Effect of 1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo) on human serotonergic cells

The tryptamine-derived dopaminergic neurotoxin 1-trichloromethyl-1,2,3,4-te trahydro-beta-carboline ('TaClo'), which was found to occur in humans after intake of the hypnotic chloral hydrate, was also shown to strongly disturb serotonergic cells. Incubation experiments using the human serotonergic ce ll line JAR clearly revealed TaClo to significantly reduce serotonin (5-HT) uptake (IC50 = 59 mu M) and to induce a distinct loss of cellular viabilit y at increasing TaClo concentrations. In contrast to well-known serotonergi c neurotoxins such as amphetamines, however, TaClo toxicity is not mediated by the 5-HT transporter (5-HTT). In the presence of the specific 5-HTT inh ibitor imipramine, the uptake of TaClo into JAR cells was not reduced, hint ing at an exclusively passive penetration of this highly lipophilic beta-ca rboline through cell membranes. Similar toxic effects towards JAR cells wer e also observed for the 5-HT-related TaClo analog 6-hydroxy-1-trichlorometh yl-1,2,3,4-tetrahydro-beta-carboline ('6-OH-TaClo') (IC50 = 26 mu M). The d opamine-derived alkaloid-type heterocycle 6,7-dihydroxy-1-trichloromethyl-1 ,2,3,4-tetrahydroisoquinoline ('DaClo'), by contrast, was found to be less toxic, showing only a weak inhibitory activity (IC50 = 260 mu M) on 5-HT up take. The pronounced toxicitiy of TaClo and 6-OH-TaClo against serotonergic cells became also evident from morphological findings: Dose-dependently, t he survival of JAR cells was significantly impaired, while human dopaminerg ic IMR-32 cells were only moderately affected at similar toxin concentratio ns.