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.

Neuronal Nicotinic Acetylcholine Receptors: Common Molecular Substrates of Nicotine and Alcohol Dependence

“…Finally, systemic injection of the α3β4* nAChR-selective antagonist 18-methoxycoranaridine (18-MC) reduces ethanol consumption in alcohol-preferring rats (Rezvani et al, 1997). However, direct infusion of 18-MC into the VTA fails to reduce alcohol consumption (Carnicella et al, 2010) in rats consistent with data indicating low expression of β4* nAChRs in VTA DAergic neurons (Gotti et al, 2010; Zhao-Shea et al, 2011). …”

Coronaridine congeners inhibit human α3β4 nicotinic acetylcholine receptors by interacting with luminal and non-luminal sites

“…Animal behavioral results show that (−)-noribogaine possess a similar anti-addictive profile as that for (−)-ibogaine (Glick et al, 1996). Interestingly, the infusion of (−)-noribogaine directly into the ventral tegmental area results in a significant and long-lasting decrease in ethanol self-administration by rats that is not observed by (±)-18-MC (Carnicella et al, 2010). Based on these results, the authors suggested that (−)-noribogaine and (±)-18-MC have different mechanisms and sites of action.…”

Varenicline decreases nicotine but not alcohol self-administration in genetically selected Marchigian Sardinian alcohol-preferring (msP) rats

“…These well-documented anti-alcohol properties of varenicline seem to be dependent on the activation of α4 nAChRs (Hendrickson et al, 2010). In contrast, α7 (Kuzmin et al, 2009) and α3β4 nAChRs (Carnicella et al, 2010; Cippitelli et al, 2015b) may not be involved in alcohol reinforcement. Consistent with this literature, we have recently demonstrated the efficacy of varenicline in decreasing alcohol self-administration at doses that also decreased nicotine self-administraton in an operant co-administration paradigm (Cippitelli et al, 2015c).…”