Biochemical and behavioural effects of isamoltane, a β-adrenoceptor antagonist with affinity for the 5-HT_1B receptor of rat brain

Summary

The biochemical and behavioural effects of isamoltane, a \-adrenoceptor and 5-HT_1B receptor antagonist that has higher affinity for 5-HT_1B receptors than for 5-HTIA 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-HT_1B receptor than for the 5-HT_1A receptor (K_i 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 μmol/l, consistent with inhibition of the terminal 5HT 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 β-adrenoceptor blocking action of isamoltane since the β-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.