Mechanistic model of acute autoinhibitory feedback action after administration of SSRIs in rats: application to escitalopram-induced effects on brain serotonin levels

Abstract

This study presents the development and evaluation of a feedback turnover model that mimics drug-induced effects on brain extracellular levels of serotonin (5-HT) after acute administration of the selective serotonin reuptake inhibitor (SSRI) escitalopram (S-citalopram) in rats. The extracellular 5-HT output in the hippocampus was continuously monitored by intracerebral microdialysis in conjunction with serial arterial blood sampling for evaluation of escitalopram pharmacokinetics. 5-HT levels were significantly increased following administration of 2.5, 5 and 10 mg/kg of escitalopram and the 5-HT levels gradually declined to its baseline value within 360 min. However, at 5 and 10 mg/kg, the response-time curves were almost identical. This might be explained by activation of serotonergic autoreceptors exerting negative feedback, leading to a reduced release of new 5-HT into the synapse. The dynamics of escitalopram-evoked changes of 5-HT response was characterized by a turnover model, which included an inhibitory feedback moderator component. Thus, the response acted linearly on the production of the moderator, which acted inversely on the production of response. The plasma kinetics served as input to an inhibitory function acting on the loss of response. Simultaneous fitting of the model after three constant rate infusions demonstrated the flexibility of the system. The efficacy (I(max)) and potency (IC(50)) of inhibition of reuptake were 0.9+/-0.03 and 4.4+/-1.4 ng/ml, respectively, corresponding to an EC(50) of escitalopram about 30 ng/ml. In conclusion, the model lends itself to 'what-if' predictions at different drug exposure scenarios, and has potential for extrapolation of the pharmacodynamics of SSRIs in man.