Biochemical effects and drug levels in rats after long-term treatment with the specific 5-HT-uptake inhibitor, citalopram

Abstract

The effects in rats of long-term administration of the potent, specific 5-HT uptake inhibitor citalopram have been investigated. Citalopram hydrobromide (MW=405) was given in the diet, 99 or 25 μmol/kg daily, for 13 days or orally, 49 μmol/kg twice a day, for 14 days. High plasma and brain levels of citalopram were found during the treatment period, whereas negligible amounts were found 24 h after withdrawal. The 5-HT uptake mechanism in blood platelets was completely blocked, since levels of whole blood 5-HT during and shortly (2 days) after treatment were decreased by 75–90%. The drug load after the two highest doses in terms of plasma drug levels was the same as in depressed patients treated with citalopram. Receptor binding technique ex vivo was applied to different brain parts to measure receptor parameters for several neurotransmitters. All data were evaluated by Eadie-Hoffstee analysis. No changes were seen in B _max and K _d for β-receptors (³H-dihydroalprenolol) in frontal cortex, occipital+temporal cortex, whole cortex and limbic structures, 5-HT₂ receptors (³H-spiroperidol) in frontal and whole cortex, α₁-receptors (³H-prazosin) in “rest of brain” and DA D-2 receptors (³H-spiroperidol) in corpus striatum and limbic structures. The uptake mechanism for 5-HT as well as the inhibitory effect of citalopram on this uptake remained unaffected in brain synaptosomes derived from control and from citalopram (99 μmol/kg)-treated rats. Thus long-term treatment with citalopram does not induce changes in neurotransmitter receptors as seen with most tricyclic as well as newer “atypical” antidepressants. Most striking is the lack of β- and 5-HT₂ receptor down-regulation. Since citalopram clinically shows clear antidepressant activity, this down-regulation does not seem to be a prerequisite of antidepressant activity.