Serotonin Uptake Inhibitors

Established tricyclic antidepressants either affect transmission of both noradrenaline(NA) and serotonin(5-HT), or NA alone. Many newer antidepressants preferentially potentiate 5-HT transmission by inhibiting 5-HT uptake. Selective 5-HT-uptake inhibitors are those which have a high ratio of 5-HT-uptake inhibition as compared to NA-uptake inhibition, together with slight or no effect on other uptake mechanisms, neurotransmitter receptors, enzymes etc. By measuring inhibition of uptake into synaptosomes the following compounds are classified as selective 5-HT-uptake inhibitors (ratio IC50 NA/IC50 5-HT well above one): Citalopram (4400), indalpine (1000), sertraline (840), CGP 6085/A (630), alaproclate (390), paroxetine (280), fluvoxamine (160), cyanimipramine (69), zimelidine (55), fluoxetine (54), femoxetine (37), trazodone (24), and chlorimipramine (14). A similar rank order of selectivity is found in biochemical in vivo studies and in behavioral studies. Potency and selectivity for 5-HT uptake do not coincide. 5-HT uptake inhibitors show high affinity for the 5-HT-uptake sites labeled by radioactive ligands (e. g. 3H -imipramine, 3H-paroxetine), whereas it has low affinity for the NA-and dopamine (DA)-uptake sites as measured using 3H- desipramine and 3H-GBR 12935, respectively. In contrast to tricyclic antidepressants most of which inhibit receptors for acetylcholine, histamine, NA, 5-HT or DA, most selective 5-HT-uptake inhibitors neither bind to nor inhibit these receptors. 5-HT-uptake inhibitors potentiate the effect of 5-HT and 5-HT agonists thereby giving rise to exaggerated 5-HT responses like tremor, hyperactivity, lordosis and abduction of hind limbs. The potentiation of 5-HT is also seen in the hind limb flexor reflex model in spinal rats, as wet-dog shake and as reciprocal forepaw treading in rats. During chronic administration many antidepressant treatments down-regulate the NA-coupled adenylate cyclase system in brain. This is often linked to a reduction of the density of s-receptors. Many selective 5-HT- uptake inhibitors like citalopram do not cause this down-regulation. Since these drugs show clear antidepressant effect this down-regulation seems not to be a prerequisite for clinical antidepressant activity. The same holds true for the behavioural despair test, where many 5-HT uptake inhibitors are inactive.