Do imipramine and dihydroergosine possess two components--one stimulating 5-HT1 and the other inhibiting 5-HT2 receptors?
The mechanisms by which imipramine and dihydroergosine stimulate the 5-HT syndrome in rats and inhibit the head-twitch response in rats and mice were studied. Imipramine- and dihydroergosine-induced stimulation of the 5-HT syndrome was inhibited stereoselectively by propranolol, a high affinity ligand for 5-HT1 receptor sites, but not by ritanserin, a specific 5-HT2 receptor antagonist. (-)-Propranolol potentiated the inhibitory effect of imipramine, but not of dihydroergosine on the head-twitch response, while ritanserin was without effect. Neither imipramine nor dihydroergosine were able to stimulate the 5-HT syndrome in the animals pretreated with p-chlorophenylalanine. As expected, 8-OH-DPAT, a selective 5-HT1A receptor agonist, stimulated, and 5-HT1B agonists CGS 12066B and 1-(trifluoromethylphenyl)piperazine (TFMPP) failed to stimulate the 5-HT syndrome induced in rats by pargyline and 5-HTP administration. A higher dose of ritanserin inhibited the syndrome. While 8-OH-DPAT alone produced all behavioral components of the 5-HT syndrome, dihydroergosine or imipramine alone even at very high doses never produced tremor or a more intensive forepaw padding as seen when these drugs were given in combination with pargyline and 5-HTP. A single administration of (-)-propranolol also inhibited the head-twitch response. This effect lasted in mice longer than after ritanserin administration. In in vitro experiments dihydroergosine expressed approximately twenty-fold higher affinity for 3H-ketanserin binding sites than imipramine. The results suggest that imipramine and dihydroergosine possess two components--one stimulating the 5-HT syndrome in rats by a presynaptic, presumably 5-HT1A-mediated mechanism, and the other inhibiting 5-HT2 binding sites.
Pericić
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Department of Experimental Biology and Medicine, Rudjer Bosković Institute, Zagreb, Yugoslavia.
Mück-Seler
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D000818:Animals; D001921:Brain / Q000187:drug effects*; D004879:Ergotamines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D007099:Imipramine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D009043:Motor Activity / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D011919:Rats, Inbred Strains; D016713:Ritanserin; D012702:Serotonin Antagonists; D013577:Syndrome
D004879:Ergotamines; D010880:Piperidines; D012702:Serotonin Antagonists; D016713:Ritanserin; C037580:9,10-dihydroergosine; D011433:Propranolol; D007099:Imipramine