 restored the cocaine-induced increase in [ 3H]serotonin release. U-62066 (1 mg/kg, SC) potentiated cocaine-induced behavior and maintained an increased locomotor activity after ibogaine treatment. The results suggest that ibogaine may block the cocainemediated effects on serotonergic transmission, that subsequently modulate dopamine release. The k-opioid modulation of serotonergic transmission is also involved.

Receptor binding profile suggests multiple mechanisms of action are responsible for ibogaine's putative anti-addictive activity.

The indole alkaloid ibogaine (NIH 10567, Endabuse) is currently being examined for its potential utility in the treatment of cocaine and opioid addiction. However, a clearly defined molecular mechanism of action for ibogaine's putative anti-addictive properties has not been delineated. Radioligand binding assays targeting over 50 distinct neurotransmitter receptors, ion channels, and select second messenger systems were employed to establish a broad in vitro pharmacological profile for ibogaine. These studies revealed that ibogaine interacted with a wide variety of receptors at concentrations of 1-100 microM. These included the mu, delta, kappa, opiate, 5HT2, 5HT3, and muscarinic1 and 2 receptors, and the dopamine, norepinephrine, and serotonin uptake sites. In addition, ibogaine interacted with N-methyl-D-aspartic acid (NMDA) associated ion and sodium ion channels as determined by the inhibition of [3H]MK-801 and [3H]bactrachotoxin A 20-alpha-benzoate binding (BTX-B), respectively. This broad spectrum of activity may in part be responsible for ibogaine's putative anti-addictive activity.

The effect of ibogaine on κ-opioid- and 5-HT 3-induced changes in stimulation-evoked dopamine release in vitro from striatum of C57BL/6BY mice

Ibogaine is an kndole alkaloid that has bean suggested to have potential efficacy for internrpdng dependermy on stimulant drugs. The κ-opiold and serotonkr 5-HT 3 systems may be involved in the action of Ibogaine, related to their modulation of dopaminergic transmission. The κ-opioid agonist U 62066 attenuated the in vitrostimulation-evoked efflux of tritium label from striatal tissue prelabeled with ( 3H)dopamine. In mice protreated with Ibogaine·HCl (40 mg/kg IP given 2 h prior or 2 × 40 mg/kg and animals killed 18 h later), the Inhibitory effect of U 62066 on stimulation-evoked release of tritium was eliminated. The 5-HT 3 agonist phernylbiguanide had a biphasic effect on stimulation-evoked release of tritium; at 10 −6 M phenylbiguanide, stimulation-evoked release was attenuated. At 10 −5 M the basal outflow of tritium was increased. Ibogaine pretreatment had no effect on basal or stimulation-evokedrelease in the presence of 10 −6 M phenylbiguanide, but increased the stimulation-evoked outflow of bftkan in the presence of 10 −5 M phenylbiguanide. Cocaine (10 −6 M), a dopanlne uptake blocker, increased the electrically-evoked release of dopamine; ibogaine pretreatment did not affect the enhanced electrically-induced release of ( 3H]dopamine by in vitro cocalne. The effects of ibogaine on the κ-opioid and 5-HT 3 receptors, located presynaptically on stristal dopamine terminals, modulating dopamine release may partly underlie its putative antiaddictive properties.

Effect of ibogaine on serotonergic and dopaminergic interactions in striatum from mice and rats

The effect of ibogaine (Endabuse, NIH 10567) on serotonin uptake and release, and on serotonergic modulation of dopamine release, was measured in striatal tissue from rats and mice. Two hours after treatment in vivo with ibogaine (40 mg/kg i.p.) the uptake of labeled [3H]serotonin and [3H]dopamine uptake in striatal tissue was similar in the ibogaine-treated animal to that in the control. The 5HT1B agonist CGS-12066A (10(-5) M) had no effect on stimulation-evoked tritium release from mouse or rat striatal tissue preloaded with [3H]serotonin; however, it elevated tritium efflux from striatal tissue preloaded with [3H]dopamine. This increase was not seen in mice treated with ibogaine 2 or 18 hours previously, or in rats treated 2 hours before. Dopamine autoreceptor responses were not affected by ibogaine pretreatment in either mouse or rat striatal tissue; sulpiride increased stimulation-evoked release of tritium from tissue preloaded with [3H]dopamine. The long-lasting effect of ibogaine on serotonergic functioning, in particular, its blocking of the 5HT1B agonist-mediated increase in dopamine efflux, may have significance in the mediation of its anti-addictive properties.

Local effects of ibogaine on extracellular levels of dopamine and its metabolites in nucleus accumbens and striatum: interactions with d-amphetamine

Systemic administration of ibogaine (40 mg/kg, i.p.) has been reported to induce both acute (1–3 h) and persistent (19–20 h) changes in extracellular levels of dopamine and its metabolites in the nucleus accumbens and striatum. In the present study, local administration of ibogaine to the striatum and nucleus accumbens produced effects that mimicked both the acute and persistent effects of systemic administration: perfusion with high concentrations (200 and 400 μM) of ibogaine mimicked the acute effects (decreased extracellular dopamine levels and increased extracellular metabolite levels) whereas perfusion with a low concentration (10 μM) of ibogaine mimicked the persistent effects (decreased extracellular levels of DOPAC). These results indicate that ibogaine acts directly in brain regions containing dopaminergic nerve terminals and that long-lasting effects of systematically administered ibogaine might be mediated by persisting low levels of ibogaine. Locally administered ibogaine (10 μM) was also found to enhance the effects of systematically administered d-amphetamine (1.25 mg/kg, i.p.) on extracellular dopamine levels, and conversely, systemically administered ibogaine (40 mg/kg, i.p.: 19 h pretreatment) enhanced the effects of locally administered d-amphetamine (1–10 μM). These results indicate that, in addition to a metabolic mechanism implicated previously, a pharmacodynamic mechanism contributes to the interaction between ibogaine and d-amphetamine. The relevance of such mechanisms to claims regarding ibogaine's anti-addictive properties is unclear.

Inhibitory effects of ibogaine on cocaine self-administration in rats

In order to determine the potential anti-addictive properties of ibogaine, we used the cocaine self-administration model in rats. The results indicate that a single injection of ibogaine (40 mg/kg i.p.) produced a significant decrease of cocaine intake, which remained unaltered for more than 48 h. Since the half-life time of ibogaine is short, this might suggest the involvement of one or several active metabolites of ibogaine in cocaine intake. Repetitive administration of ibogaine on three consecutive days also induced a pronounced decrease of cocaine intake. However, a more prominent inhibitory effect on cocaine intake was observed in animals treated repeatedly with ibogaine (40 mg/kg i.p.), once each week for 3 consecutive weeks. These results indicate that ibogaine or its metabolite(s) is a long-lasting interruptor of cocaine dependence, which supports similar observations from uncontrolled clinical studies.

Degeneration of purkinje cells in parasagittal zones of the cerebellar vermis after treatment with ibogaine or harmaline

The indole alkaloids ibogaine and harmaline are β-carboline derivatives that cause both hallucinations and tremor. Reports that ibogaine may have potent anti-addictive properties have led to initiatives that it be tested for the treatment of opiate and cocaine addiction. In this study, ibogaine-treated rats were analysed for evidence of neurotoxic effects because human clinical trials of ibogaine have been proposed. We recently found that ibogaine induces a marked glial reaction in the cerebellum with activated astrocytes and microglia aligned in parasagittal stripes within the vermis. 28 Based on those findings, the present study was conducted to investigate whether ibogaine may cause neuronal injury or degeneration. The results demonstrate that, after treatment with ibogaine or harmaline, a subset of Purkinje cells in the vermis degenerates. We observed a loss of the neuronal proteins microtubule-associated protein 2 and calbindin co-extensive with loss of Nissl-stained Purkinje cell bodies. Argyrophilic staining of Purkinje cell bodies, dendrites and axons was obtained with the Gallyas reduced silver method for degenerating neurons. Degenerating neurons were confined to narrow parasagittal stripes within the vermis. We conclude that both ibogaine and harmaline have selective neurotoxic effects which lead to degeneration of Purkinje cells in the cerebellar vermis. The longitudinal stripes of neuronal damage may be related to the parasagittal organization of the olivocerebellar climbing fiber projection. Since these drugs produce sustained activation of inferior olivary neurons, we hypothesize that release of an excitatory amino add from climbing fiber synaptic terminals may lead to excitotoxic degeneration of Purkinje cells.

Interactions between ibogaine and cocaine in rats: in vivo microdialysis and motor behavior

To investigate a possible basis for the proposed anti-addictive property of ibogaine, the effects of an ibogaine (40 mg/kg i.p.) pretreatment on in vivo neurochemical and motor effects induced by cocaine (20 mg/kg i.p.) were studied. Ibogaine, administered 19 h earlier, potentiated the increase in extracellular dopamine levels in striatum and nucleus accumbens as well as the stimulated motor activity induced by cocaine. Although high doses of cocaine can become aversive by producing an anxiogenic reaction, it is unknown whether the potentiation of cocaine's effects by ibogaine would also cause aversion and lead to a decrease in cocaine addiction.

Mechanisms of action of ibogaine and harmaline congeners based on radioligand binding studies.

Assays using radioligands were used to assess the actions of ibogaine and harmaline on various receptor types. Ibogaine congeners showed affinity for opiate receptors whereas harmaline and harmine did not. The Ki for coronaridine was 2.0 microM at mu-opiate receptors. The Kis for coronaridine and tabernanthine at the delta-opiate receptors were 8.1 and 3.1 microM, respectively. Ibogaine, ibogamine, coronaridine and tabernanthine had Ki values of 2.08, 2.6, 4.3 and 0.15 microM, respectively, for kappa-opiate receptors. Long-lasting, dose-dependent behavioral effects of ibogaine have been reported. The possibility that these effects were due to irreversible binding properties of ibogaine at kappa-receptors was considered; however, radioligand wash experiments showed a rapid recovery of radioligand binding after one wash. A voltage-dependent sodium channel radioligand demonstrated Ki values in the microM range for all drugs tested. Using radioligand binding assays and/or 36Cl- uptake studies, no interaction of ibogaine or harmaline with the GABA receptor-ionophore was found. The kappa-activity of ibogaine (or an active metabolite) may be responsible for its putative anti-addictive properties whereas the tremorigenic properties of ibogaine and harmaline may be due to their effects on sodium channels.