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Effects on drug disposition, brain monoamines and behavior after chronic treatment with the antidepressant venlafaxine in rats with experimental hepatic encephalopathy
- Source :
- European Neuropsychopharmacology. 12:327-336
- Publication Year :
- 2002
- Publisher :
- Elsevier BV, 2002.
-
Abstract
- Patients with chronic hepatic encephalopathy (HE) may present affective symptoms and antidepressant drug treatment in this condition is not uncommon. The present microdialysis study investigated treatment with the chronic antidepressant venlafaxine (VEN) in experimental HE with regard to tentative changes in pharmacokinetic and/or pharmacodynamic parameters. Three weeks after portacaval shunt (PCS) or sham operation in rats, VEN (10 mg/kg daily) was administered by implanted osmotic minipumps. VEN treatment for 14 days resulted in higher concentrations of VEN in PCS rats than in sham controls in serum and brain compartments, and the VEN levels in serum and brain were strongly inter-correlated. The serum N-desmethylvenlafaxine concentration did not differ between the groups, but correlated with the serum VEN levels. The other VEN metabolites were below the quantification limits. VEN treatment for 9-12 days significantly stimulated locomotion and rearing in the open field in sham controls, but failed to do so in the PCS rats. The concentrations of noradrenaline, dopamine, 5-HT, and 5-HIAA in neocortical dialysates were higher in PCS than in sham rats after 14 days of VEN treatment, but the elevations reached statistical significance only in the case of dopamine and 5-HIAA. In summary, there were significant pharmacokinetic and pharmacodynamic alterations in rats with experimental HE as compared to controls. The described experimental HE model may be useful for continued pharmacokinetic/pharmacodynamic interaction studies to unravel the pathophysiological consequences of HE on the CNS.
- Subjects :
- Male
medicine.medical_specialty
Microdialysis
Venlafaxine Hydrochloride
Venlafaxine
Portacaval shunt
Motor Activity
Pharmacology
Rats, Sprague-Dawley
Pharmacokinetics
Dopamine
Dialysis Solutions
Internal medicine
medicine
Animals
Biogenic Monoamines
Pharmacology (medical)
Enzyme Inhibitors
Hepatic encephalopathy
Biological Psychiatry
Analysis of Variance
Behavior, Animal
business.industry
Brain
Cyclohexanols
medicine.disease
Rats
Disease Models, Animal
Psychiatry and Mental health
Endocrinology
Neurology
Hepatic Encephalopathy
Ven
Neurology (clinical)
business
medicine.drug
Subjects
Details
- ISSN :
- 0924977X
- Volume :
- 12
- Database :
- OpenAIRE
- Journal :
- European Neuropsychopharmacology
- Accession number :
- edsair.doi.dedup.....ecb3b5b2390c19d41b4de4944eca156c