ABSTRACT
The blood-brain barrier penetration of tetrahydropapaveroline (THP) was studied in male rats of the Sprague-Dawley strain. THP was not found in brains of untreated animals. However, THP was observed in the brains of animals that received THP.HBr by intraperitoneal (IP) injection 30 minutes before decapitation. Animals that received IP injections of 0.10, 1.0, 5.0, or 10 mg THP.HBr/kg exhibited brain levels of 3.1, 25, 95 or 126 pmoles THP per gram brain, respectively. Another group of rats received THP.HBr (5.0 mg/kg) IP 30 minutes before decapitation. The brain of each animal was dissected into nine regions and each region assayed for THP. All brain regions assayed had measurable levels of THP. The highest concentration of THP (132 pmoles/g) was observed in the olfactory lobes-frontal cortex while the lowest concentration of THP (27.3 pmol/g) was in the striatum. These results demonstrate that THP penetrates the blood-brain barrier in rats. They also suggest that if THP is formed in the periphery, it may penetrate the blood-brain barrier, and be localized in discrete brain regions.
Subject(s)
Blood-Brain Barrier , Tetrahydropapaveroline/pharmacokinetics , Animals , Brain/metabolism , Injections, Intraperitoneal , Male , Rats , Rats, Inbred Strains , Tetrahydropapaveroline/administration & dosageABSTRACT
A sensitive and selective method for detection of tetrahydropapaveroline (THP) in rat brain has been developed. The procedure employs a multiple-stage separation scheme that selectively isolates THP from rat brain tissue and utilizes the sensitivity and resolution of reversed-phase high-performance liquid chromatography with electrochemical detection to provide an analysis with high specificity for THP. The mean (+/- SD) recovery of THP from rat brain homogenates, fortified at levels ranging from 0.25 to 3.0 pmol per whole brain, was 43.4 +/- 3.5%. The concentration of THP in brains of rats pretreated with L-dopa was 0.44 +/- 0.14 (SD) pmol per gram. The limit of detection of THP was approximately 0.1 pmol (0.03 ng) per gram brain.
Subject(s)
Brain Chemistry , Papaverine/analogs & derivatives , Tetrahydropapaveroline/analysis , Adsorption , Animals , Chromatography, High Pressure Liquid/methods , Electrochemistry , Male , Microchemistry , Rats , Rats, Inbred StrainsABSTRACT
The effect of ethanol on the concentration of the aberrant dopamine metabolite, tetrahydropapaveroline (THP), in brains of L-dopa-treated rats has been evaluated. THP was isolated from rat brain extract by a newly developed multiple stage separation technique that is highly specific for the alkaloid. THP, dopa, and dopamine were assayed by high-performance liquid chromatography with electrochemical detection. THP was not found in brains of untreated animals. However, levels of 0.42 pmol THP per g brain were observed in animals that received L-dopa (200 mg/kg) by intraperitoneal injection (IP) 90 min before decapitation. Administration of ethanol (3g/kg) IP to L-dopa-treated animals at time intervals ranging from 60 to 240 min before decapitation resulted in significant increases in brain levels of THP as compared to L-dopa-treated animals. Maximum levels of THP (4.02 to 4.82 pmol/g brain) were observed when ethanol was given at time intervals ranging from 80 to 180 min before the animals were killed. Administration of ethanol and L-dopa, as compared to the administration of L-dopa only, markedly increased brain levels of dopa and dopamine. Maximum brain levels of THP, dopa, and dopamine in animals administered ethanol plus L-dopa as compared with L-dopa-treated animals represented a 1048%, 325%, and 84% increase, respectively. These results strongly support the concept that the concentration of THP in the brain of intact animals can be enhanced by ethanol administration.