Abstract

This study investigates the possibility that mianserin, a serotonin-2 (5HT2) receptor antagonist, produces a prolonged antagonism of quipazine discrimination, consistent with its prolonged biochemical effects. Rats were trained on a saline-quipazine (1.5 mg/kg) discrimination; following acquisition, the animals were assigned to groups and given injections of 2.0 mg/kg mianserin. Individual groups were tested at 45 min and successive 12-hr intervals for their ability to discriminate 0.75 mg/kg of quipazine, a dose that elicited 75% responding on the quipazine lever. Blockade of the quipazine cue persisted for 48 hr following mianserin administration. The above procedure was replicated using lower doses of mianserin (0.25, 0.10 and 0.05 mg/kg) and two other 5HT2 antagonists, pizotifen and metergoline (2.0 mg/kg), both of which showed similar profiles of extended antagonism. Changes in both receptor density and receptor sensitivity were investigated as possible mechanisms of mianserin's prolonged activity. Analysis of [3H]ketanserin binding revealed that a single 2.0-mg/kg dose of mianserin produced a significant decrease in the number of receptor sites (44%) 24 hr after treatment; however, this loss of sites recovered by 36 hr post-injection and could therefore not account for mianserin's continued antagonism at this and later times. 5HT-mediated phosphoinositide hydrolysis in cerebral cortex slices was used as a measure of 5HT2 receptor sensitivity. Treatment of rats with 2 mg/kg of mianserin caused a marked reduction in the maximum phosphoinositide response to 5HT that persisted for up to 36 hr. Hence, the time course for recovery of 5HT2 receptor sensitivity corresponded more closely to behavioral recovery than did 5HT2 receptor binding.