Cholinergic mediation of the inhibitory effect of methylphenidate on neuronal activity in the reticular formation.
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Biomedical subjects
Publications and source records attributed to I Hanin.
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The effects of delta8- and delta9-tetrahydrocannabinol on the biosynthesis of 3H-acetylcholine (ACh) from 3H-choline in cortical, hypothalamic and striatal rat brain slices were examined. The two cannabinols were found to inhibit the synthesis of 3H-ACh in the three brain regions. Treatment with cannabidiol did not alter ACh synthesis. Delta8-tetrahydrocannabinol was approximately twice as effective as the delta9-isomer. This effect was not associated with alterations in striatal and cortical choline acetyltransferase or with an impaired high-affinity uptake system for choline in the striatum. Treatment with delta8- and delta9-cannabinols, likewise, did not change striatal choline and ACh levels. Antagonism of the ACh biosynthesis inhibition occurred when slices from treated animals were incubated in depolarizing concentration of K+ ion. These results suggest that the inhibition of ACh synthesis observed in tetrahydrocannabinol-treated rats may be related to interference with the propagated action potential or with the depolarization process in cholinergic neurons.
The time course of lithium concentration in plasma and RBCs was measured in normal adult males following administration of single and multiple doses of lithium carbonate. From the single dose profiles, it was determined that lithium distribution between plasma and RBCs is not a simple partitioning phenomenon. The single dose time course measurements in both blood components were fit to a two compartment pharmacokinetic model in which the plasma was representative of the central compartment and the RBCs were representative of the tissue compartment. The importance of correction for trapped plasma volume in studies measuring lithium RBC kinetics was emphasized. In this study it was also demonstrated that one can accurately predict plasma and RBC lithium concentrations which are observed following multiple dosing, on the basis of single dose parameters obtained in the same subject.
The effect of chlorothiazide on the pharmacokinetics of lithium in both plasma and RBCs was studied in normal adult males. This was accomplished by administering single, 300 mg. doses of lithium carbonate alone and concurrently with chlorothiazide (0.5 grams/day for one week). Thiazide administration resulted in increases in plasma and RBC concentrations of 26.2 and 25.4%, respectively, as well as a 26.5% decrease in renal lithium clearance. The data were analyzed in terms of a two compartment pharmacokinetic model as previously reported (8). The results of this analysis showed that the change in renal lithium clearance could be accounted for by a 24.1% reduction in the value of ke, the excretion rate constant. It was also shown that changes in plasma lithium concentration during chronic lithium therapy would be expected to increase by 25-30% when chlorothiazide therapy is employed. The model also predicts that changes in RBC concentrations would parallel those occurring in plasma and thus no change in the RBC/plasma lithium ratio would be expected.
An in vitro system that can be used to measure both uptake and efflux of lithium by erythrocytes (RBCs) is described. Using this system, RBC lithium accumulation in vitro was compared with in vivo RBC lithium concentrations observed in 6 normal volunteers. A significant correlation was demonstrated between in vitro RBC lithium accumulation after 48-hr incubation and in vivo RBC lithium concentration at 24, 48, 72, and 96 hr following the beginning of lithium ingestion. In addition, when efflux of lithium from RBCs in vitro was studied, a significant correlation was observed between residual lithium in RBCs and in vitro RBC lithium accumulation. Finally, it has been demonstrated that storage of blood in ice for 5 hr prior to incubation with lithium results in increased RBC lithium accumulation. A potential role for this in vitro incubation system as a model for in vivo RBC lithium accumulation is suggested.
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The rate of metabolism of acetylcholine (ACh) in mouse brain in vivo has been estimated utilizing a radio gas chromatographic approach and pulse labeling with radioactive phosphorylcholine. A kinetic model describing the change with time of the plasma choline (Ch), brain Ch and ACh specific radioactivities as interdependent variables is postulated. The experimental results are analyzed kinetically according to this model using two methods: the finite difference method described by Neff et al. (J. Pharmacol. Exp. Ther. 176: 701-710, 1971) and a simple graphic method based on the transformation of the data in terms of the decline of plasma Ch radioactivity described in this paper. The accuracy of the latter is evaluated by the classic method of the least mean squares. Calculations with the two methods yield comparable results. This method is simple and can be used to study drug effects on brain ACh turnover rate. ACh turnover rate in mouse brain has been calculated to be 0.36 mumol/g/hr with the latter method, whereas the finite difference method yields slightly lower values. Because of the compartmentalization of brain Ch and the inherent assumptions, the new method can be used only for data collected during the exponential decline of plasma radioactive choline.
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We have measured the turnover rate of acetylcholine (ACh) in the brains of mice injected with doses of oxotremorine and physostigmine that cause a prolonged increase of ACh concentration in brain. The method used to measure turnover rate of ACh is an application of principles of steady-state kinetics to the change with time of brain choline (Ch) and ACh specific radioactivities after an intravenous pulse injection of phosphorylcholine. We have found that when the concentration of brain ACh and Ch is increased to a new steady state as a result of oxotremorine and physostigmine injections the turnover rate of brain ACh decreases from 0.34 mumol/g/hr (in saline-treated mice) to 0.12 and 0.061 mumol/g/hr, respectively. The possibility that an increase of brain Ch or ACh concentrations plays a role in the control of brain ACh turnover rate is discussed.
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Turnover rates of acetylcholine (ACh) were estimated in mouse brain after intravenous injection of phosphoryl(Me-14C)choline by applying principles of steady-state kinetics to the change with time of choline and ACh specific radioactivities. Turnover rate of brain ACh was estimated: 1) 45 minutes after a single injection of morphine (350 mumol/kg); 2) 3.5 days after implantation of a morphine pellet (250 mumol/pellet); 3) 15 minutes after 24 mumol/kg of naloxone to precipitate withdrawal in mice implanted with morphine pellets for 3.5 days; and 4) 15 minutes after 24 mumol/kg of naloxone. Brain ACh turnover rate was unchanged in mice that were given a single injection of morphine but was increased significantly in mice that had been made physically dependent upon morphine. During naloxone-precipitated withdrawal, the brain ACh turnover rate was found to be equal to that of mice treated only with naloxone.
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An aqueous extract from roasted seeds of Carum copticum (omum) has cholinomimetic effects. It shows muscarinic effects on rabbit duodenum, guinea-pig ileum and rat jejunum, and on the blood pressure of rat and cat. These effects are blocked by atropine. It also has a nicotinic action on the frog rectus preparation and atropinized cat blood pressure. Its effect is potentiated by physostigmine and antagonized by cholinesterase or alkalinization. Paper and gas chromatography have confirmed the presence of acetylcholine and choline in the roasted omum seed extract.
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