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PubMed1986

Depletion of striatal beta-phenylethylamine following dopamine but not 5-HT denervation.

The effects of lesions of the substantia nigra (electrolytic 2 mA 10 sec, or 6-OHDA 2 or 8 micrograms) and of the midbrain raphé nuclei (electrolytic 2 X 1.0 mA 10 sec) at 7 days postlesion on striatal levels of beta-phenylethylamine, DA, DOPAC, HVA, 5-HT and 5-HIAA and on hypothalamic levels of beta-phenylethylamine, DA, NA, 5-HT and 5-HIAA were investigated. In the presence of deprenyl (2 mg kg-1 2 hr SC), both electrolytic and 6-OHDA-induced dopamine-depleting lesions of the nigra but not 5-HT-depleting lesions of the raphé nuclei resulted in a marked decrease in the accumulation of beta-phenylethylamine. The marked reduction in accumulation of striatal beta-phenylethylamine in response to lesions of the substantia nigra indicates that the intraneuronal compartment is a major site of striatal beta-phenylethylamine synthesis. An equivalent decrease (approximately 40%) in the accumulation of 5-HT was observed following electrolytic lesions of the substantia nigra or raphé nuclei after administration of L-5-HTP (200 mg kg-1 hr IP). As L-5-HTP at the dose employed in this study is taken up non-selectively by both DA- and 5-HT-containing neurones the loss of L-AAD following nigral and raphé lesions was apparently equivalent. These results indicate that depletion of beta-phenylethylamine may not be simply attributable to a general loss of L-AAD following lesions of monoamine-containing neurones and suggest either co-localisation of beta-phenylethylamine and DA or the existence of distinct beta-phenylethylamine-containing neurones.

Animals↗

PubMed1998

Antagonistic effects of beta-phenylethylamine on quinpirole- and (-)-sulpiride-induced changes in evoked dopamine release from rat striatal slices.

To assess the role of beta-phenylethylamine in aspects of dopamine release, we measured the level of beta-phenylethylamine in the rat striatum after killing the rats by microwave irradiation. We then investigated the effect of beta-phenylethylamine on electrically evoked dopamine release from rat striatal slices in vitro. The striatal beta-phenylethylamine level was 46.5 +/- 3.5 ng/g wet tissue, equivalent to 0.3 micromol/l. Superfusion with low concentrations of beta-phenylethylamine up to 1 micromol/l had no effect on spontaneous or electrically evoked dopamine release from striatal slices. Quinpirole reduced the evoked dopamine release from slices in a concentration-dependent manner. The quinpirole-induced reduction of evoked dopamine release was attenuated 30% by superfusion with 0.3 micromol/l beta-phenylethylamine. Moreover, the (-)-sulpiride (0.1 micromol/l)-induced increase in evoked dopamine release was also attenuated by superfusion with 0.3 micromol/l beta-phenylethylamine. These data indicate that submicromolar levels of beta-phenylethylamine could modify the dopamine autoreceptor mediated changes in evoked dopamine release from rat striatal slices.

Animals↗

PubMed1999

Does phenylethylamine act as an endogenous amphetamine in some patients?

In brain capillary endothelium and catecholaminergic terminals a single decarboxylation step effected by aromatic amino-acid decarboxylase converts phenylalanine to phenylethylamine, at a rate comparable to that of the central synthesis of dopamine. Phenylethylamine, however, is not stored in intra-neuronal vesicles and is rapidly degraded by monoamine oxidase-B. Despite its short half-life, phenylethylamine attracts attention as an endogenous amphetamine since it can potentiate catecholaminergic neurotransmission and induce striatal hyperreactivity. Subnormal phenylethylamine levels have been linked to disorders such as attention deficit and depression; the use of selegiline (Deprenyl) in Parkinson's disease may conceivably favour recovery from deficient dopaminergic neurotransmission by a monoamine oxidase-B inhibitory action that increases central phenylethylamine. Excess phenylethylamine has been invoked particularly in paranoid schizophrenia, in which it is thought to act as an endogenous amphetamine and, therefore, would be antagonized by neuroleptics. The importance of phenylethylamine in mental disorders is far from fully elucidated but the evolution of phenylethylamine concentrations in relation to symptoms remains a worthwhile investigation for individual psychotic patients.

Journal Article↗

PubMed1991

Electrical stimulation of the substantia nigra and changes of 2-phenylethylamine synthesis in the rat striatum.

In rats pretreated with deprenyl (2 mg/kg), electrical stimulation of the left substantia nigra produced an increase in the concentrations of 3,4-dihydroxyphenylacetic acid and homovanillic acid in the left striatum by 57 and 45%, but the levels of 2-phenylethylamine and p-tyramine decreased by 22 and 41%, respectively, as compared with those in the right striatum. The administration of alpha-methyl-p-tyrosine (1.25 mg/kg, i.p.), a tyrosine hydroxylase inhibitor, 1 h before nigral stimulation, did not affect the concentration of 2-phenylethylamine in unstimulated striata but prevented the stimulation-induced decrease in the concentration of 2-phenylethylamine. Neither stimulation nor alpha-methyl-p-tyrosine affected the activity of monoamine oxidase A or B, and stimulation did not produce any change in striatal blood flow, a finding demonstrating that the changes in the rate of accumulation of 2-phenylethylamine were not due to changes in catabolism or removal of 2-phenylethylamine from the brain. These experiments demonstrate that the rate of synthesis of striatal 2-phenylethylamine is decreased following nigral stimulation and that this effect is blocked after partial inhibition of tyrosine hydroxylase. This suggests that 2-phenylethylamine is present in tyrosine hydroxylase-containing neurons and therefore supports the coexistence of 2-phenylethylamine and dopamine in the nigrostriatal pathway.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1987

2-Chloro-2-phenylethylamine as a mechanistic probe and active site-directed inhibitor of monoamine oxidase from bovine liver mitochondria.

The reaction of 2-chloro-2-phenylethylamine with monoamine oxidase B was investigated to study the mechanism of this enzyme and its inactivation by this compound. 2-Chloro-2-phenylethylamine is a substrate with a Km of 30 microM and a turnover number of 80 min-1 at pH 6.5 at 30 degrees C. Incubation of 2-chloro-2-phenylethylamine with the enzyme led to the normal oxidation product, 2-chloro-2-phenylacetaldehyde, but only traces (0.25 mol%) of 2-phenylacetaldehyde, the product anticipated if the oxidation of substrate involved a stabilized carbanion at C-1 and elimination of chloride ion. These data suggest that a carbanion is not a likely intermediate in the oxidation of amines by monoamine oxidase. During the mechanistic studies we noted time-dependent inactivation of monoamine oxidase B by 2-chloro-2-phenylethylamine under both aerobic and anaerobic conditions. Inactivation was not reversible. Aerobically 2-chloro-2-phenylethylamine is oxidized to 2-chloro-2-phenylacetaldehyde which covalently modifies the enzyme (tau 1/2 = 40 min). Benzyl alcohol, a substrate analog, gives substantial protection against inactivation under aerobic conditions (tau 1/2 = 320 min), suggesting that an active site residue is modified. Anaerobic reaction of 2-chloro-2-phenylethylamine with monoamine oxidase B probably proceeds by direct alkylation of an enzyme residue (tau 1/2 = 140 min). Reduction with [3H]NaBH4 of the inactivated enzyme gave from 0 to 0.7 and from 4.5 to 5.6 mol of hydride incorporation for enzyme inactivated anaerobically and aerobically, respectively. The latter results are in agreement with inactivation by unmodified inhibitor and inactivation by oxidized inhibitor for the anaerobic and aerobic reactions, respectively. It is suggested that 2-chloro-2-phenylethylamine or its oxidation product 2-chloro-2-phenylacetaldehyde may serve as an active site affinity reagent for monoamine oxidase.

Aerobiosis↗

PubMed1998

Characterization of beta-phenylethylamine-induced monoamine release in rat nucleus accumbens: a microdialysis study.

In vivo microdialysis was used to investigate the effect of beta-phenylethylamine on extracellular levels of monoamines and their metabolites in the nucleus accumbens of conscious rats. At all doses tested (1, 10 and 100 microM), infusion of beta-phenylethylamine through the microdialysis probe significantly increased extracellular levels of dopamine in the nucleus accumbens. These increases were dose-related. The increase in dopamine levels induced by 100 microM beta-phenylethylamine was not affected by co-perfusion of 4 microM tetrodotoxin. The ability of 100 microM beta-phenylethylamine to increase the extracellular level of dopamine was comparable to that of the same dose of methamphetamine. On the other hand, beta-phenylethylamine had a much less potent enhancing effect on 5-hydroxytryptamine (5-HT) than dopamine levels. Only the highest dose (100 microM) caused a statistically significant effect on 5-HT levels. Over the dose range tested (1, 10 and 100 microM), beta-phenylethylamine had no effect on extracellular metabolite levels of dopamine and 5-HT. The results suggest that beta-phenylethylamine increases the efflux of monoamines, preferentially dopamine, without affecting monoamine metabolism, in the nucleus accumbens.

Animals↗

PubMed1993

Induction of functional down-regulation of beta-adrenoceptors in rats by 2-phenylethylamine.

The effects of chronic administration of antidepressant drugs and 2-phenylethylamine on beta-adrenoceptor function were assessed. Monoamine oxidase inhibitors [phenelzine sulfate, 5 or 10 mg kg-1 per day, and (-)-deprenyl HCl, 1 mg kg-1 per day] and 2-phenylethylamine HCl (10 mg kg-1 per day) were administered to male Sprague-Dawley rats via Alzet osmotic minipumps. On days 21 and 22, the motor-suppressant actions of the beta-adrenoceptor agonist salbutamol hemisulfate (3 mg kg-1 intraperitoneally after 15 min) were assessed as a measure of beta-adrenoceptor sensitivity. On day 28, the animals were killed, and their brains were used for the measurement of monoamine oxidase activity and concentrations of 2-phenylethylamine, an endogenous amine and a metabolite of phenelzine. Phenelzine sulfate at 10 mg kg-1 per day (but not 5 mg kg-1 per day) and the combination of (-)-deprenyl and 2-phenylethylamine resulted in a decrease in the response to salbutamol. These treatments also resulted in substantial increases in brain 2-phenylethylamine concentrations. The phenelzine treatments each resulted in an equivalent inhibition of brain monoamine oxidase activity. These results support the proposal that 2-phenylethylamine may, at least in part, mediate the effects of phenelzine on beta-adrenoceptor function.

Albuterol↗

PubMed1989

Effects of beta-phenylethylamine on polyphosphoinositide turnover in rat cerebral cortex.

The effects of the trace amine, beta-phenylethylamine, on the hydrolysis of inositol phospholipids in rat cerebral cortical slices was studied using a direct assay involving prelabeling with [3H]inositol and then examining the production of [3H]inositol phosphates in the presence of lithium. Phenylethylamine exhibited two different effects. Millimolar concentrations of phenylethylamine stimulated the production of [3H]inositol phosphates to about 200% of control, while much smaller concentrations (micromolar) inhibited noradrenaline(NE)-stimulated [3H]inositol phosphate formation dose-dependently. The alpha 1-antagonist, prazosin, inhibited the increases in [3H]polyphosphoinositide turnover stimulated by phenylethylamine and by NE, though it inhibited phenylethylamine to a lesser extent than NE. It appears, therefore, that phenylethylamine affects [3H]inositol phosphate formation by acting as a partial alpha 1-agonist.

Animals↗

PubMed1992

Absence of 2-phenylethylamine binding after monoamine oxidase inhibition in rat brain.

Earlier work has suggested the existence of saturable and highly specific binding sites for [3H]2-phenylethylamine in rat forebrain membranes. Since monoamine oxidase (MAO) was not inhibited during the assay, the [3H]2-phenylethylamine binding may have been affected by an interaction between 2-phenylethylamine and the enzyme. This is an investigation of [3H]2-phenylethylamine binding to rat forebrain membranes in the presence of two MAO inhibitors, (-)-deprenyl and pargyline. The results show that the high affinity specific binding of [3H]2-phenylethylamine to rat forebrain membranes is inhibited by pretreatment of the membrane with the MAO inhibitors and in vivo injection of the MAO inhibitors in a concentration-dependent manner. In the presence of higher concentrations of MAO inhibitors, the specific binding of [3H]2-phenylethylamine is completely blocked, suggesting that the binding sites reported earlier represent binding to MAO-B.

Animals↗

PubMed1988

In vivo relationship between monoamine oxidase type B and alcohol dehydrogenase: effects of ethanol and phenylethylamine.

The role of acute ethanol (2.5 g/kg i.p.) and phenylethylamine (100 mg/kg i.p.) on the brain and platelet monoamine oxidase activities, hepatic cytosolic alcohol dehydrogenase, redox state and motor behaviour were studied in male rats. Ethanol on its own decreased the redox couple ratio, as well as, alcohol dehydrogenase activity in the liver whilst at the same time it increased brain and platelet monoamine oxidase activity due to lower Km with no change in Vmax. The elevation in both brain and platelet MAO activity was associated with ethanol-induced hypomotility in the rats. Co-administration of phenylethylamine and ethanol to the animals, caused antagonism of the ethanol-induced effects described above. The effects of phenylethylamine alone, on the above mentioned biochemical and behavioural indices, are more complex. Phenylethylamine on its own, like ethanol, caused reduction of the cytosolic redox ratio and elevation of monoamine oxidase activity in the brain and platelets. However, in contrast to ethanol, this monoamine produced hypermotility and activation of the hepatic cytosolic alcohol dehydrogenase activity in the animals. The results suggest that some of the toxic actions of ethanol in rats may be mediated through the activation of monoamine oxidase type B, with the consequent depletion of the endogenous levels of phenylethylamine. The data appear to support the concept of phenylethylamine involvement in affective disorders.

Alcohol Dehydrogenase↗

PubMed1983

In vivo release of endogenous dopamine from rat caudate nucleus by phenylethylamine.

The in vivo release of endogenous dopamine (DA) from the rat caudate nucleus has been measured in the presence and absence of beta-phenylethylamine. A push-pull cannula was implanted into the brain and the tissue was perfused with artificial cerebrospinal fluid (CSF) containing phenylethylamine in concentrations ranging from 5 X 10(-3) to 5 X 10(-7) M. The DA released into the perfusate was determined radioenzymatically. Dopamine was released at rates significantly greater than its resting rate by concentrations of phenylethylamine of 5 X 10(-3) to 5 X 10(-5)M; 5 X 10(-6)M phenylethylamine caused a slight increase in release, but the difference from the resting rate was not significant. The absence of calcium in the perfusing medium did not significantly alter either the unstimulated release rate of DA or the release rate stimulated by 5 X 10(-5)M phenylethylamine. The concentrations of phenylethylamine required to increase release of DA in vivo are discussed briefly in relation to the doses required to elicit behavioural effects.

Animals↗

PubMed1991

The effects of some neuroleptics and d-amphetamine on striatal 2-phenylethylamine in the mouse.

1. Mouse striatal 2-phenylethylamine was not changed at 2 hr following the administration of chlorpromazine, fluphenazine or spiperone. 2. In contrast, when the mice were first given pargyline (2 mg kg-1), treated with chlorpromazine, fluphenazine or spiperone 2 hr later and killed at 4 hr, a significant increase (to 130-170%) in the accumulation of 2-phenylethylamine was observed with respect to the pargyline controls. 3. The effect of chlorpromazine was consistently observed after pretreatment with either deprenyl (2 mg kg -1) or high doses (200 mg kg-1) of pargyline that produced different degrees of MAO inhibition. 4. Following pretreatment with pargyline (2 mg kg-1), d-amphetamine (5 mg kg-1) produced a significant reduction in striatal 2-phenylethylamine concentrations (to 39% of pargyline-treated controls). 5. The findings show that inhibition of dopamine transmission by neuroleptics increases the rate of 2-phenylethylamine accumulation. 6. Conversely, a stimulation of dopamine transmission by d-amphetamine results in a reduction in the rate of accumulation of 2-phenylethylamine and supports the concept of 2-phenylethylamine may be a neuromodulator of dopamine transmission.

3,4-Dihydroxyphenylacetic Acid↗

PubMedDate not supplied

Identification of alpha-phenylethylamine in judicial samples.

alpha-Phenylethylamine was recently identified in samples from several judicial cases using chromatographic (high-performance liquid chromatography-diode-array detection, gas chromatography-mass spectrometry, and gas chromatography-Fourier transform infrared detection) and spectrometric (nuclear magnetic resonance) techniques. In the first case, 1 kg of a white powder was found in a basement laboratory. It contained caffeine and more than 15% alpha-phenylethylamine. In the second case, two white powders were seized from a female. One powder consisted of pure amphetamine, and the other was a mixture of caffeine, amphetamine, and alpha-phenylethylamine. Four months later, a couple, who were known drug users, were found dead in their apartment. Urine samples of both victims contained large amounts of amphetamine together with alpha-phenylethylamine. Recently, 0.13 kg of a white powder and 0.30 kg of an orange powder were seized during a law enforcement operation. Both powders were mixtures of caffeine, amphetamine, and alpha-phenylethylamine. The data presented demonstrate the recent and unrelated repetitive occurrence of alpha-phenylethylamine in the circuit of illicit drugs.

Chromatography, High Pressure Liquid↗

PubMedDate not supplied

Quantitative determination of amphetamine and alpha-phenylethylamine enantiomers in judicial samples using capillary gas chromatography.

alpha-Phenylethylamine was recently reported by us in various samples seized from the illicit drug circuit. At first, alpha-phenylethylamine was identified in powders that generally contained amphetamine and caffeine. Then, a couple, who were known drug users, was found dead in their apartment. Urine samples from both victims contained large amounts of amphetamine and alpha-phenylethylamine. All of the positive samples were re-examined with gas chromatography to determine the chirality of the detected drug or drugs. The homochiral derivatizing reagent N-trifluoroacetyl-L-prolyl chloride was used to convert the drug enantiomers into their corresponding diastereomeric derivatives. These derivatives were separated on an achiral stationary phase and detected using either flame ionization detection (FID) or on-line Fourier-transform infrared spectrometry (FTIR) for quantitative or qualitative purposes, respectively. Excellent separation was realized between all diastereomeric derivatives, and interference of excess, nonvolatile derivatizing reagent was reduced to a minimum. All powder samples consisted of racemic mixtures for alpha-phenylethylamine and for amphetamine. The urine samples also contained both enantiomers of alpha-phenyl ethylamine and amphetamine, albeit in varying proportions. These findings again substantiate the synthetic origin of alpha-phenylethylamine, attributing its presence in the urine of both victims to intentional or accidental intake. The disproportionate isomeric composition found in the urine samples confirms previous reports of a stereoselective metabolism for amphetamine enantiomers and suggests a similar pharmacokinetic profile for alpha-phenylethylamine.

Amphetamine↗

PubMed1979

Cardiovascular actions of beta-phenylethylamine.

beta-Phenylethylamine increased mean aortic blood pressure, total peripheral vascular resistance, left ventricular dP/dt, and (dP/dt)/P in chloralose-anesthetized dogs. Pretreatment with phentolamine reduced the increases in aortic blood pressure and total peripheral vascular resistance produced by beta-phenylethylamine, whereas, the effects of beta-phenylethylamine on left ventricular dP/dt and (dP/dt)/P were abolished by propranolol. beta-Phenylethylamine pretreatment, but increased both after phentolamine pretreatment. Furthermore, both the cardiac and vascular effects of beta-phenylethylamine were abolished by desipramine. These results indicate that beta-phenylethylamine exerts both positive inotropic and vasoconstrictory effects, probably by releasing endogenous norepinephrine from the adrenergic nerve endings.

Animals↗

PubMed1979

Factors influencing the response of the cerebral circulation to phenylethylamine.

The cerebrovascular actions of phenylethylamine, an amine that has been implicated in the pathogenesis of migraine, were investigated in 16 anesthetized baboons. The influence of monoaminergic blocking agents and of a specific inhibitor of monoamine oxidase upon the cerebral circulatory and metabolic actions of phenylethylamine were examined. The reductions in cerebral blood flow (28 percent) and cerebral oxygen consumption (31 percent) that accompany the intracarotid administration of phenylethylamine (2 X 10(-6) moles per kilogram per minute) were unaffected by the prior administration of either phenoxybenzamine (1.5 mg per kilogram, IV) or pimozide (0.5 mg per kilogram, IV). The administration of phenoxybenzamine and pimozide per se did not significantly disturb cerebral blood flow or oxygen consumption. The ability of migraine patients to oxidatively deaminate phenylethylamine is reduced at the time of their attacks. In the present experiments, the administration of the monoamine oxidase type B inhibitor, deprenyl (1 mg per kilogram, IV), did not effect significant changes in cerebral blood flow or cerebral oxygen consumption. However, following deprenyl, the administration of phenylethylamine (4 X 10(-8) moles per kilogram per minute), a concentration which was without effect in normal animals, significantly reduced cerebral blood flow. Some of the possible mechanisms influencing the sensitivity of the cerebral circulation to phenylethylamine, and their relationship to migraine, are considered.

Animals↗

PubMed1992

Octopamine and phenylethylamine inhibit prolactin secretion both in vivo and in vitro.

Trace amines are a group of biogenic amines that are present in neural tissue in concentrations ranging from 0.1 to 100 ng/g. In the present work, we examined the action of two trace amines, octopamine and phenylethylamine, which are found in the hypothalamus, on pituitary hormone secretion in different experimental situations in vivo and in dispersed anterior pituitary cells. Both octopamine and phenylethylamine decreased high prolactin levels due to swimming or immobilization stress without affecting other adenohypophysial hormones. With regard to the hypoprolactinemic potencies in the immobilization stress model, it was observed that p-tyramine, another trace amine, was as potent as octopamine. Phenylethylamine was the least effective. To evaluate the site of action of the effect described, the three trace amines were tested in dispersed anterior pituitary cell cultures in vitro. Tyramine and octopamine reduced prolactin secretion in a concentration-dependent manner, at concentrations of 10(-8) to 10(-5) M, whereas the hypoprolactinemic effect observed for phenylethylamine was very weak. In pharmacologic experiments, neither octopamine nor phenylethylamine reduced prolactin release when dopaminergic receptors were blocked. This could mean that their hypoprolactinemic action was mediated through the release of dopamine, or it could be a direct action at a dopaminergic receptor. This is the first description of a specific endocrine action both in vivo and in vitro for octopamine and phenylethylamine. Further studies are needed to ascertain the physiologic or pathologic implication of these findings.

Analysis of Variance↗

PubMed1989

Rapid and sensitive determination of beta-phenylethylamine in animal brains by high performance liquid chromatography with fluorometric detection.

A reversed phase HPLC method with fluorometric detection for the analysis of beta-phenylethylamine has been developed using p-methoxyphenylethylamine as an internal standard. Two columns, containing 200 microL of Dowex 50-X8 and Amberlite CG-50 respectively, were used to prepare a fraction containing beta-phenylethylamine. The recoveries of beta-phenylethylamine and p-methoxyphenylethylamine were 53.9 +/- 9.4% and 68.1 +/- 12.4%, respectively, and elution profile of p-methoxyphenylethylamine was sufficiently well correlated with that of beta-phenylethylamine. Regional distributions of beta-phenylethylamine in rat and mouse brains were determined. The highest concentrations were found in hypothalamus and hippocampus in both animals.

Animals↗