engleski

The effect of antidepressants on platelet serotonin uptake in rats genetically selected for these traits

Tricyclic antidepressives (TCAs) and selective serotonin reuptake inhibitors (SSRIs) are the most potent drugs interacting at the level of 5HT transporters. In spite of being chemically heterogeneous and pharmacologically distinct classes of drugs, all of them posses clinical antidepressant (and other) activity. Therapeutic response rate, however, reflects great variability. Besides clinical efficiency, treatments with TCAs and SSRIs result in decreased platelet serotonin level (PSL) and activity of serotonin transporters (5HTt) on platelet membrane. Therefore, these two platelet serotonergic measures are studied in biological psychiatry as peripheral indicators of pharmacodynamic action of these drugs. In the present work we have studied changes in PSL and the activity of platelet 5HTt in rats differing markedly in basal values of these parameters, after acute and chronic treatments with TCA (clomipramine) and SSRIs (fluvoxamine, fluoxetine). Sublines of Wistar-derived rats with constitutionally high or low PSL and analogously high or low activity of platelet 5HT transporter have been recently developed in our laboratory by the use of selective breeding procedure (Jernej et al., 1990, 1992 ; iin-ain et al. 1995). Animals from these two sublines differ significantly in their PSL and the activity of 5HTt and, as such, might be expected to differ in response to pharmacological treatments with drugs acting on transporter mechanism. Clomipramine and fluvoxamine were given in dose of 20 mg/kg/day i.p. for 14 and 10 days respectively, and changes in PSL were monitored 24 hours after the 3rd, 7th and the last injection. Fluoxetine was given in a single injection in dose of 10 mg/kg and PSL and activity of 5HTt were determined after 16 hours. The procedure for measuring of PSL and activity of 5HT transporter in small blood samples in the individual rat ex vivo, recently developed in our laboratory, was used throughout. This method permits repetitive measurements of platelet serotonergic parameters in the rat, enabling so comparison of values obtained after pharmacological treatment with the basal value of the same animal. Determination of PSL was performed fluorometrically and activity of 5HTt was assessed by the use of radioisotopic method. In addition, the in vitro potency of fluoxetine to inhibit platelet 5HT uptake, as well as the IC50 values, were compared in platelets of rats from two mentioned sublines differing in their basal values of activity of 5HT transporter. In all experiments similar pattern of pharmacodynamic response between rats deriving from two sublines emerged. Notwithstanding the drug used, a duration of pharmacological treatment and in vivo or in vitro approach, decrease of both PSL and the activity of 5HTt was proportional to the pretreatment values. Considering the absolute amount of serotonin (μ g 5HT per mg of platelet protein) that was depleted from platelet granular store, the same drug dose produced much larger depletion in platelets of rat subline genetically selected for higher PSL. The same was true for the activity of 5HTt - a larger number of uptake sites, measured as pmol of 14C-5HT internalized per mg of platelet protein per minute, was inhibited when basal values of platelet 5HT transporter activity was higher. The observed proportionality of the pharmacodynamic response of 5HT transporter (and, consequently of PSL) to its basal activity could be of help in understanding individual variability in effectiveness of these drugs. Still, although platelets express the identical transporter protein to the one found on 5HT neurons, further studies confirming the validity of platelet model in this respect are needed.

serotonin; uptake

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