Lin-Whei Chuang

Metabolism of (‐) deprenyl to amphetamine and methamphetamine may be responsible for deprenyl's therapeutic benefit A biochemical assessment

The urinary excretion of some important phenylethylamines, catecholamines, their metabolites, amphetamine, and methamphetamine were measured in parkinsonian patients on Sinemet (L-dopa plus carbidopa, a peripheral dopadecarboxylase inhibitor) and depressed patients after chronic (-) deprenyl treatment. Deprenyl was efficiently metabolized to amphetamine and methamphetamine. It increased the excretion of phenylethylamine and of m-and p-tyramine, and reduced the output of norepinephrine metabolites, but failed to alter the excretion of dopamine-deaminated metabolites. These changes were attributed more to amphetamine and methamphetamine than to inhibition of monoamine oxidase type B. Sinemet treatment alone increased the excretion of dopamine, 3-methoxytyramine, and their respective deaminated metabolites, 3, 4-dihydroxyphenylacetic acid and homovanillic acid. It is concluded that conversion of deprenyl to amphetamine and methamphetamine may contribute to some of the therapeutic benefits of deprenyl.

Reduced metabolism and turnover rates of rat brain dopamine, norepinephrine and serotonin by chronic desipramine and zimelidine treatments

As part of of an ongoing effort to compare changes in whole body turnover of catecholamines and serotonin in man with those induced by antidepressants in the rat brain, we have evaluated the chronic effects of desipramine (DMI) and zimelidine (ZMI) on brain catecholamines and serotonin in the rat. The amines and metabolites measured include norepinephrine (NE), dopamine (DA) and their metabolites, 3-methoxy-4-hydroxyphenylglycol (MHPG), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). Three brain areas were analysed; the hypothalamus, caudate nucleus and frontal cortex. Chronic DMI and ZMI reduced hypothalamic MHPG and caudate nucleus DA metabolites, in particular HVA. Both drugs reduced NE and DA turnover rates (estimated after alpha-methyl-p-tyrosine injection) and the rate of MHPG formation in the hypothalamus (estimated after pargyline treatment). They did not change NE turnover rate, but reduced DA turnover rate and rate of HVA formation in the caudate nucleus. Chronic DMI but not ZMI reduced DOPAC rate of formation in the caudate nucleus. Apparently changes in DA turnover and metabolism produced by these antidepressants are better related to changes in HVA than DOPAC concentrations. Similar to their influence on hypothalamic and caudate nucleus catecholamines, both chronic DMI and ZMI produced changes in serotonin concentration in the caudate nucleus and frontal cortex serotonin that suggest a reduction in its turnover rate and metabolism. The reduction in NE turnover in hypothalamus is consistent with the effects of chronic DMI and ZMI on whole body NE turnover observed in man.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of desipramine, zimelidine, electroconvulsive treatment and lithium on rat brain biogenic amines: A comparison with peripheral changes

The effects of 4 common treatments for affective disorders on total body norepinephrine (NE) and dopamine (DA) turnover and metabolism were evaluated in rats. The treatments were chronic desipramine (DMI), zimelidine (ZMI), electroconvulsion (ECT) and lithium (Li). The central effects of ECT and Li were also assessed in the brain. The results obtained were compared with the effects of these 4 treatments on total NE (Sum NE) and DA (Sum DA) turnover in depressed patients. We have also evaluated central and/or peripheral effects of these treatments on phenylethylamine, p-tyramine and serotonin metabolism. The urinary changes in Sum NE and DA observed after DMI, ZMI and Li in the rat were similar to those found in depressed patients; Sum NE was significantly reduced. In contrast to its effects on depressed patients, chronic ECT significantly increased Sum NE. Similar to depressed patients, ECT reduced the fraction of NE escaping re-uptake in the rat. Sum DA was not affected by DMI, ZMI or ECT, but was significantly reduced by chronic Li treatment. All 4 treatments significantly reduced serotonin metabolism as indicated by reduced 5-hydroxyindoleacetic acid excretion rates. DMI, ZMI and Li treatments significantly reduced phenylethylamine urinary but not p-tyramine urinary outputs. The opposite effect was observed after ECT. Consistent with their effects on Sum NE, Li reduced while ECT increased hypothalamic NE turnover as deduced from the changes in 3-methoxy-4-hydroxyphenylglycols rate of formation. As for Sum DA, Li had no effect on 3,4-dihydroxyphenylacetic acid or homovanillic acids rates of formation in the caudate nucleus. Chronic ECT produced a small, but significant increase in homovanillic acids rate of formation in the caudate nucleus.

d-DOPA and l-DOPA similarly elevate brain dopamine and produce turning behavior in rats

In the intact rat, intragastric administration of D-dihydroxyphenylalanine (D-DOPA) together with carbidopa (alpha-methyldopa hydrazine, a peripheral dopadecarboxylase inhibitor) increased striatal dopamine concentration to the same extent as a similar treatment with L-DOPA plus carbidopa. In rats with unilateral 6-hydroxydopamine-induced lesions of their substantia nigra, both stereoisomers of DOPA produced significant increases in dopamine and its metabolites in the intact striata. Although dopamine concentrations in the lesioned striata did not change, a significant increase in dopamine metabolites was observed, indicating some extraneuronal formation of dopamine. These results suggest that D-DOPA can be converted to dopamine in the normal striatum as well as in the striatum devoid of dopamine nerve terminals. D- and L-DOPA produced turning behavior in unilaterally lesioned rats with a similar efficacy. The onset of turning after D-DOPA was delayed compared with L-DOPA. Turning behavior elicited by these amino acids was attributed to stimulation of supersensitive dopamine receptors in the lesioned striata by the extraneuronally formed dopamine. Preliminary results suggest that D-DOPA is converted to dopamine via transamination and/or D-amino acid oxidation to 3,4-dihydroxyphenylpyruvic acid which upon further transamination gives rise to L-DOPA and hence dopamine. The relatively fast and slow onset of stimulation of dopamine receptors L-DOPA and D-DOPA respectively suggests that the use of the racemic mixture of DOPA combined with a peripheral dopadecarboxylase inhibitor may prove useful in the treatment of parkinsonism.

On the enzymatic hydrolysis of the sulfate conjugate of 3-methoxy-4-hydroxyphenylglycol (MHPG)

Abstract The hydrolysis of 3-methoxy-4-hydroxyphenylglycol sulfate conjugate (MHPG-SO 4 ) by three enzyme preparations (crude sulfatase, pure sulfatase, and glucuronidase) was evaluated. The stability of free MHPG and MHPG-SO 4 to incubation with and without the above enzyme preparation was also assessed. From the results obtained, we concluded that free MHPG is subjected to very little or no decomposition during overnight incubation. The enzyme in the crude sulfatase from Helix Pomatia was found to be superior when compared to the pure sulfatase. It was further determined that 500 units of sulfatase of this enzyme preparation can completely hydrolyze 1 μg MHPG equivalent of MHPG-SO 4 within 1 hr at 40°C or overnight at −10°C. The usefulness of this latter unusual property is discussed.

Different effects of behaviorally equipotent doses of amphetamine and methamphetamine on brain biogenic amines: Specific increase of phenylethylamine by amphetamine

The effects of acute semichronic (twice daily for three days) treatments with the same doses of amphetamine (AMPH) and methamphetamine (M-AMPH) on rat brain phenylethylamine (PEA) and catecholamines were evaluated. These treatments produced similar behavioral responses and hence are assumed to be generally equipotent. Both drugs entered the brain rapidly but at different rates. While AMPH and M-AMPH produced comparable changes in the contents of catecholamines and their metabolites in the hypothalamus and caudate nucleus, only AMPH significantly elevated PEA. The elevated brain PEA produced by AMPH was not due to alpha-demethylation of AMPH. It is concluded that brain PEA may mediate some of AMPH behavioral effects but not those of M-AMPH. The catecholamines appear to be involved in the effects of both drugs.

A STUDY ON THE ACUTE EFFECT OF AMPHETAMINE ON THE URINARY EXCRETION OF BIOGENIC AMINES AND METABOLITES IN MONKEYS

1 The effects of an acute dose (3mg/kg) of amphetamine on the urinary excretion of phenylethylamine (PEA), p‐tyramine, their metabolites, catecholamine metabolites and p‐hydroxymandelic acid, a major metabolite of p‐octopamine were evaluated in the monkey. Amphetamine excretion was also measured. 2 Amphetamine was slowly eliminated from the body, being found in the urine at least six days after administration. 3 Amphetamine increased the excretion of PEA and decreased that of its major metabolite, phenylacetic acid (PAA). This pattern of changes is similar to that previously found in the urine of chronic schizophrenics. 4 The excretion of the dopamine metabolite, 3,4‐dihydroxphenylacetic acid (DOPAC) was markedly reduced, that of vanilmandelic acid (VMA) remained unchanged while 3‐methoxy‐4‐hydroxyphenylglycol (MHPG) was increased on the day of drug administration and persisted for at least a further six days. A similar extended effect on the excretion of p‐hydroxymandelic acid (it was reduced) was also observed. 5 The excretion of p‐tyramine but not its metabolite, p‐hydroxyphenylacetic acid, was decreased by amphetamine during treatment and returned to normal levels six days later. 6 From the results obtained, it was concluded that amphetamine effects on behaviour cannot exclusively be attributed to its influence on catecholamines and that other biogenic amines may be involved. 7 Since PEA elicits many behavioural changes similar to those seen with amphetamine, and since amphetamine increases PEA excretion, we suggest that amphetamine may exert some of its behavioural responses through the release of PEA.

Metabolism of carbidopa to alphamethyldopamine and alphamethylnorepinephrine in rats

Abstract Recent observations on the central and peripheral actions of carbidopa (CD) combined with our own results with the compound led us to examine its metabolism and effects on brain catecholamines in rats. CD was found to undergo a two-stage N-deamination process in vivo giving rise to alpha-methyldopa (AMD) and alpha-methyldopamine respectively. Further, beta-hydroxylation yielded alpha-methylnorepinephrine. These metabolic products were demonstrated in rat brain with reductions in norepinephrine and 3-methoxy-4-hydroxyphenylglycol, and little effect on dopamine. These results are consistent with the alpha-2 agonist effects of alpha-methylnorepinephrine. The relative formation of alpha-methyldopamine from CD was about 26% of an equivalent dose of AMD. It is concluded that some of the central effects of CD may be mediated by its metabolism to AMD. which readily crosses the blood-brain barrier. Possible implications of the findings are discussed.

Cerebrospinal Fluid Concentration of Biogenic Amine Metabolites in Idiopathic Apnea of Prematurity

The concentration of homovanillic acid and 3-methoxy-4-hydroxyphenylglycol (MHPG), the major metabolites of dopamine and norepinephrine, respectively, were studied in the cerebrospinal fluid (CSF) of 34 newborn infants. No significant difference was found in the levels of MHPG and homovanillic acid between preterm and term infants. Apneic preterm infants had significantly higher levels of MHPG than nonapneic prematures. Theophylline did not change the levels of these metabolites in CSF. There was a progressive rise of MHPG levels in CSF in preterm infants as their postnatal age increased. We suggest that idiopathic apnea of prematurity is not associated with depletion of catecholamine stores in the central nervous system. Theophylline does not seem to relieve apnea by stimulation of the central adrenergic system.

Depression during methadone withdrawal: No role for β-phenylethylamine

Abstract An atypical depression, resembling β-phenylethylamine (PEA) deficiency states, frequently complicates methadone withdrawal. We undertook a study of 24-h urinary free PEA excretion in steady-dosed and withdrawing methadone patients, hypothesizing that abstinent patients would excrete less PEA than controls and that methadone would show a dose-dependent effect on PEA turnover. As hepatic dysfunction, frequent in methadone patients, might affect PEA turnover, we also evaluated liver chemistries, [ 13 C]aminopyrine excretion, 2-hydroxylation of estradiol, and ‘blind’, global severity ratings in each subject. PEA excretion did not significantly differ between eight fully detoxified methadone patients (median 4.76 μg/24 h) and seven normal controls (median 5.80 μg/24 h). Moreover, PEA excretion bore no relation to methadone dosage among 24 steadydosed subjects. PEA excretion in seven withdrawing subjects each receiving 4–8 different doses of methadone similarly showed no relation to dose. Despite significant liver disease, several measures of impairment did not correlate with PEA excretion. These findings argue against a role for PEA deficiency in withdrawal depression.