Ayahuasca and Its DMT- and β-carbolines - Containing Ingredients Block the Expression of Ethanol-Induced Conditioned Place Preference in Mice: Role of the Treatment Environment

Abstract

Ayahuasca is a hallucinogenic beverage produced from the decoction of Banisteriopsis caapi (Bc) and Psychotria viridis (Pv), β-carboline- and N,N-dimethyltryptamine(DMT)-containing plants, respectively. Accumulating evidence suggests that ayahuasca may have therapeutic effects on ethanol abuse. It is not known, however, whether its effects are dependent on the presence of DMT or if non-DMT-containing components would have therapeutic effects. The aim of the present study was to investigate the rewarding properties of ayahuasca (30, 100, and 300 mg/kg, orally), Bc (132, 440, and 1320 mg/kg, orally) and Pv (3.75, 12.5 and 37.5 mg/kg, i.p.) extracts and their effects on ethanol (1.8 g/kg, i.p.) reward using the conditioned place preference (CPP) paradigm in male mice. Animals were conditioned with ayahuasca, Bc or Pv extracts during 8 sessions. An intermediate, but not a high, dose of ayahuasca induced CPP in mice. Bc and Pv did not induce CPP. Subsequently, the effects of those extracts were tested on the development of ethanol-induced CPP. Ayahuasca, Bc or Pv were administered before ethanol injections during conditioning sessions. While Bc and Pv exerted no effects on ethanol-induced CPP, pretreatment with ayahuasca blocked the development of CPP to ethanol. Finally, the effects of a post-ethanol-conditioning treatment with ayahuasca, Bc or Pv on the expression of ethanol-induced CPP were tested. Animals were conditioned with ethanol, and subsequently treated with either ayahuasca, Bc or Pv in the CPP environment previously associated with saline or ethanol for 6 days. Animals were then reexposed to ethanol and ethanol-induced CPP was quantified on the following day. Treatment with all compounds in the ethanol-paired environment blocked the expression of ethanol-induced CPP. Administration of an intermediate, but not a high, dose of ayahuasca and Bc, as well as Pv administration, in the saline-paired compartment blocked the expression of ethanol-induced CPP. The present study sheds light into the components underlying the therapeutic effects of ayahuasca on ethanol abuse, indicating that ayahuasca and its plant components can decrease ethanol reward at doses that do not exert abuse liability. Importantly, the treatment environment seems to influence the therapeutic effects of ayahuasca and Bc, providing important insights into clinical practice.

Keywords: N; N-dimethyltryptamine; ayahuasca; conditioned place preference; ethanol; mice; reward; β-carboline alkaloids.

FIGURE 1

Conditioned place preference (CPP) protocol design. H, habituation; PreCT, drug-free pre-conditioning test; Conditioning, ayahuasca (30, 100, or 300 mg/kg, Experiment 1), Banisteriopsis caapi (132, 440 or 1320 mg/kg, Experiment 2), ethanol (1.8 g/kg, Experiments 5, 6, 7 and 8) – preceded by vehicle or ayahuasca (100 or 300 mg/kg, Experiment 3) or Banisteriopsis caapi (440 or 1320 mg/kg, Experiment 4) pretreatment – or saline conditioning; PostCT, drug-free post-conditioning test; Treatment, vehicle, ayahuasca (100 or 300 mg/kg, Experiments 5 and 6) or Banisteriopsis caapi (440 or 1320 mg/kg, Experiments 7 and 8) treatment in the compartment previously paired with ethanol (Experiments 5 and 7) or saline (Experiments 6 and 8); ER, ethanol (1.8 g/kg) reexposure in previously ethanol-paired compartment; PTT, drug-free post-treatment test.

FIGURE 2

Effects of (A) ayahuasca (Aya), (B) extract of Banisteriopsis caapi (EBc) and (C) extract of Psychotria viridis (EPv) on the conditioned place preference (CPP) paradigm. CPP score (difference between the time spent in the drug-paired and in the saline-paired compartments) during the pre-conditioning and post-conditioning test sessions. Data are reported as means ± SEM. ^∗p < 0.05 compared with the pre-conditioning test.

FIGURE 3

Effects of pretreatments with (A) ayahuasca (Aya), (B) extract of Banisteriopsis caapi (EBc) or (C) extract of Psychotria viridis (EPv) before ethanol conditioning sessions on the development of ethanol-induced conditioned place preference (CPP). CPP score (difference between the time spent in the ethanol-paired and in the saline-paired compartments) during the pre-conditioning and post-conditioning test sessions. Data are reported as means ± SEM. ^∗p < 0.05 compared with the pre-conditioning test.

FIGURE 4

Effects of post-conditioning treatments with ayahuasca on the expression ethanol-induced conditioned place preference (CPP). (A,C) CPP score (difference between the time spent in the ethanol-paired and in the saline-paired compartments) during the pre-conditioning test and the post-ethanol conditioning test sessions. (B,D) CPP score during the post-treatment test conducted after treatment with ayahuasca (Aya) in the (B) ethanol- or (D) saline-paired compartments and subsequent ethanol reexposure. Data are reported as means ± SEM. ^∗p < 0.05 compared with the Pre-Conditioning Test; ^#p < 0.05 compared with the Vehicle group.

FIGURE 5

Effects of post-conditioning treatments with Banisteriopsis caapi on the expression ethanol-induced conditioned place preference (CPP). (A,C) CPP score (difference between the time spent in the ethanol-paired and in the saline-paired compartments) during the pre-conditioning test and the post-ethanol conditioning test sessions. (B,D) CPP score during the post-treatment test conducted after treatment with extract of Banisteriopsis caapi (EBc) in the (B) ethanol- or (D) saline-paired compartments and subsequent ethanol reexposure. Data are reported as means ± SEM. ^∗p < 0.05 compared with the Pre-Conditioning Test; ^#p < 0.05 compared with the Vehicle group.

FIGURE 6

Effects of post-conditioning treatments with and Psychotria viridis on the expression ethanol-induced conditioned place preference (CPP). (A,C) CPP score (difference between the time spent in the ethanol-paired and in the saline-paired compartments) during the pre-conditioning test and the post-ethanol conditioning test sessions. (B,D) CPP score during the post-treatment test conducted after treatment with extract of Psychotria viridis (EPv) in the (B) ethanol- or (D) saline-paired compartments and subsequent ethanol reexposure. Data are reported as means ± SEM. ^∗p < 0.05 compared with the Pre-Conditioning Test; ^#p < 0.05 compared with the Vehicle group.