Infusing GDNF directly into the ventral tegmental area (VTA) of rats rapidly and dose-dependently reduces their operant self-administration of alcohol, but not sucrose. This effect is specific to the VTA, as infusion into the neighboring substantia nigra does not alter alcohol responding. GDNF activates the MAPK signaling pathway in the VTA, and blocking this pathway prevents the reduction in alcohol self-administration. GDNF also blocks the reacquisition of alcohol self-administration after extinction, indicating it reduces relapse-like behavior. The findings suggest GDNF, via MAPK activation, acts as a fast-acting and selective agent to diminish alcohol consumption and seeking.
Noribogaine, a metabolite of ibogaine, increases GDNF expression in cell cultures and reduces alcohol self-administration when infused into the ventral tegmental area (VTA) of rats, whereas 18-MC, a synthetic ibogaine derivative, does not affect GDNF expression or alcohol responding in the VTA. These findings indicate that noribogaine and 18-MC act through different mechanisms and brain sites to reduce alcohol consumption, and that noribogaine may share ibogaine's anti-addictive properties without some of its side effects.