Biochemical and behavioural effects of isamoltane, a ?-adrenoceptor antagonist with affinity for the 5-HT1B receptor of rat brain

Abstract

The biochemical and behavioural effects of isamoltane, a beta-adrenoceptor and 5-HT1B receptor antagonist that has higher affinity for 5-HT1B receptors than for 5-HT1A receptors, on 5-HT neurotransmission in the rat brain were examined. In binding experiments isamoltane was found to be about five times more potent as a ligand for the 5-HT1B receptor than for the 5-HT1A receptor (Ki values 21 and 112 nmol/l, respectively). Isamoltane increased the K(+)-evoked overflow of 3H from 3H-5-HT loaded slices of rat occipital cortex at 0.1 mumol/l, consistent with inhibition of the terminal 5-HT autoreceptor. In vivo, isamoltane significantly increased the concentration of 5-hydroxyindoleacetic acid in hypothalamus and hippocampus indicating an increased 5-HT turnover with a maximal effect at 3 mg/kg s.c. A higher dose produced a less pronounced effect. This effect did not seem to be due to the beta-adrenoceptor blocking action of isamoltane since the beta-adrenoceptor antagonists. (-)-alprenolol, betaxolol or ICI 118.551 had no significant effects on 5-HT turnover at 5 mg/kg s.c. Isamoltane at 3 mg/kg s.c. induced the wet-dog shake response which was blocked by the tryptophan hydroxylase inhibitor p-chlorophenylalanine. In contrast, the same response induced by the 5-HT2 receptor agonist quipazine was not blocked by pretreatment with p-chlorophenylalanine. The wet-dog shakes evoked by isamoltane and quipazine were blocked by ritanserin, which indicates that 5-HT2 receptors are involved in their expression. These observations indicate that isamoltane, by inhibiting the terminal 5-HT autoreceptors, increased the synaptic concentration of 5-HT to a level that induced a behavioural response.

Reversal of Inflammatory and Noninflammatory Visceral Pain by Central or Peripheral Actions of Sumatriptan

“…Our data show that the antinociceptive effect of RVM sumatriptan was blocked by concurrent microinjection of the 5HT1 B receptor antagonist isamoltane, not microinjection the 5HT1 D receptor antagonist BRL15722. In our study we used antagonists at doses known to block their respective receptors with high affinity using in vitro assays 26, 27 . While isamoltane has been reported to have activity at beta-2 adrenergic receptors, the possibility that this mechanism may mediate the observed antihyperalgesic actions of sumatriptan appear unlikely due to the reported absence of these receptors within the RVM 42, 43 .…”

“…Sumatriptan was given intraperitoneally at doses of 100, 200 and 300 μg/kg 25 . The 5HT1 B antagonist isamoltane 26 and the 5HT1 D antagonist BRL15722 27 were obtained from Tocris (Elllisville, MO). Isamoltane was dissolved in saline to a concentration of 3 μg in 1 μl for RVM microinjection and injected systemically at 4 mg/kg 28 .…”

Facilitation and inhibition of male rat ejaculatory behaviour by the respective 5‐HT1Aand 5‐HT1Breceptor agonists 8‐OH‐DPAT and anpirtoline, as evidenced by use of the corresponding new and selective receptor antagonists NAD‐299 and NAS‐181

“…Thus, NAD-299 (Johansson et al, 1997) represents a new antagonist at the 5-HT 1A receptor site. Anpirtoline (Engel et al, 1989;Swedberg et al, 1992) has been characterized as a 5-HT 1B receptor agonist, whereas isamoltane (Renyi et al, 1991) and NAS-181 (Berg et al, 1998) in particular, represents new 5-HT 1B receptor antagonists. As 5-HT 1A receptor agonist we used the well de®ned prototype agent 8-hydroxy-2-di-npropylamino)tetralin (8-OH-DPAT) (Arvidsson et al, 1981;Hjorth et al, 1982).…”

Serotonin (5-HT) Activation of Immortalized Hypothalamic Neuronal Cells Through the 5-HT1B Serotonin Receptor

“…These results demonstrate that, despite the presence of G s protein-coupled 5-HT receptors, namely the 5-HT 6 R, 5-HT exerts an overall inhibitory effect on the cAMP-PKA pathway and that this inhibition is mediated primarily by the 5-HT 1B R. Interestingly, administration of isamoltane hemifumarate alone caused a slight, but significant, increase in basal cAMP levels. This observation was unexpected given the inhibitory effect that this 5-HT 1B R antagonist has been documented to have on G s protein-coupled ␤-adrenergic receptors (28), which are present in the mHypoA-2/30 neurons (Fig. 1A).…”