Ibogaine and Glial Cell Line-Derived Neurotrophic Factor (GDNF)

"Ibogaine is a natural alkaloid reported to reverse the adverse actions of multiple drugs of abuse including opiates, psychostimulants, nicotine and alcohol in humans, as well as in rodent models (Popik et al., 1995; Mash et al., 1998; Glick & Maisonneuve, 2000; Alper et al., 2008; Maciulaitis et al., 2008). Despite its attractive properties, Ibogaine can induce severe side-effects such as hallucinations, whole-body tremors and ataxia that may be related to neurotoxicity in the cerebellum and dysregulation of the cardiovascular system (O'Hearn & Molliver, 1993; Popik et al., 1995; Maas & Strubelt, 2006; Maciulaitis et al., 2008). We previously demonstrated that systemic administration of low non-toxic doses of Ibogaine in rats reduces ethanol self-administration and relapse (He et al., 2005). We were therefore interested in identifying the molecular pathway mediating the beneficial actions of Ibogaine on ethanol-drinking behaviors. We found that Ibogaine increased GDNF [glial cell line-derived neurotrophic factor] expression resulting in the activation of the GDNF pathway (He et al., 2005). Importantly, we showed that the actions of Ibogaine to reduce ethanol intakewere localized to the VTA [ventral tegmental area], and that infusion of anti-GDNF neutralizing antibodies into the VTA attenuated the Ibogaine-mediated decrease in ethanol self-administration (He et al., 2005). Together, these results suggest that the desirable actions of this drug are mediated, as least partially, by GDNF. A potential strategy to overcome these undesirable actions of Ibogaine is the use of derivatives that share only its valuable actions. In this regard, the main metabolite of Ibogaine, noribogaine, and 18-methoxycoronaridine (18-MC) a synthetic congener, may have promising profiles. Noribogaine has been shown to induce a long-lasting reduction in morphine and cocaine, but notwater, self-administration in rats (Glick et al., 1996b), and 18-MC was found to reduce morphine, psychostimulant and nicotine self-administration, as well as ethanol intake in rodents, without affecting water consumption (Rezvani et al., 1997; Maisonneuve & Glick, 2003). Importantly, in contrast to Ibogaine, noribogaine and 18-MC have no tremorigenic effects (Glick et al., 1996b; Baumann et al., 2001; Maisonneuve & Glick, 2003), and no evidence of cerebellar toxicity was found for 18-MC in rats, even after administration of a high dose (Glick et al., 1996a). Taken together, these data suggest that Ibogaine derivatives may be an effective treatment of addiction and safer than the parent compound. However, it should be noted that it is currently unknown whether the desirable actions of noribogaine and 18-MC are mediated by GDNF."