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Upon injection of beta-phenylethylamine (PEA) into the subconjunctival space of rabbit, intraocular pressure increased. This effect went parallel with the amount of PEA transferred into the anterior chamber, which indicates that intraocular pressure was elevated by direct action of PEA.
Repeated daily administration of an endogenous trace amine, beta-phenylethylamine (PEA), produces behavioral sensitization such that the intensity of PEA-induced stereotyped behaviors in rats increases gradually during the treatment, and a challenge injection with PEA reinstates the enhanced stereotypy even long after withdrawal. In the present study, we examined the neurochemical changes in the central dopaminergic neurons systems in the rat for 7 drug-free days after repeated treatment with PEA (50 mg/kg, IP day for 14 or 28 days). During withdrawal, a decrease in steady-state levels of tissue dopamine (DA) and its metabolite, dihydroxyphenylacetic acid (DOPAC), was found in the mesolimbic DA nerve terminal areas of the rat brain receiving repeated PEA treatment. Fifteen minutes after challenge administration of PEA at varying doses from 6.3 to 75 mg/kg, the rats with repeated PEA treatment required smaller doses of PEA challenge than the rats with acute PEA treatment in order to obtain a significant decrease in striatal DOPAC content compared to the saline control in each treatment group. These results imply that the behavioral sensitization to PEA is accompanied by enduring modifications of the specific dopaminergic neuron systems in the rat brain. This suggestion was strongly supported by the results of the study using in vivo intracerebral dialysis, which indicated that 25 mg/kg PEA challenge elicited a remarkable increase in the extracellular DA concentrations in striatal perfusates collected from the PEA-pretreated rats, in accordance with the intensity of stereotyped behaviors. These findings argue that the hyper-responsiveness to PEA of the striatal dopaminergic neuron systems persists long after withdrawal from repeated treatment with PEA.
Beta-phenylethylamine (PEA) is an endogenous amine which is metabolised by MAO B. The function of this enzyme is known to be modified by ethanol so we have studied the interactions of PEA with ethanol. Rectal temperatures of rats were determined and animals pretreated with ethanol (2.5 g kg-1 IP) 90 min before PEA 20, 40, 100 mg kg-1 IP). Spontaneous locomotor activity (SLA) was then recorded, for 30 min, temperatures redetermined and blood ethanol levels evaluated. PEA increased SLA but did not alter rectal temperatures, and at 40 mg kg-1 it not only attenuated ethanol hypothermia and blood levels but also modified ethanol hypomotility. The highest dose of PEA (100 mg kg-1) decreased blood ethanol concentration and sedation but did not counteract the hypothermia. Thus PEA increased ethanol clearance, though the underlying mechanism is not totally clear. This finding is discussed in relation to its catecholaminergic and enzyme inducing characteristics.
RATIONALE AND OBJECTIVE: Sufficiently high doses of beta-phenylethylamine (beta-PEA), a trace amine that is rapidly metabolized by monoamine oxidase-type B (MAO-B), can produce effects comparable to those of cocaine or methamphetamine (MA). The present experiments were conducted to study how the discriminative-stimulus (S(D)) and reinforcing-stimulus (S(R)) effects of beta-PEA in monkeys are modified by treatment with inhibitors of MAO-B [R-(-)-deprenyl and MDL 72974]. METHODS AND RESULTS: In studies of its S(D) effects, doses of beta-PEA up to 30 mg/kg engendered only sporadic responding on the drug-associated lever in squirrel monkeys that discriminated intramuscular injections of 0.3 mg/kg MA from vehicle whereas lower doses of 0.3-1.0 mg/kg beta-PEA produced full substitution when administered after either R-(-)-deprenyl or MDL 72974 (0.3 mg/kg). The MA-like S(D) effects of beta-PEA were attenuated by either dopamine D(1) or D(2) receptor blockers. In studies of its S(R) effects, high doses of beta-PEA maintained responding in two of three monkeys under a second-order fixed-interval schedule (3.0 or 10 mg/kg per injection) and two of three monkeys under a simple fixed ratio (FR) schedule (0.3-1.0 mg/kg per injection) of intravenous (i.v.) self-administration. MAO-B inhibition by R-(-)-deprenyl or MDL 72974 enhanced the S(R) effects of beta-PEA in all monkeys and, under the FR schedule, induced a 30-fold or greater leftward shift in the dose-response function for its i.v. self-administration. Based on time-course determinations, the enhanced S(R) effects of beta-PEA under the FR schedule were long-lasting and dissipated gradually over 3-7 days. CONCLUSIONS: These results show that inhibition of MAO-B enhances S(D) and S(R) effects of beta-PEA in monkeys, presumably by delaying its inactivation. MAO-B inhibition leading to increased levels of beta-PEA may be useful, alone or in combination with other therapeutic agents, in the pharmacological management of selected aspects of drug dependence.
Amino acids in rat brain were assayed after IP injection d-amphetamine or beta-phenylethylamine (PEA). Results revealed elevated values when one utilized 2.0-12 mg/kg of d-amphetamine. At 15 mg/kg, however, all amino acids fell into the control range except tryptophan which was elevated nearly threefold, and methionine which showed a tenfold decrease. When utilizing PEA to induce the behavioral changes only methionine is decreased at all concentrations of PEA. Chlorpromazine did not disturb the amino acid distribution induced by amphetamine or PEA. When haloperidol was utilized as the neuroleptic to prevent behavioral change there was a significant increase above control of all the amino acids including homocysteine. The implications of this are discussed in the text.
The hypothesis that phenylethylamine (PEA) is an endogenous psychotogen in schizophrenics, particularly those with the paranoid subtype, has been previously studied by measuring PEA levels in urine and cerebrospinal fluid (CSF) of schizophrenic patients. However, plasma PEA may more accurately reflect simultaneous alterations of PEA in many organ systems, as might occur in a genetic disorder of PEA metabolism. No study to date has examined phenylalanine (Phe), which is thought to be a precursor of PEA, in the same patients who had PEA measured. In this study, we measure both plasma PEA and Phe in 17 drug-free schizophrenic patients and 17 matched controls. Plasma PEA in normal controls was found to be lower by three orders of magnitude compared to normal controls from previous studies--a finding that has not previously been reported. PEA was significantly lower in those schizophrenic patients who had a Research Diagnostic Criteria diagnosis of paranoid schizophrenia. PEA did not differ between patients and controls, and the correlation between plasma Phe and PEA was not significant.
Like the anxiogenic drugs caffeine, pentylenetetrazole, and yohimbine, the endogenous neuroactive monoamine beta-phenylethylamine (PEA) is effective in three tests for anxiogens in mice. In a social interaction test it reduced both the number and duration of contacts. In a conflict situation test (a dark-light chamber) it reduced the number of transitions between dark and light compartments. Diazepam, a standard anxiolytic, prevented both effects of PEA. Intracerebroventricular administration of PEA induced generalized clonic seizures which were antagonized by various anxiolytics but not by the tested doses of butyrophenone neuroleptics and standard anticonvulsants effective in other tests for convulsants.
Plasma samples were collected from 41 patients who met DSM-III criteria for schizophrenia and from 34 healthy controls. Phenylethylamine (PE) levels were determined using a gas chromatography-mass spectrometry negative chemical ionization method. PE was significantly higher in the schizophrenic patients compared with controls. There were no differences in PE between paranoid and nonparanoid patients. Plasma PE did not appear to be influenced by the severity of schizophrenic symptoms (rated by BPRS, SANS, and SAPS) or by the amount of dietary phenylalanine ingested within 24 hr of testing. Plasma PE did not correlate with current or past exposure to neuroleptic medication. It was not possible, however, to test individual patients during two periods when they were taking and not taking medication. Thus it is possible that neuroleptic exposure may have confounded the results. This study provides further evidence that PE excess may play a role in the etiology of schizophrenia but does not support previous studies which suggest that such an abnormality is limited to the paranoid subgroup.
The ability of beta-phenylethylamine (PEA) to reverse (1) chlorpromazine-induced activation of striatal tyrosine hydroxylase, and (2) catalepsy produced by chlorpromazine, was examined. PEA, in a dose of 75 mg/kg, caused approximately 50% reduction in the degree of tyrosine hydroxylase stimulation produced by 20 mg/kg chlorpromazine. After 150 mg/kg PEA, complete reversal of tyrosine hydroxylase activation and partial reversal of catalepsy was observed. In these experiments, PEA was found to be about 10 times less potent than amphetamine and 25 times less potent than apomorphine. Thus, the ability of PEA to reverse the neurochemical and behavioral effects of striatal dopamine blockade is similar to known dopamine agonists.
A sensitive and specific method for the fluorometric determination of beta-phenylethylamine (PEA) in human urine is described. PEA in urine was separated from phenylalanine and 5-hydroxytryptamine by n-heptane extraction, and determined by the ninhydrin reaction in the presence of L-leucyl-L-alanine. Using this method, the amounts of free PEA in urine samples of normal subjects and schizophrenics were measured. Normal subjects excreted 15.9 +/- 6.4 microgarm/day of free PEA, and chronic schizophrenics 9.3 +/- 2.7 microgram/day of free PEA. In normal subjects, the highest excretion of free PEA was observed in the period from 4:00 p.m. to 12:00 p.m. in a day.
The activity of blood platelets monoamine oxidase (MAO) was significantly reduced in a group of insulin-dependent diabetics when compared to sex- and age-matched controls. This enzymatic change was accompanied by a dramatic increase in the plasma levels of phenylethylamine, whereas no significant changes were observed for the concentration of either p-tyramine or phenylethanolamine. Levels of the o- and m-isomers of tyramine were below detectable limits (less than 0.050 ng/ml). A possible role of the MAO/monoamine system in the pathophysiology of diabetes is discussed.
The intrastriatal injection of dopamine-like compounds in the guinea pig caused the development of abnormal involuntary movements (dyskinesias) which were observed as facial grimacing, biting/gnawing/licking, severe hear and neck twisting, limb movements, whole body rocking, head and neck rocking and marked locomotor hyperactivity. With the exception of the whole body and head and neck rocking movements the dyskinesias were specifically induced by dopamine-like agents. The most conspicuous dyskinesias which followed the administration of phenylethylamine derivatives were the movements of biting/gnawing/licking and the development of marked locomotor hyperactivity. This effect was shown to be highly specific for dopamine. Tetrahydroisoquinohydroxy-1,2,3,4-tetrahydronaphthalene (ADTN) caused locomotor hyperactivity and gnawing/biting/licking dyskinesias. Of all compounds investigated 1-(3,4-dihydroxyphenyl)pierazine (DHPP) induced the most marked dyskinetic disturbances upon intrastriatal injection: intense facial grimacing, biting/gnawing/licking, head and neck twisting and limb movements were observed although the locomotor hyperactivity was absent. Of the 1-phenylpiperazine derivatives examined, dyskinetic activity was only demonstrated using compounds with a hydroxyphenyl substitution. Results are discussed in terms of the structure--activity relationships for the stimulation of different types of dopamine receptive structures within the neostriatum.
Mazindol, a new anorexigenic agent which possesses a different chemical structure from phenylethylamine derivatives such as amphetamine, causes anorexia along with increases in locomotor activity and body temperature. Mazindol also induces stereotyped behaviour and, if injected into rats with unilateral nigro-striatal lesions, causes turning towards the lesioned side. Mazindol-induced anorexia is antagonized by pretreatment with alpha-methyl-p-tyrosine or pimozide. Pimozide pretreatment prevents the rotation induced by Mazindol in rats with unilateral nigro-striatal lesions. The involvement of dopamine in the mechanism whereby Mazindol elicits anorexia and turning behaviour is discussed.
Phenylethylamine (PEA) has been implicated in a number of central and peripheral nervous system disorders. Its possible mechanisms of action include stimulation via catecholamine release and direct stimulation by PEA. We have examined the effects of PEA on isolated vascular smooth muscle (VSM) to further explore the mechanism by which PEA produces contraction in this tissue. Helical strips of rat aorta were suspended in a muscle bath. Smooth muscle contractions were recorded via force transducer. PEA elicited a concentration dependent contraction from these strips with a threshold near 10(-6) M and a maximum response at 5 X 10(-3) M. Pretreatment of rats with reserpine dramatically reduced the norepinephrine (NE) content of kidney, heart and spleen of these animals but did not prevent the action of PEA on VSM. The presence of phentolamine (10(-4) M) completely blocked the strip response to PEA. The presence of propranolol (10(-7) or 10(-4) M) altered but did not block the VSM response to PEA. These results argue that the effects of PEA upon the aortic strip preparation involve a direct action of this amine upon VSM.
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.
The concentrations of p-tyramine (p-TA), m-tyramine (m-TA), dopamine (DA) and their principal metabolites, p-hydroxyphenylacetic acid (p-HPAA), m-hydroxyphenylacetic acid (m-HPAA) and homovanillic acid (HVA) were determined in the corpus striatum of Swiss mice at various times after the subcutaneous administration of beta-phenylethylamine (PE) (50 mg/kg). Initially p-TA concentrations were reduced but rapid synthesis was apparent up to 2 h after PE administration. PE treatment increased m-TA and these increases reached significance at 1 and 8 h. PE caused a bimodal increase in p-HPAA and m-HPAA concentrations with the first peak observed at 0.5-1 h due to initial release of p-TA and m-TA. Rapid synthesis of p-TA and m-TA resulted in increased acid concentrations at 4 h. HVA concentrations were increased up to 1 h after PE administration. The synthesis of p-TA and m-TA is related to that of DA probably as a result of the activation of tyrosine hydroxylase. PE may serve as a precursor for p-TA synthesis when the endogenous PE concentration is greatly elevated.
The conditioned place preference paradigm was used to study the reinforcing properties of beta-phenylethylamine (PEA), d-amphetamine and l-amphetamine. The results confirmed that each drug produced place preferences for a distinctive environment that had previously been paired with the drug treatment. PEA proved as effective as the amphetamine isomers, although substantially less potent. This is the first report of a reinforcing effect of PEA in the rat and supplements previous evidence that PEA is self-administered intravenously in the dog.
In slices of the rat hippocampus, alpha 2-adrenoceptors located presynaptically on serotonergic nerve terminals modulate the electrically evoked calcium-dependent release of [3H]serotonin [( 3H]5HT). We have investigated the effects of a naturally occurring trace amine, beta-phenylethylamine (beta-PEA), on noradrenergic transmission in the rat hippocampus. Under experimental conditions in which MAO of type B is inhibited by deprenyl-exposure to beta-PEA (0.1-10 microM) facilitates the spontaneous outflow of [3H]noradrenaline and inhibits the electrically evoked release of [3H]5HT. The inhibitory effect of beta-PEA (3 microM) on the evoked release of [3H]5HT was antagonized by the alpha 2-adrenoceptor antagonist idazoxan at 1 microM, and by pretreatment with alpha-methyl-p-tyrosine (alpha-MpT, 300 mg/kg i.p., 2 h). The inhibition of tyrosine hydroxylase activity by alpha-MpT does not modify the inhibition of the evoked release of [3H]5HT by the alpha 2-adrenoceptor agonist, 6-fluoronoradrenaline, or the serotonin receptor agonist, 5-methoxytryptamine. Pretreatment with the neurotoxin DSP4 (50 mg/kg i.p., 10 days) markedly antagonized the inhibitory action of beta-PEA on [3H]5HT release. These results indicate that the noradrenaline-releasing action of beta-PEA inhibits the electrically evoked release of [3H]5HT through the activation of alpha 2-adrenoceptors. This inhibitory effect appears to be mediated exclusively through the release of newly synthesized noradrenaline, and does not involve the direct activation by beta-PEA of the inhibitory 5HT autoreceptors which modulate [3H]5HT release in the rat hippocampus.