Glial Cell Line-Derived Neurotrophic Factor Mediates the Desirable Actions of the Anti-Addiction Drug Ibogaine against Alcohol Consumption

Abstract

Alcohol addiction manifests as uncontrolled drinking despite negative consequences. Few medications are available to treat the disorder. Anecdotal reports suggest that ibogaine, a natural alkaloid, reverses behaviors associated with addiction including alcoholism; however, because of side effects, ibogaine is not used clinically. In this study, we first characterized the actions of ibogaine on ethanol selfadministration in rodents. Ibogaine decreased ethanol intake by rats in two-bottle choice and operant self-administration paradigms. Ibogaine also reduced operant self-administration of ethanol in a relapse model. Next, we identified a molecular mechanism that mediates the desirable activities of ibogaine on ethanol intake. Microinjection of ibogaine into the ventral tegmental area (VTA), but not the substantia nigra, reduced self-administration of ethanol, and systemic administration of ibogaine increased the expression of glial cell line-derived neurotrophic factor (GDNF) in a midbrain region that includes the VTA. In dopaminergic neuron-like SHSY5Y cells, ibogaine treatment upregulated the GDNF pathway as indicated by increases in phosphorylation of the GDNF receptor, Ret, and the downstream kinase, ERK1 (extracellular signal-regulated kinase 1). Finally, the ibogaine-mediated decrease in ethanol selfadministration was mimicked by intra-VTA microinjection of GDNF and was reduced by intra-VTA delivery of anti-GDNF neutralizing antibodies. Together, these results suggest that GDNF in the VTA mediates the action of ibogaine on ethanol consumption. These findings highlight the importance of GDNF as a new target for drug development for alcoholism that may mimic the effect of ibogaine against alcohol consumption but avoid the negative side effects.

Natural Products for the Prevention and Treatment of Hangover and Alcohol Use Disorder

“…Ibogaine, a natural alkaloid, isolated from the root bark of Tabernanthe iboga, has been reported to markedly reduce voluntary alcohol intake in alcohol-preferring rats in 2-bottle choice and operant self-administration paradigms [132]. The possible mechanism was mediated by the glial cell line-derived neurotrophic factor (GDNF) in the ventral tegmental area [133].…”

“…Rats Reduced alcohol intake and blood alcohol levels through curbing alcohol absorption [110] Rats Reduced alcohol intake and delayed acquisition of alcohol-drinking behavior [111] Idn 5082 Rats Delayed acquisition of alcohol drinking behavior, and relapse prevention by suppressing the extra alcohol consumption after deprivation [112,113] salvianolic acid B Rats Attenuation of acute alcohol-induced hepatocyte apoptosis through SIRT1-mediated deacetylation of the p53 pathway [115] Scutellariae Radix Baicalein, baicalin and wogonin Root Rats Attenuated liver fibrosis through liver sinusoidal endothelial cell activation and HSC migration [121] Rhizoma coptidis Berberine Rhizome Rats Reduced alcohol intake and withdrawal induced hyperexcitability through its neuromodulatory action [127,128] Rats Attenuated acute alcohol-induced gastrointestinal mucosa damage through regulation of cytokines [129] Stephania ambigua and Corydalis teranda Levo-tetrahydro-palmatine Rats Reduced alcohol intake through dopamine D2 receptor-mediated PKA signaling in caudate-putamen [130] Strychnos nux-vomica L. Brucine Fruit Rats Decreased alcohol consumption through glycine receptor antagonist [131] Tabernanthe iboga Ibogaine Root Rats Reduced alcohol intake through mediation of glial cell line-derived neurotrophic factor [132] Jodina rhombifolia Unclear Leave Rats Reduced alcohol intake without tolerance and apparent side-effects [134,135] …”

Driving GDNF expression: The green and the red traffic lights

“…A MEK inhibitor inhibits ibogaine-induced GDNF up-regulation (He and Ron, 2006). In addition, after systemic administration to rodents, ibogaine increases GDNF expression in the VTA (He et al, 2005). Since GDNF has been implicated as a negative regulator of drug and alcohol addiction (reviewed by Ron and Janak, 2005), the effect of ibogaine on GDNF expression likely contributes to its positive impact on the treatment of addiction.…”

The Dopamine D3Receptor Is Part of a Homeostatic Pathway Regulating Ethanol Consumption

“…The operant self-administration procedure is as described previously (He et al, 2005) except that the rats were habituated to drink ethanol in their home cages, rather than in the self-administration chambers, beginning 1 week after surgery. After 3 weeks of exposure to ethanol in the home cage, the rats were trained 5 d a week in 60 min sessions for 2 months to self-administer a solution of 10% ethanol.…”