Dynamic and kinetic effects of chronic citalopram treatment in experimental hepatic encephalopathy

Chronic hepatic encephalopathy (HE) is a neuropsychiatric syndrome that ari ses in liver-impaired subjects. Patients with HE display various neuropsych iatric symptoms including affective disturbances and may therefore likely r eceive treatment with novel thymoleptics like citalopram (CIT). The simulta neous pharmacokinetic and pharmacodynamic outcome of the commonly used sero tonin-selective thymoleptic drugs in liver-impaired subjects with pending c hronic HE is far from understood today. We therefore investigated the effec ts of chronic, body-weight-adjusted (10 mg . kg(-1) . day(-1)), treatment w ith CIT in rats with and without portacaval shunts (PCS). Open-field activi ty was monitored. The 5-HT, 5-HIAA, noradrenaline (NA), and dopamine (DA) o utput were assessed in the frontal neocortex. The racemic levels of CIT and its metabolites DCIT and DDCIT, including the S- and R-enantiomers, were d etermined in serum, brain parenchyma, and extracellular fluid. The rats wit h PCS showed higher (2-3-fold) levels of CIT than rats undergoing a sham tr eatment with CIT in all compartments investigated. The PCS rats also showed elevated levels of DCIT and DDCIT. No major differences in the SIR ratios between PCS rats and control rats could be detected. The CIT treatment resu lted in neocortical output differences between PCS rats and control rats ma inly within the 5-HT and DA systems but not within the NA system. For the 5 -HT system, this change was further evidenced by outspoken elevation in 5-H T output after KCl-depolarizing challenges. Moreover, the CIT treatment to PCS rats was shown to "normalize" the metabolic turnover of 5-HT, measured as a profound lowering of a basal elevation in the 5-HIAA levels. The CIT t reatment resulted in an increased or "normalized" behavioral activity in th e PCS group. Therefore, a dose-equal chronic treatment with CIT in PCS rats produced pharmacokinetic and pharmacodynamic changes not observed in contr ol rats. The results further support the. contention of an altered 5-HT neu rotransmission prevailing in the chronic HE condition. However, the tentati vely beneficial behavioral response also seen following chronic CIT treatme nt to PCS rats in this study has to be viewed in relation to both the pharm acokinetic and pharmacodynamic changes observed.