Ibogaine Blocks Cue- and Drug-Induced Reinstatement of Conditioned Place Preference to Ethanol in Male Mice

This study explored the effects of ibogaine (10 or 30 mg/kg) on ethanol-induced conditioned place preference (CPP) in mice. The study found that ibogaine blocked ethanol-induced CPP during a drug priming reinstatement test and during a drug-free test, after mice had been re-exposed to ethanol. These findings suggest ibogaine may be useful for treating alcohol use disorder.

Abstract

“Introduction: Ibogaine is a psychedelic extracted from the plant Tabernanthe iboga Baill. (Apocynaceae), natural from Africa, and has been proposed as a potential treatment for substance use disorders. In animal models, ibogaine reduces ethanol self-administration. However, no study to date has investigated the effects of ibogaine on ethanol-induced conditioned place preference (CPP).

Methods: The present study aimed to investigate the effects of repeated treatment with ibogaine on the reinstatement of CPP to ethanol in male mice. The rewarding effects of ethanol (1.8 g/kg, i. p.) or ibogaine (10 or 30 mg/kg, p. o.) were investigated using the CPP model. Furthermore, we evaluated the effects of repeated treatment with ibogaine (10 or 30 mg/kg, p. o.) on the reinstatement of ethanol-induced CPP. Reinstatement was evaluated under two conditions: 1) during a priming injection re-exposure test in which animals received a priming injection of ethanol and had free access to the CPP apparatus; 2) during a drug-free test conducted 24 h after a context-paired re-exposure, in which subjects received an injection of ethanol and were confined to the compartment previously conditioned to ethanol.

Results: Our results show that ethanol, but not ibogaine, induced CPP in mice. Treatment with ibogaine after conditioning with ethanol blocked the reinstatement of ethanol-induced CPP, both during a drug priming reinstatement test and during a drug-free test conducted after re-exposure to ethanol in the ethanol-paired compartment.

Discussion: Our findings add to the literature suggesting that psychedelics, in particular ibogaine, may have therapeutic properties for the treatment of alcohol use disorder at doses that do not have rewarding effects per se.”

Authors: Gabrielle M. Henriques, Alexia Anjos-Santos, Isa R. S. Rodrigues, Victor Nascimento-Rocha, Henrique S. Reis, Matheus Libarino-Santos, Thaísa Barros-Santos, Thais S. Yokoyama, Natalia B. Bertagna, Cristiane A. Favoretto, Célia R. G. Moraes, Fábio C. Cruz, Paulo C. R. Barbosa, Eduardo A. V. Marinho, Alexandre J. Oliveira-Lima & Laís F. Berro

Summary

INTRODUCTION

Alcohol use disorder (AUD) is a global public health problem, but current treatment options are not always effective, and less than 20% of individuals with lifetime prevalence of AUD have ever sought treatment.

Psychedelics have long been proposed as a treatment for drug abuse, including alcohol abuse disorder. Studies have shown that ayahuasca, a hallucinogenic substance, blocks the development and expression of ethanol-induced behavioral sensitization and conditioned place preference in mice.

Ibogaine is an extract from the plant Tabernanthe iboga Baill., which is commonly consumed during religious ceremonies. It has been proposed as a potential treatment for substance use disorder.

Studies have shown that IBO reduces ethanol self-administration in rats and improves withdrawal and cravings in patients with SUD. However, no study has investigated the effects of IBO on ethanol-induced CPP.

We investigated whether IBO induced CPP in mice during a priming injection re-exposure test and a drug-free test conducted 24 h after a context-paired re-exposure test.

Animals

Three-month-old Swiss male mice were used. They were group housed in polypropylene cages under controlled temperature and light conditions and were provided with chow and water ad libitum throughout the experiments.

The dose of ethanol and Iboga used was 1.8 g/kg and 10 ml/kg of body weight, respectively. The dose of Iboga used was based on previous studies investigating its effects on ethanol self-administration.

Drugs

The CPP apparatus consisted of two conditioning compartments connected by a central choice compartment, and the time spent in each compartment was registered using the ANY-maze software and a webcam suspended overhead. The CPP score was established by randomly assigning a reference compartment.

The CPP procedure consisted of a treatment phase, post-treatment test, alcohol re-exposure and post-re-exposure (reinstatement) test. This protocol has been used in our laboratory for several years with reliable results.

Mice were randomly assigned to an experimental group and to an “ethanol-paired compartment” in a counterbalanced manner, and were confined to one of the conditioning compartments for 8 consecutive days.

Twenty-four hours after the post-treatment test, half of the animals received an i.p. injection of ethanol (1.8 g/kg) and were placed in the center of the apparatus with the door open with free access to both compartments.

The post-context-paired re-exposure test was performed on day 23 after the context-paired re-exposure test.

All behavioral sessions were conducted during the same period of time within an experiment, and the CPP apparatus was cleaned with ethanol-water (5%) solution before each behavioral session/test.

Statistical Analysis

All variables were checked for normality and homogeneity of variances, and multiple comparisons were performed using one-way or two-way analysis of variance. Bonferroni’s post-hoc test was used for multiple comparisons between groups.

DISCUSSION

Studies have shown that IBO, a plant extract, blocks some abuse-related effects of ethanol in rats and humans, and the present study shows that IBO blocks prime- and cue-induced reinstatement of CPP to ethanol in mice at doses that did not induce CPP per se.

Ethanol-induced increased dopamine levels in the nucleus accumbens (NAc) via increased firing of dopaminergic cells in the ventral tegmental area (VTA) have been proposed to mediate its rewarding effects. IBO acts as a 5-HT2 receptor agonist and has higher affinity for 5-HT2C over 5-HT2A receptors.

IBO, an agonist at 5-HT2C receptors and -opioid receptors, decreases the motivation for ethanol-seeking behavior and, consequently, blocks reinstatement. It also acts as an antagonist at NMDA receptors, which is a key mechanism responsible for the generation of conditioned responses of dopamine neurons to reward cues.

Treatment with IBO in the ethanol-paired compartment may have facilitated the retrieval of ethanol-associated conditioned memories, and may have prevented a subsequent reinstatement of ethanol-induced CPP upon an ethanol reexposure.

IBO attenuated ethanol self-administration in rats and withdrawal and craving in users of ethanol and other drugs. Its pharmacology is complex and further studies are needed to elucidate the precise receptor subtypes and mechanisms underlying the therapeutic effects of IBO on ethanol reward, reinforcement and reinstatement.

AUTHOR CONTRIBUTIONS

LB, AO-L, EM and CF conceptualised and designed the study, and GH, AA-S, IR, VR, HR, ML-S, TB-S, TY, NB, CF and CM performed the analysis and interpretation of data.