A pivotal role for serotonin (5HT) in the regulation of beta adrenoceptors by antidepressants: reversibility of the action parachlorophenylalanine by 5-hydroxytroptophan.
An acute reduction in the synaptic availability of serotonin (5HT) by p-chlorophenylalanine (PCPA) nullifies the decrease in the density of cortical beta adrenoceptors caused by desipramine (DMI) but does not appreciably alter the attenuation of the norepinephrine (NE) sensitive adenylate cyclase. The analysis of competition-binding curves of [3H]-dihydroalprenolol shows that the affinity of the agonist (-)-isoproterenol for cortical beta adrenoceptors is profoundly reduced following PCPA. This reduction in agonist affinity is enhanced by DMI. Resupplying 5HT by by-passing tryptophan hydroxylase inhibition, by administering 5-hydroxytryptophan, converts a DMI non-responsive to a DMI responsive beta adrenoceptor population and shifts the markedly decreased agonist affinity towards the affinity values found in control preparations. The results demonstrate the pivotal role of 5HT in the regulation of the density and agonist affinity characteristics of cortical beta adrenoceptors and contribute to the scientific basis of the 'serotonin-norepinephrine link hypothesis' of affective disorders.
D006916:5-Hydroxytryptophan / Q000494:pharmacology*; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive; D002540:Cerebral Cortex / Q000378:metabolism; D003891:Desipramine / Q000494:pharmacology*; D004082:Dihydroalprenolol / Q000378:metabolism; D010134:Fenclonine / Q000494:pharmacology*; D007545:Isoproterenol / Q000378:metabolism; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism*; D012701:Serotonin / Q000502:physiology*; D013569:Synapses / Q000378:metabolism; D014365:Tryptophan Hydroxylase / Q000037:antagonists & inhibitors
D011943:Receptors, Adrenergic, beta; D012701:Serotonin; D004082:Dihydroalprenolol; D006916:5-Hydroxytryptophan; D014365:Tryptophan Hydroxylase; D000262:Adenylyl Cyclases; D007545:Isoproterenol; D010134:Fenclonine; D003891:Desipramine; D009638:Norepinephrine