Biochemical and behavioural effects of isamoltane, a beta-adrenoceptor antagonist with affinity for the 5-HT1B receptor of rat brain.
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.
Rényi
L
L
CNS 1, Astra Research Centre AB, Södertälje, Sweden.
Larsson
L G
LG
Berg
S
S
Svensson
B E
BE
Thorell
G
G
Ross
S B
SB
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000378:metabolism* / Q000648:ultrastructure; D002540:Cerebral Cortex; D008297:Male; D011188:Potassium / Q000494:pharmacology; D011412:Propanolamines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011985:Receptors, Serotonin / Q000378:metabolism*; D012701:Serotonin / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects; D014316:Tritium
D000319:Adrenergic beta-Antagonists; D014151:Anti-Anxiety Agents; D011412:Propanolamines; D011985:Receptors, Serotonin; D014316:Tritium; D012701:Serotonin; C058392:isamoltane; D011188:Potassium