Desensitisation of 5-HT autoreceptors upon pharmacokinetically monitored chronic treatment with citalopram

Rats were chronically treated with the selective serotonin re-uptake inhibi tor citalopram [1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-5-phtalancarbo nitril], by means of osmotic minipumps. Using an infusion concentration of 50 mg/ml citalopram, steady-state plasma concentrations of approximately 0. 3 mu M citalopram were maintained for 15 days. Citalopram plasma levels dro pped below pharmacologically active concentrations 48 h after removal of th e minipumps. Although chronic treatment with citalopram did induce an atten uated response by extracellular levels of 5-hydroxytryptamine (5-HT) after systemic administration of the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-pr opylamino)tetralin (8-OH-DPAT), no effect of chronic citalopram treatment w as observed when 5-HT1B receptor function was evaluated with a local infusi on of 5-HT1B/D receptor agonist, sumatriptan (3-[2-dimethylamino]ethyl-N-me thyl-1 H-indole-5methane sulphonamide). Controversially, no augmentation of the increase of 5-HT levels was observed upon systemic administration of c italopram It is concluded that, although chronic treatment with citalopram does induce desensitisation of 5-HT1A receptors, the absence of augmented e ffects of citalopram on 5-HT levels indicates that other mechanisms compens ate for the loss of autoreceptor control. (C) 2000 Elsevier Science B.V. Al l rights reserved.