Noribogaine, but not 18-MC, exhibits similar actions as ibogaine on GDNF expression and ethanol self-administration

Abstract

Ibogaine is a naturally occurring alkaloid that has been reported to decrease various adverse phenotypes associated with exposure to drugs of abuse and alcohol in human and rodent models. Unfortunately, ibogaine cannot be used as a medication to treat addiction because of severe side effects. Previously, we reported that the desirable actions of ibogaine to reduce self-administration of, and relapse to, alcohol consumption are mediated via the upregulation of the expression of the glial cell line-derived neurotrophic factor (GDNF) in the midbrain ventral tegmental area (VTA), and the consequent activation of the GDNF pathway. The ibogaine metabolite, noribogaine, and a synthetic derivative of ibogaine, 18-Methoxycoronaridine (18-MC), possess a similar anti-addictive profile as ibogaine in rodent models, but without some of its adverse side effects. Here, we determined whether noribogaine and/or 18-MC, like ibogaine, increase GDNF expression, and whether their site of action to reduce alcohol consumption is the VTA. We used SH-SY5Y cells as a cell culture model and found that noribogaine, like ibogaine, but not 18-MC, induces a robust increase in GDNF mRNA levels. Next, we tested the effect of intra-VTA infusion of noribogaine and 18-MC on rat operant alcohol self-administration and found that noribogaine, but not 18-MC, in the VTA decreases responding for alcohol. Together, our results suggest that noribogaine and 18-MC have different mechanisms and sites of action.

Figure 1

Ibogaine and noribogaine, but not 18-MC, dose-dependently increase GDNF expression in the dopaminergic-like SH-SY5Y cell line. SH-SY5Y cells were treated for 3 hours with ibogaine (5, 10 or 50 μM; a), noribogaine (5, 10 or 50 μM; b) or 18-MC (10, 20, 50 or 100 μM; c), and GDNF expression was analyzed by RT-PCR. Data are expressed as mean ±SD of the GDNF/Actin ratios. n = 6–8. *P < 0.05, **P < 0.01, ***P < 0.001 compared with control

Figure 2

Escalation of ethanol intake and preference in an intermittent access two-bottle choice paradigm and representation of the cannulae placement. (a–c), Mean ±standard error of the mean (SEM) of ethanol (a), water (b) intake and ethanol preference (c) during acquisition of voluntary consumption of a 20% ethanol solution. (d), Schematic representation of the cannulae placement on coronal section (Paxinos & Watson 2007). The location of the injector tips is represented by gray circles. Numbers on the left side indicate the distance posterior to bregma in millimeters. n = 13

Figure 3

Intra-VTA infusion of noribogaine, but not 18-MC, decreases operant ethanol self-administration in rats. Rats were infused into the VTA with noribogaine (1, 10 or 100 μM; a, c), 18-MC (1, 10 or 100 μM; b, d) or vehicle 3 hours before the beginning of the test session. (a&b), Mean ±SEM of the number of ethanol deliveries for noribogaine (a) and 18-MC (b). (c&d), Mean ±SEM of the ethanol intake for noribogaine (c) and 18-MC (d). n = 13. **P < 0.01, ***P < 0.001

Figure 4

Intra-VTA infusion of noribogaine, but not 18-MC, induces a long-lasting decrease in operant ethanol self-administration in rats. Noribogaine or 18-MC (10 μM) was infused into the VTA and operant ethanol self-administration was monitored over 4 consecutive sessions. The same subjects as in Fig. 2 were tested 24 hours (session 2), 48 hours (session 3) and 72 hours (session 4) after the intra-VTA infusion of the drugs. Session 1 recapitulates the results obtained 3 hours after the infusion and represented in Fig. 2. (a&b), Mean ±SEM of the number of ethanol deliveries for noribogaine (a) and 18-MC (b). (c&d), Mean ±SEM of the ethanol intake for noribogaine (c) and 18-MC (d). n = 13. *P < 0.05, ***P < 0.001