The noradrenaline receptor coupled adenylate cyclase system in brain. Lack of modification by changes in the availability of serotonin.
The present studies were undertaken to ascertain whether or not an alteration in the availability of serotonin (5HT) can modify central noradrenergic function at the level of the noradrenaline (NA) receptor coupled adenylate cyclase system in brain. The chronic but not acute administration of the 5HT uptake inhibitors amitriptyline and chlorimipramine reduced the sensitivity of the cyclic AMP generating system to NA in the limbic forebrain. This subsensitivity was linked to a decrease in the Bmax value of beta-adrenergic binding sites without appreciable changes in the Kd values, as assessed by specific 3H-dihydroalprenolol binding. The specific 5HT uptake inhibitor fluoxetine did not change either the responsiveness of the cyclic AMP generating system to NA or the density of beta-adrenergic receptor sites. Raphé lesions which selectively reduced the level of 5HT also did not cause any changes in the neurohormonal responsiveness or the density of beta-adrenergic receptor sites. In contrast, medial forebrain bundle lesions which reduced the levels of both 5HT and catecholamines (NA and dopamine) in the forebrain, increased the responsiveness of the cyclic AMP generating system to NA. It can thus be concluded that a selective change in the availability of 5HT per se does not modify noradrenergic receptor function at the level of the NA receptor coupled adenylate cyclase system. The subsensitivity of the noradrenergic receptor system developed following amitriptyline and chlorimipramine may in all likelihood be due to the in vivo conversion to the secondary amines, nortriptyline and desmethylchlorimipramine respectively. These secondary amine metabolites are potent inhibitors of the NA reuptake and consequently could be responsible for the demonstrated in vivo down-regulation of central adrenergic receptor function (homospecific down-regulation).
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D001679:Biogenic Amines / Q000378:metabolism; D001921:Brain / Q000201:enzymology*; D008032:Limbic System / Q000502:physiology; D008297:Male; D008474:Medial Forebrain Bundle / Q000502:physiology; D011903:Raphe Nuclei / Q000378:metabolism; D051381:Rats; D011941:Receptors, Adrenergic / Q000378:metabolism*; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D012701:Serotonin / Q000502:physiology*; D012702:Serotonin Antagonists / Q000494:pharmacology
D001679:Biogenic Amines; D011941:Receptors, Adrenergic; D011943:Receptors, Adrenergic, beta; D012702:Serotonin Antagonists; D012701:Serotonin; D000262:Adenylyl Cyclases