Ibogaine, a noncompetitive inhibitor of serotonin transport, acts by stabilizing the cytoplasm-facing state of the transporter.
The Journal of biological chemistry – October 05, 2007
Source: PubMed
Summary
Ibogaine, a compound with anti-addiction potential, uniquely influences brain chemistry. It blocks the serotonin transporter (SERT), crucial for mood regulation, by stabilizing it in a state that encourages serotonin release *into* brain cells. This distinct mechanism, observed through tracking serotonin movement and transporter shape changes, clarifies how ibogaine impacts brain function, offering new insights into its therapeutic potential.
Abstract
Ibogaine, a hallucinogenic alkaloid with purported anti-addiction properties, inhibited serotonin transporter (SERT) noncompetitively by decreasing V(max) with little change in the K(m) for serotonin (5-HT). Ibogaine also inhibited binding to SERT of the cocaine analog 2beta-2-carbomethoxy-3-(4-[(125)I]iodophenyl)tropane. However, inhibition of binding was competitive, increasing the apparent K(D) without much change in B(max). Ibogaine increased the reactivity of cysteine residues positioned in the proposed cytoplasmic permeation pathway of SERT but not at nearby positions out of that pathway. In contrast, cysteines placed at positions in the extracellular permeation pathway reacted at slower rates in the presence of ibogaine. These results are consistent with the proposal that ibogaine binds to and stabilizes the state of SERT from which 5-HT dissociates to the cytoplasm, in contrast with cocaine, which stabilizes the state that binds extracellular 5-HT.