Effects of iproniazid and tranylcypromine of the half-life of N,N-dimethyltryptamine in rat brain and liver.

The time course of N.N-dimethyltryptamine (DMT) levels in brain and liver of adult male Holtzman rats was determined with and without pretreatment with the monoamine oxidase inhibitors iproniazid (32 mg/kg) and tranylcypromine (IO mg/kg) given i.p. DMT was given in doses of 1.0. 3.2 and 10.0 mg/kg i.p. DMT was assayed spectrophotofluorometrically and in some Instances by a radioisotopic method. The results show that the half-life of DMT varied with different doses m the brain but not in the liver. Pretreatment with the monoamine oxidase inhibitors prolonged the total period during which DMT was found. A linear relationship exists between the mean time required to reach minimal DMT concentrations and the mean duration of suppression of FR, barpressing behavior in rats trained for a milk reward. The results suggest a direct involvement of DMT in inducing behavioral toxicity. N,N-dimethyltryptamine (DMT) is one of the hallucinogenic indolealkylamines [l-3]. Biosynthetic pathways exist for the potential synthesis of DMT irk ciz:o [4-S]. This hallucinogen has been implicated in the pathogenesis of schizophrenia [9, lo] although the findings are controversial [Il. 121. DMT is also abused as a hallucinogen 113, 141. DMT is known to produce abnormal behavior in animals [15-211. Much of the speculation on the mode of action of DMT is centered on its interaction with 5-hydroxytryptamine (5-HT) [22,23]. Nevertheless, the time course of the increase in brain 5-HT [23] seems in disagreement with the duration of its behavioral deficits [24]. Many explanations can be offered for this discrepancy. Nevertheless, the direct involvement of DMT in inducing behavioral deficits is the most parsimonious. DMT can readily be detected in the rat brain after systemic injections [25]. It is known to disappear very rapidly from biological tissues. However, to our knowledge no attempt has been made to determine its half-life in various tissues. The purpose of this study is to determine in rats the rate of disappearance of DMT and to determine whether DMT-induced behavioral deficits are correlated with its concentration in the brain. Sai-Hal&z [26] reported that the hallucinatory response to DMT in humans was diminished upon pretreatment with iproniazid. However, iproniazid prolonged and potentiated the toxic effects of DMT in animals using various behavioral endpoints [24].t Therefore, the effects of both iproniazid and the now more widely used monoamine oxidase (MAO) inhibitor tranylcy* Supported in part by a grant from the State of Michigan for schizophrenia research. Part of this material was presented at the ASPET Meeting in Montreal. August 1974 (PharmacologisT 16. 237. 1974). t M. Lutz and E. F. Domino. unpublished data. promine were studied to determine if such behavioral potentiation in rats was a direct result of an elevated tissue DMT level.