CLONAZEPAM INDUCES DECREASED SEROTONINERGIC ACTIVITY IN THE MOUSE-BRAIN

Clonazepam induced a dose-dependent increase in cerebral 5-hydroxytryptamine (5HT), 5-hydroxyindoleacetic acid (5HIAA) and tryptophan levels in mice. This effect was unrelated to a decrease in body temperature caused by the drug. In animals pretreated with a MAOI clonazepam further elevated both 5HT and 5HIAA levels, suggesting altered 5HT synthesis or utilization to occur together with a blockade of 5HIAA egress. Pretreatment with probenecid did not prevent the increase in 5HIAA caused by clonazepam indicating an action involving altered 5HT breakdown. However, clonazepam did not alter 5HT synthesis as judged by the accumulation of 5-hydroxytryptophan (5HTP) produced following inhibition of central decarboxylase activity. Following inhibition of tryptophan hydroxylase activity, clonazepam reduced the resulting depletion of 5HT suggesting the drug to cause a decrease in 5HT utilization. This was confirmed by pulse labelling of cerebral 5HT pools using l-[G-3H]-tryptophan. Clonazepam appears therefore to increase brain tryptophan without altering 5HT synthesis, to decrease 5HT utilization and to inhibit the egress of 5HIAA from the brain. © 1979.