Phenylethylamine in paranoid chronic schizophrenia.

Phenylethylamine (PEA) is an endogenous amine that is structurally and pharmacologically related to amphetamine. Urinary PEA excretion is significantly higher in paranoid chronic schizophrenics than in nonparanoid chronic schizophrenics and normal controls. Diet, hospitalization, and medication do not account for differences in PEA concentrations. These findings offer some indication that PEA may be an endogenous amphetamine.

Stimulants, urinary catecholamines, and indoleamines in hyperactivity. A comparison of methylphenidate and dextroamphetamine.

Children with attention deficit disorder with hyperactivity were given either methylphenidate hydrochloride or dextroamphetamine sulfate to compare the effects on urinary excretion of catecholamines, indoleamines, and phenylethylamine (PEA). Methylphenidate's effects were distinctly different from those of dextroamphetamine. After methylphenidate administration, both norepinephrine (NE) and normetanephrine (NMN) concentrations were significantly elevated, and there was a 22% increase in excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG). In contrast, after dextroamphetamine treatment, MHPG excretion was significantly reduced and NE and NMN values were unchanged. Excretion of dopamine and metabolites was unchanged by either drug. Urinary PEA excretion was not significantly changed after methylphenidate treatment, but increased 1,600% in response to dextroamphetamine. Methylphenidate treatment did not significantly alter serotonin or 5-hydroxyindoleacetic acid excretion. Effects of dextroamphetamine were not tested.

Phenylacetic acid excretion in schizophrenia and depression: the origins of PAA in man.

Urinary phenylacetic acid (PAA) excretion was found to be decreased in a group of chronic schizophrenic patients, particularly in a nonparanoid subtype. No significant change in PAA excretion was observed in a group of 21 unipolar depressed patients. Urinary PAA was studied following the administration of phenylethylamine, monoamine oxidase inhibitors, a dopa decarboxylase inhibitor, a low phenylalanine diet, and phenylalanine loads in several groups of psychiatric patients and normal volunteers. While Phenylethylamine ingestion increased urine PAA, inhibition of both phenylethylamine metabolism and synthesis failed to alter urine PAA. These studies suggest that urine PAA is primarily derived from phenylalanine transamination or pathways not involving monoamine oxidase or both. The observed decrease in PAA excretion in some schizophrenic patients may reflect an alteration in this pathway. The high phenylethylamine excretion previously reported in some chronic schizophrenic patients is not directly related to the observed low PAA excretion. Therefore measurement of urine PAA is not expected to be useful in assessing any phenylethylamine abnormalities in psychiatric disorders. The possible contribution of reduced phenylalanine transamination and its subsequent increased availability for the possible synthesis of phenylethylamine in schizophrenia is discussed.

Urinary phenethylamine response to d-amphetamine in 12 boys with attention deficit disorder.

Urinary phenethylamine (PEA), an endogenous amine similar to amphetamine in both molecular structure and pharmacological properties, was studied in 12 boys with attention deficit disorder with hyperactivity. d-Amphetamine and placebo were given for 14 days each in a counterbalanced crossover design; double-blind teacher behavior ratings and motor activity measurements were also obtained. Excretion of PEA, phenylacetic acid, creatinine, and d-amphetamine were measured. PEA was significantly increased and phenylacetic acid was unchanged after d-amphetamine administration, and change in PEA excretion correlated significantly with d-amphetamine excretion. There was no significant relationship between either clinical response to drug and change in PEA or phenylacetic acid excretion.

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.

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 (3 mg/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-dihydroxyphenylacetic 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 alpha-methyldopamine and alpha-methylnorepinephrine in rats.

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.

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.

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.

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-hydroxyphenylglycol's rate of formation. As for Sum DA, Li had no effect on 3,4-dihydroxyphenylacetic acid or homovanillic acid's rates of formation in the caudate nucleus. Chronic ECT produced a small, but significant increase in homovanillic acid's rate of formation in the caudate nucleus.

Depression during methadone withdrawal: no role for beta-phenylethylamine.

An atypical depression, resembling beta-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, [13C]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 micrograms/24 h) and seven normal controls (median 5.80 micrograms/24 h). Moreover, PEA excretion bore no relation to methadone dosage among 24 steady-dosed 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.

Fluctuating high urinary phenylethylamine excretion rates in some bipolar affective disorder patients.

Five women with primary major bipolar affective disorders had variable and at times very high urinary phenylethylamine (PEA) excretion rates. The clinical picture of these patients was characterized by periodic bizarre behaviors and short psychotic episodes. These patients were generally nonresponsive to the usual treatment modalities, and their symptoms were exacerbated by nonspecific monoamine oxidase inhibitors which further increased PEA excretion rates.

Plasma and cerebrospinal fluid concentration of phenylacetic acid in humans and monkeys.

A rapid and reliable mass-fragmentographic method for assay of plasma and cerebrospinal fluid (CSF) concentrations of free and conjugated phenylacetic acid (PAA) is described. The method is used to compare plasma and CSF concentrations of PAA in humans and monkeys. Both packed and capillary columns are used. In humans approximately 45% of total plasma PAA is conjugated in contrast to approximately 60% in monkeys. Both free and conjugated PAA concentrations tend to be higher in monkeys than in humans. Plasma mean concentration of total PAA in humans and monkeys are, respectively, 459.1 and 838 ng/ml. Approximately 55 and 25% of total PAA in the CSF are conjugated in humans and monkeys, respectively. Total PAA mean concentrations in human and monkey CSF are 41.6 and 84.2 ng/ml. Because over 90% of total urine PAA in humans is conjugated, it is concluded that over 50% of urine phenylacetylglutamine may be derived from kidney conjugation of free plasma PAA and/or from the kidney's preferential filtration of conjugated PAA as contrasted with free PAA.

Biochemical and pharmacological characteristics of conjugated catecholamines in the rat brain.

Mass-fragmentographic methods are described that enable the simultaneous measurement of total, free, and conjugated catecholamines in brain tissues. These methods were used to assess the distribution, kinetics, and pharmacological characteristics of total, free, and conjugated catecholamines in the hypothalamus, caudate nucleus, hippocampus, and septum. Conjugated norepinephrine (NE) represents approximately 20% of total NE in the hypothalamus, septum, and hippocampus, whereas the percentage is approximately 50% in the caudate nucleus. The percentages of conjugated dopamine (DA) in these brain areas are consistently less than those of NE (approximately 13%). Although in the hypothalamus the steady-state concentrations of total, free, and conjugated NE are over four times higher than those of the corresponding total, free, and conjugated DA, the turnover rates of this DA are comparable with those of the corresponding NE. Further, the ratios of conjugated NE or DA turnover rates to those of the total amines are higher than the corresponding ratios of their steady-state concentrations. Treatments with pargyline (75 mg/kg, i.p.; rats killed 30 and 60 min later) failed to change the contents of conjugated catecholamines in the hypothalamus and the caudate nucleus significantly. Pharmacological manipulation with a number of prototypic drugs revealed that although the assay of conjugated catecholamines might shed additional light on the effects of drugs on central catecholamines, the assessment of total or free amines are on the whole equally informative. In conclusion, a detailed assessment of brain conjugated catecholamines is reported. The information provided, fills a gap in our knowledge that has up to now not been adequately addressed.