N,N-dimethyltryptamine (DMT) is neither formed nor retained in serotonin terminals in the rat brain

Abstract

Mammalian brain may contain an endogenous pool of the psychedelic substance N,N-dimethyltryptamine (DMT), which may act as a co-transmitter with serotonin (5-HT). We tested the joint hypotheses that endogenous DMT would accumulate in rat brain after inhibiting monoamine oxidase with pargyline, whereas its acidic metabolite 3-indoleacetic acid (3-IAA) would accumulate after pretreatment with the inhibitor of acidic metabolic transport, probenecid. We also tested the hypothesis that pretreatment with inhibitors of plasma membrane 5-HT uptake (escitalopram, ESC) or the vesicular monoamine transporter 2 (dihydrotetrabenazine, DTBZ) would reduce the retention in brain of exogenous DMT after administration of DMT + harmine (1 mg/kg each). We first established the time courses of brain DMT, 3-IAA, and harmine concentrations for 210 min following DMT + harmine administration. The peak DMT concentration occurred at 45 min and peak 3-IAA levels at 60 min after DMT + harmine administration, with nearly complete washout of exogenous DMT at 210 min. Endogenous DMT levels were below the detection limit of our analytic method, despite pargyline pretreatment, and endogenous 3-IAA was slightly elevated by probenecid treatment, suggesting formation from tryptamine, especially in striatum. ESC did not alter the disposition of exogenous DMT or its metabolite 3-IAA, whereas DTBZ slightly increased 3-IAA formation in some brain regions. In summary, we could not detect an endogenous DMT pool in rat brain, and saw scant evidence of retention of exogenous DMT in 5-HT terminals.

Keywords: 3-IAA; DMT; DTBZ; Endogenous; HPLC-MS; Harmine; Pargyline; Pharmacokinetics; Probenecid; Turnover.