The unique effect of methiothepin on the terminal serotonin autoreceptor in the rat hypothalamus could be an example of inverse agonism

Abstract

Slices of rat hypothalamus were pre-incubated with [³H] 5-hydroxytryptamine ([³H ] 5-HT), then superfused continuously and twice stimulated electrically. The effects of methiothepin, metergoline and alprenolol, all considered to be terminal 5-HT autoreceptor antagonists (although they also act at a number of other receptors), were studied. The stimulation-evoked overflow of tritium was increased by methiothepin in a concentration- dependent manner. The slight enhancing effect of alprenolol was not concentration dependent and metergoline, at concentrations which did not modify spontaneous outflow, was devoid of effect on evoked tritium overflow. The concentration-dependent inhibition by the terminal 5-HT autoreceptor agonist, lysergic acid diethylamide (LSD), of the electrically induced release of [³H] 5-HT was antagonized by methiothepin, alprenolol and metergoline. The stimulatory effect of methiothepin on tritium release was diminished by metergoline and by alprenolol at a concentration which slightly enhanced the evoked overflow of [³H ] 5-HT when given alone. Thus methiothepin induced an effect opposite to that of an agonist, in contrast to alprenolol and metergoline which under our conditions had no effect by themselves but reduced the effect of an agonist. In addition, the stimulating effect of methiothepin on release was reversed by two terminal 5-HT autoreceptor antagonists, alprenolol and metergoline. These results are consistent with methiothepin being an inverse agonist at the terminal 5-HT autoreceptor.