Methamphetamine N-demethylation and p-hydroxylation activities of rat liver were located mainly in the microsomal fraction. The Km values for methamphetamine and p-hydroxymethamphetamine demethylations were 1.0 and 1.6 mM, respectively. The Km value for amphetamine p-hydroxylation was 10.2 microM; substrate inhibition occurred at high substrate concn. Two Km values were obtained for the aromatic hydroxylation of methamphetamine (10.6 microM and 2.2 mM). N-Demethylation of methamphetamine and p-hydroxymethamphetamine were depressed in rats pretreated with 3-methylcholanthrene, CoCl2 or SKF 525-A. In rats pretreated with phenobarbital, methamphetamine demethylase was induced and p-hydroxymethamphetamine demethylase was depressed. The p-hydroxylation of methamphetamine and amphetamine in rats pretreated with phenobarbital, CoCl2, SKF 525-A or iprindole were depressed.
A sensitive and specific gas chromatography/mass spectrometry (GC/MS) method has been developed for the simultaneous analysis of methampthetamine and its metabolites (amphetamine, p-hydroxymethamphetamine, and p-hydroxyamphetamine) in monkey urine. The method has been applied to the analysis of urine samples from monkeys singly and repeatedly treated with methamphetamine. We have shown that the repeated administration of methamphetamine causes the reduction of urinary excretion of aromatic hydroxylated metabolites. We propose that the method described here can be used for biological monitoring.
Abstract-Repeated administration of a large dose of methamphetamine (MA) (25 mg/kg, i.p. twice daily for 4 days) to mice enhanced locomotor activity and decreased stereotyped behavior following a subsequent injection of MA. Simul taneous determinations of catecholamines revealed a depletion of brain dopamine. The moderate doses of haloperidol significantly enhanced MA-induced locomotor activity in mice. A significant enhancement of MA-induced locomotor activity was observed in the rats pretreated with 6-hydroxydopamine into the striatum, and this effect correlated negatively with the striatal dopamine level. These results suggest that hypofunction of striatal dopaminergic neuron systems induced by repeated administration of MA may be one of possible mechanisms of the enhance ment of MA-induced locomotor activity due to the decrease of stereotyped behavior.
Abstract-The effects of bifemelane hydrochloride (BF) upon various cholinergic markers, muscarinic receptors, acetylcholinesterase (AChE) and choline acetyl transferase (CAT), in the aged rat brain were examined. Marked reduction of the density of muscarinic receptors (BmaX) as well as AChE and CAT activity con comitant with aging was observed. Administration of BF in daily doses of 10 mg/ kg for 4 weeks to aged rats significantly decreased the apparent dissociation constant (Ku) for QNB in muscarinic receptors in the forebrain, but did not affect the value of Bmax. CAT activity also increased significantly compared with that of control aged rats, but administration of BF did not alter AChE activity. These results indicate that long-term treatment with BF enhances the affinity of muscarinic receptors for QNB as well as CAT activity and that BF may have therapeutic application in the treatment of CNS cholinergic dysfunctions.
Abstract-Cerebrospinal fluid (CSF) from dogs competitively inhibited A-form MAO, but was non-competitive with B-form MAO. Heat treatment of CSF (90°C, 20 min) had no effect on the inhibition.Digestion with trypsin and chymotrypsin reduced the MAO inhibitory activity. After ultrafiltration of the CSF through a membrane to remove substances of >5,000 M.W., significant inhibitory activity persisted.These results suggest that CSF contains endogenous substances that act like MAO inhibitor to inhibit A and B-form MAO, and these substances are peptides of less than 5,000 M.W.
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