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Brain serotonin and 5-hydroxyindoleacetic acid concentrations and serotonin synthesis following tetrahydro-β-carboline administration in mice

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Summary

The effects of various tetrahydro-β-carboline (THβC) compounds on serotonin (5-hydroxytryptamine, 5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) concentrations and serotonin synthesis in mouse brain were investigated. 6-Methoxy-THβC (6-MeO-THβC) (100 mg/kg i.p.) significantly increased 5-HT concentrations from 15 min until 4 h after administration, and decreased 5-HIAA concentrations from 15 min until 10 h. The lowest dose of 6-MeO-THβC which produced a significant 5-HT increase was 25 mg/kg whereas 12.5 mg/kg produced a significant decrease of 5-HIAA. Comparisons among the THβC's in their ability to decrease 5-HIAA concentrations showed the following order of potency: THβC>6-MeO-THβC>6-MeO-tetrahydroharman>6-OH-THβC, In order to determine the mechanism for the increase in 5-HT and decrease in 5-HIAA produced by 6-MeO-THβC, its effect was compared to that of reference drugs known to inhibit monoamine oxidase (e. g. clorgyline, deprenyl, pargyline) and synaptosomal 5-HT uptake (chlorimipramine, fluoxetine). These comparisons suggested that the increased 5-HT concentration produced by 6-MeO-THβC was primarily the result of its monoamine oxidase-A inhibiting properties, whereas the decrease in 5-HIAA was the result of a combination of monoamine oxidase-A inhibition and 5-HT uptake inhibition.

Serotonin synthesis in mouse brain following treatment with various tetrahydro-β-carboline compounds and other drugs affecting serotonin metabolism was determined using the so-called in vivo tryptophan hydroxylase method. This involved administering either saline or test drug followed at various times later by an injection of the decarboxylase inhibitor RO4-4602 (800 mg/kg), killing the mouse 30 min later, and measuring 5-hydroxytryptophan (5-HTP) in brain. 6-MeO-THβC at 100 mg/kg decreased the formation of 5-HTP with respect to saline controls from 1 to 4 h after administration, and this decrease was shown to be dose-dependent as measured at 2 h. The other THβC's including THβC, 6-OH-THβC and 6-MeO-tetrahydroharman also decreased 5-HTP formation at 2 h. In order to determine the mechanism for this decreased 5-HTP formation produced by the THβC's, their effects were compared to those of reference drugs known to inhibit monoamine oxidase-A (clorgyline, Lilly 51641), to inhibit synaptosomal serotonin uptake (fluoxetine, chlorimipramine), or to be a serotonin receptor agonist (quipazine). These comparisons suggested that the decrease in 5-HTP formation produced by the THβC's was most likely the result of a combination of monoamine oxidase inhibition plus serotonin uptake inhibition with the latter effect somewhat more potent.

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  1. Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, 29403, Charleston, SC, USA

    Neil S. Buckholtz

  2. Department of Biochemistry, Medical University of South Carolina, 29403, Charleston, SC, USA

    Neil S. Buckholtz

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Buckholtz, N.S. Brain serotonin and 5-hydroxyindoleacetic acid concentrations and serotonin synthesis following tetrahydro-β-carboline administration in mice. Naunyn-Schmiedeberg's Arch. Pharmacol. 314, 215–221 (1980). https://doi.org/10.1007/BF00498542

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  • DOI: https://doi.org/10.1007/BF00498542

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