9-10-dihydroergosine and Syndrome

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.

Topics: Animals; Brain; Ergotamines; Imipramine; Male; Mice; Mice, Inbred CBA; Motor Activity; Piperidines; Propranolol; Radioligand Assay; Rats; Rats, Inbred Strains; Ritanserin; Serotonin Antagonists; Syndrome

Effects of the classic antidepressant imipramine and of an imipramine-like potential antidepressant dihydroergosine were studied in mice, rats and guinea pigs using behavioural models associated with the activation of 5-HT2 and 5-HT1 receptors respectively. Both drugs given in a single dose inhibited the 5-HT2 mediated behaviour for 24 and 48 h respectively and simultaneously stimulated 5-HT1 mediated behaviour for 6 days. Blockade of 5-HT2 receptors could have reduced their inhibitory influence on 5-HT1 receptors. We propose that the interplay between the two receptor subtypes controls the serotoninergic transmission. This idea throws a new light on the mode of action of antidepressants.

Topics: Animals; Behavior, Animal; Ergotamines; Guinea Pigs; Head; Imipramine; Male; Mice; Myoclonus; Pargyline; Rats; Receptors, Serotonin; Serotonin; Syndrome

The duration of the stimulating effect of one single i.p. injection of a possible antidepressant dihydroergosine (50 mg/kg) on the 5-HT syndrome was studied in rats. Dihydroergosine produced a very pronounced stimulation of the 5-HT syndrome which was still present after 1-144 h (6 days). The results suggest that dihydroergosine produces a long-lasting stimulation of serotoninergic neurons.

Topics: Animals; Antidepressive Agents; Behavior, Animal; Ergotamines; Male; Pargyline; Rats; Rats, Inbred Strains; Receptors, Serotonin; Syndrome