Harmine is a β-
carboline alkaloid and major component of ayahuasca, a traditional South American psychoactive
tea with anecdotal efficacy for treatment of
cocaine dependence.
Harmine is an inhibitor of
monoamine oxidase A (
MAO-A) and interacts in vitro with several pharmacological targets which modulate
dopamine (DA) neurotransmission. In vivo studies have demonstrated
dopaminergic effects of
harmine, attributed to
monoamine oxidase inhibitor (MAOI) activity, however none have directly demonstrated a pharmacological mechanism. This study investigated the acute effects, and pharmacological mechanism(s), of
harmine on electrically evoked DA efflux parameters in the nucleus accumbens both in the absence and presence of
cocaine. Fast cyclic voltammetry in rat brain slices was used to measure electrically evoked DA efflux in accumbens core and shell.
Harmine (300 nM) significantly augmented DA efflux (148±8% of baseline) in the accumbens shell.
Cocaine augmented efflux in shell additive to
harmine (260±35%).
Harmine had no effect on efflux in the accumbens core or on reuptake in either sub-region. The effect of
harmine in the shell was attenuated by the 5-HT(2A/2C) antagonist
ketanserin. The MAOI
moclobemide (10 µM) had no effect on DA efflux. These data suggest that
harmine augments DA efflux via a novel, shell-specific, presynaptic
5-HT(2A) receptor-dependent mechanism, independent of MAOI activity. A DA-releasing 'agonist
therapy' mechanism may thus contribute to the putative therapeutic efficacy of ayahuasca for
cocaine dependence.