Maprotiline: an antidepressant with an unusual pharmacological profile

Maprotiline, which differs from other typical tricyclic antidepressants for its tetracyclic structure, is a highly selective inhibitor of norepinephrine reuptake. Despite its in vitro and in vivo inhibitory activity on NE uptake, 21 repeated daily injections of maprotiline (20 mg/kg i.p.) neither attenuated the norepinephrine-stimulated cAMP accumulation nor reduced the number of beta adrenergic recognition sites in rat frontal cortex. Also, the number of brain serotonin2 recognition sites labeled by [3H]ketanserin remained virtually unchanged in rats receiving 21 daily injections of maprotiline. [3H]Desmethylimipramine and [3H]mianserin specific binding sites were also unmodified by repeated maprotiline injections. However, after 3 weeks of daily administrations, maprotiline elicited a significant decrease in the number of [3H]flunitrazepam binding sites and a decrease in the apparent affinity of [3H]beta-carboline ethylester binding to crude synaptic membranes prepared from hippocampal and hypothalamic homogenates. These changes appear to be unrelated to modifications in the concentration of endogenous gamma-aminobutyric acid present in the membrane preparation, since the addition of 100 microM bicuculline to the incubation mixture decreases [3H]flunitrazepam binding to the same extent in saline- and maprotiline-treated rats. It is suggested that repeated maprotiline injections may elicit an increase in the hypothalamic and hippocampal tissue levels of an endogenous substance(s) which binds to the benzodiazepine/beta-carboline recognition sites