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PubMed1987

Correlation between anorectic potency and affinity for hypothalamic (+)-amphetamine binding sites of phenylethylamines.

The potencies of a number of phenylethylamines and related compounds to inhibit food intake were compared with their relative affinities for hypothalamic (+)-amphetamine binding sites in vitro. There was a positive correlation (r = 0.78, P less than 0.001, n = 19) between potencies of these compounds to inhibit food intake and their potencies to inhibit [3H](+)-amphetamine binding. Individual enantiomers of amphetamine, ephedrine, norephedrine, pseudoephedrine and norpseudoephedrine all inhibited food intake with a two- to five-fold greater potency than that of their respective optical isomers. However, they did not exhibit a comparable stereospecificity to inhibit [3H](+)-amphetamine binding. Further, several compounds including imipramine and propranolol, without known anorectic properties were among the most potent agents to inhibit [3H](+)-amphetamine binding. Thus, although a positive correlation exists between relative binding affinity and potencies to inhibit food intake, the functional interrelationship is uncertain.

Animals↗

PubMed1985

Inhibition of locus coeruleus neuronal activity by beta-phenylethylamine.

The effect of beta-phenylethylamine (PEA) on brain noradrenaline (NA) neurons in the rat locus coeruleus (LC) was analyzed using single unit recording techniques including microiontophoretic methodology. Systemic injection of low doses of PEA consistently produced an instantaneous and dose-dependent inhibition of firing rate of the LC neurons. The effect was strongly antagonized by administration of the alpha 2-receptor antagonist yohimbine (1 mg/kg, i.v.) or by depletion of endogenous stores of NA by pretreatment with reserpine (10 mg/kg, i.p., 6 h), but unaffected by inhibition of tyrosine hydroxylase (alpha-met-hyl-p-tyrosine (alpha-MT), 250 mg/kg, i.p., 30 min). In contrast, the inhibitory effect of PEA on the LC neurons was strongly potentiated by pretreatment with the selective monoamine oxidase (MAO) - B inhibitor pargyline (2 mg/kg, i.p., 1 h), but, unexpectedly, also by pretreatment with the MAO-A selective inhibitors clorgyline (2 mg/kg, i.p., 1 h) or FLA 336 (2 mg/kg, i.p., 1 h). When microiontophoretically applied directly onto the LC neurons, PEA produced inhibition of a majority of the NA neurons. This action was prevented by intravenous injection of yohimbine (2.5 mg/kg). The results suggests that the action of PEA on NA neurons in the LC is an indirect effect, requiring availability of a reserpine-sensitive storage pool of NA, and mediated via activation of central alpha 2-receptors within the LC.

Action Potentials↗

PubMed1987

Phenylethylamine metabolism to tyramine by postmortem human brain preparations.

Human brain preparations obtained from either the putamen, thalamus, hippocampus or lateral occipital gyrus p-hydroxylate phenylethylamine to tyramine, a reaction carried out by a microsomal (100,000 xg pellet) membrane bound, NADPH-requiring enzyme. This is a minor metabolic pathway occurring in chronic psychiatric patients, as well as in age-comparable controls.

Aged↗

PubMed1996

Phenylethylamine and tyramine are mixed-acting sympathomimetic amines in the brain.

On the helical strip of a capacitance vessel, the pulmonary artery of the rabbit, phenylethylamine (PEA) and tyramine act solely via displacement of noradrenaline from their storage sites and this effect is inhibited by desmethylimipramine (DMI). In contrast, on a resistance vessel, the perfused central ear artery of the rabbit, PEA enhances stimulation induced contractions in 0.2-0.8 microgram/ml concentration [catecholaminergic activity enhancer (CAE) effect], and increases smooth muscle tone (noradrenaline displacing effect) in 4-6 micrograms/ml concentration. This latter effect only is blocked by DMI. Tyramine acts similarly and is more potent than PEA. On the isolated brain stem PEA, tyramine and (-)methamphetamine are, in the presence of cocaine and DMI, highly potent enhancers of stimulation induced release of 3H-noradrenaline, 3H-dopamine and 3H-serotonin. Compounds with specific CAE effect in the brain, (-)deprenyl and 1-phenyl-2-propylaminopentane [(-)PPAP], antagonize tetrabenazine-induced depression of performance of rats in the shuttle box. PEA and tyramine, which are rapidly metabolized in vivo, are ineffective in this test up to 40 mg/kg, whereas (-)methamphetamine, the stable PEA derivative, is highly effective. Compounds with CAE effect enhance at low concentrations the slow inward Ca2+ current in the sino-auricular fibers of the frog heart and inhibit it in high concentration. PEA and tyramine enhance Ca2+ influx from 0.05 to 4 micrograms/ml and inhibit it in 8 micrograms/ml. In conclusion, PEA and tyramine stimulate primarily coupling of action potential to transmitter release in the catecholaminergic neurons in the brain and displace catecholamines in higher concentration only.

Animals↗

PubMed1981

Behavioural effects of acute and chronic beta-phenylethylamine administration in the rat: evidence for the involvement of 5-hydroxytryptamine.

The behavioural consequences of daily beta-phenylethylamine (PEA) administration for a period of 6 weeks have been examined. Rats first showed signs of the 5-HT behavioural syndrome after a single injection of PEA (50mg/kg) or 7 daily injections of PEA (25mg/kg). The syndrome reached peak intensity after 3 weeks treatment and was prevented by pre-treatment with 5-HT antagonists mianserin and methysergide or the neuroloptic clozapine but relatively unaffected by pre-treatment with haloperidol. These data provide strong evidence for an effect of PEA on brain 5-HT mechanisms. Because of the similarity between PEA and amphetamine and the suggestion that PEA may be involved in the aetiology of schizophrenia, it is proposed that the mechanisms of action of PEA be reassessed taking into account its ability to affect 5-HT systems in addition to catecholaminergic systems.

Animals↗

PubMed1976

Effect of beta-phenylethylamine and d-amphetamine on electrical self-stimulation of brain.

beta-phenylethylamine (PEA) has been viewed as amphetamine-like in its effects on behavior. Support for this putative similarity of action has been derived primarily from observations that both of these structually related compounds increase locomotor activity in a dose-related manner and at higher doses evoke stereotypies. Since d-amphetamine (d-A) produces a dose-related increase in the rate of bar pressing for electrical stimulation of the medial forebrain bundle, the effect of PEA on this behavioral paradigm was examined. Male Long-Evans rats implanted with bipolar electrodes self-administered 250 msec 60 Hz constant current sine wave trains over a 30-70 micronA range of intensities in daily 20-min tests. Over a range of 1-40 mg/kg IP of PEA, a dose-related decrease in self-stimulation rate was observed; pretreatment with para-chlorophenylalanine or alpha-methyl-para-tyrosine did not alter the response to 2.5 or 3o mg/kg IP of PEA. Since within the dose range of PEA used in this study a dose-related increase in locomotor activity was observed, and since d-A increases self-stimulation rate at doses that increase locomotor activity, it would seem that there are qualitative differences in the actions of d-A and PEA on behavior.

Animals↗

PubMed1979

A comparison of the effects of acute and subacute administration of beta-phenylethylamine and d-amphetamine on mouse killing behavior of rats.

beta-Phenylethylamine (PEA) is an endogenous amine that in some instances acts biochemically and behaviorally like amphetamine. In the present experiments, the effects of PEA on mouse killing by rats were compared and constrasted with the effects of d-amphetamine on this behavior. When given acutely to experienced mouse killing rats, PEA (16 and 32 mg/kg) inhibited killing in a direct dose dependent manner. This is similar to the dose dependent inhibition of killing by amphetamine reported previously. However, d-amphetamine but not PEA showed physiologic tolerance following 8 days of twice daily administration. Cross tolerance between the two drugs only occurred when d-amphetamine was administered subacutely. It was concluded that PEA and d-amphetamine have sililar acute effects but differed when given subacutely since PEA did not show tolerance and there was not bidirectional cross-tolerance. These data suggest that these drugs have different pharmacologic actions when given repeatedly. One possible difference may be the duration of action.

Aggression↗

PubMed1980

Evidence that a preferred substrate for type B monoamine oxidase mediates stimulus properties of MAO inhibitors: a possible role for beta-phenylethylamine in the cocaine cue.

In the experiment, rats were trained to discriminate 5 mg/kg cocaine HCl from saline in a two-bar drug discrimination procedure. Stimulus generalization experiments were carried out with six inhibitor drugs of monoamine oxidase. The rank order of absolute potency of these drugs in inducing stimulus generalization with cocaine was: tranylcypromine (ED50 in mg/kg; 1.2)>pheniprazine (3.5)>deprenyl (5)>pargyline (28)>nialamide (approximately 170); at up to 40 mg/kg, clorgyline failed to produce 50% generalization. All six drugs also potentiated tryptamine in producing body tremors and clonic seizures, the rank order of potency being tranylcypromine (0.081)>clorgyline (0.14) greater than or equal to pheniprazine (0.15)>pargyline (1.97)>deprenyl (15.5)>nialamide (18.7). Tryptamine is a common substrate for both type A and type B monoamine oxidase, so that tryptamine potentiation may serve to determine the relative specificity of the doses at which the inhibitor drugs generalized with cocaine. The present data may suggest that endogenous substances which are preferred substrates for type B monoamine oxidase in rat brain can exert control of behavior by virtue of cocaine-like stimulus properties. beta-Phenylethylamine, more so than dopamine, appears to be candidate substance for mediating the discriminative stimulus properties of cocaine and, perhaps, of other central nervous system stimulants.

Animals↗

PubMed1984

Hypodipsia, stereotypy and hyperactivity induced by beta-phenylethylamine in the water-deprived rat.

beta-Phenylethylamine (PEA) is an endogenous constituent of human, rat and other mammalian brain tissue. It is rapidly metabolised by type B monoamine oxidase, and there is evidence for specific binding sites for PEA in rat brain. In the first experiment, the effects of systemically-administered PEA (3.125-50.0 mg/kg) on water consumption in water deprived male rats were investigated. PEA produced a depression of drinking within the first 15 min following its administration, with a strong linear relation between drug dose and the degree of depression. In the following 45 min, there was evidence of a dose-related recovery in the drinking. In the second experiment, the effects of PEA on activity in water-deprived rats were investigated. PEA at 12.5 m/kg produced behavioral stimulation, which was particularly evident in measures of total horizontal activity. At higher doses, 25.0 and 50.0 mg/kg, PEA induced a behavioral stereotypy syndrome, associated with a depression of horizontal and vertical activities. Relationships between the hypodipsic effect of PEA and its ability to produce psychomotor stimulation at a moderate dose level, and stereotypy at higher dose levels are considered.

Animals↗

PubMed1985

Cold-restraint stress and urinary endogenous beta-phenylethylamine excretion in rats.

Stress applied to humans increases the urinary excretion of the endogenous amphetamine-like substance beta-phenylethylamine (PEA), a potentially common mediator of amphetamine and stress effects. The present study was conducted to determine if cold-restraint stress in the rat could represent an animal model for stress-induced changes in PEA disposition in humans. The stressor markedly elevated the urinary excretion of endogenous PEA in a manner that was not attributable to changes in urinary pH, glomerular filtration rate or in food consumption. In addition, a large diurnal variation in PEA excretion was noted. The data suggest that the variables responsible for stress-induced alterations in endogenous PEA disposition in humans and rats are generally similar. However, they also indicate that in rats, in contrast to humans, PEA disposition is subject to diurnal changes.

Animals↗

PubMed1985

[3H]-Flunitrazepam binding in the presence of beta-phenylethylamine and its metabolites.

It has recently been reported that the concentration of beta-phenylethylamine (PEA) was elevated in the plasma of an individual experiencing convulsions because of an overdose of tranylcypromine. Also, high concentrations of PEA, injected into mice, were reported to induce convulsions. This convulsive effect was prevented by pretreatment with the benzodiazepines diazepam and chlordiazepoxide. In this study, PEA in concentrations from 0.5 to 100 microM failed to alter the binding of [3H]-flunitrazepam ([3H]-FLU) in membrane preparations from mouse rostral forebrain. The metabolites of PEA: phenylacetic acid, phenylethanolamine, octopamine and tyramine, also failed to affect [3H]-FLU binding. This suggests that although there are substances that act as convulsants by interacting with the benzodiazepine receptor sites, the convulsant effect of PEA and its metabolites is mediated elsewhere.

Animals↗

PubMed1985

Local application of beta-phenylethylamine to the caudate nucleus of the rat elicits locomotor stimulation.

The behavioural effects of bilateral injections of beta-phenylethylamine (PEA) into the caudate nucleus of male rats were examined. PEA in doses of 200 and 300 micrograms increased locomotion with maximal stimulation being evident 15-25 min after injection. In addition 300 micrograms PEA increased rearing 20-25 min post injection and produced increases in sniffing. This is the first report of a behavioural stimulant effect of intracranially administered PEA without concurrent monoamine oxidase inhibition. The data suggest that the stimulant action of systemically administered PEA may be mediated, at least in part, by striatal mechanisms.

Animals↗

PubMed1986

Pharmacological changes induced by repeated exposure to phenylethylamine.

Mice receiving daily injections of phenylethylamine (PEA) exhibited an enhanced PEA-induced motor stimulation, beginning on day 21 of administration. The mice receiving PEA were also more sensitive to the stimulatory effect of amphetamine and PCP. There was no change in brain or hepatic monoamine oxidase activity nor in hepatic mixed function oxidase after this treatment, indicating that altered metabolism was not a factor in the sensitization. Striatal dopamine receptors, labelled by spiroperidol, were increased after the long-term PEA, suggesting that the sensitization may be due to increased dopaminergic receptor activity.

Animals↗

PubMed1986

A behavioural and pharmacological examination of phenylethylamine-induced anorexia and hyperactivity--comparisons with amphetamine.

The discovery that trace amine beta-phenylethylamine (PEA) has a number of properties in common with amphetamine (AMPH) has led to the suggestion that PEA may be a neuromodulator of catecholamine release or an "endogenous amphetamine." The present study compared PEA-induced behavioural changes (anorexia and hyperactivity) with AMPH-induced changes in feeding and motor activity. The first experiment examined the effects of PEA (0-35 mg/kg) on the temporal profile of feeding. The results from this experiment revealed important differences between the effects of PEA as compared with AMPH, in particular PEA failed to increase the rate of eating that is characteristic of AMPH-induced anorexia. The second experiment concurrently measured food intake and motor activity following equi-anorectic doses of PEA and AMPH and pretreatment with the neuroleptic pimozide. Pimozide attenuated PEA-induced hyperactivity, AMPH-induced hyperactivity and AMPH-induced anorexia, but failed to attenuate PEA-induced anorexia. These findings are discussed in relation to the possible mechanisms of action of PEA and AMPH.

Animals↗

PubMed1987

Behaviourally specific interactions between naloxone and beta-phenylethylamine in an operant drug discrimination procedure in rats.

Rats were trained to discriminate phenylethylamine (PEA) at 30 mg/kg (IP). In subsequent generalization tests, it was found that naloxone had no effect on the discriminative stimulus (cue) properties of PEA, but it did potentiate PEA's dose-related rate suppressant effects. Thus the potentiation by naloxone of PEA's effects was behaviourally specific and confined to drug effects on motoric behaviours. These data support the results of previous in vivo and in vitro studies, which suggest that interactions between endogenous PEA and endorphin systems may be functionally important. Such interactions could be of significance in stress-related behavioural disorders.

Animals↗

PubMed1988

Phenylethylamine-induced taste aversion in rats and mice.

Phenylethylamine (PEA) has the same structure as amphetamine (AMP) except that PEA lacks a methyl group at the alpha carbon. Although these analogues produce many similar neurobehavioral actions, a previous study found that PEA did not support formation of conditioned taste aversion (CTA). Using somewhat different procedures, in the present study a transient taste aversion was seen in rats. Use of noradrenergic blocking agents to attempt to pharmacologically tailor PEA action to make it more like that of AMP did not improve efficacy to form CTA. A robust PEA-induced CTA was seen in mice even when PEA produced multiple seizures.

Amphetamine↗

PubMed1993

Anxiogenic effect of phenylethylamine and amphetamine in the elevated plus-maze in mice and its attenuation by ethanol.

In previous experiments beta-phenylethylamine (PEA), like the standard anxiogens caffeine, pentylenetetrazole, and yohimbine, has exhibited an anxiogenic effect in the two animal models of anxiety: the social interaction test and the conflict situation test. In the present study, PEA acts as an anxiogen in an elevated plus-maze, diminishing (compared to controls) the ratio of entries into open arms over the total number of entries and shortening the time spent in the open arms. DL-Amphetamine sulfate (AMPH) also had a similar action. These data support the previous suggestion that PEA may belong to the group of endogenous anxiety-inducing compounds. Pretreatment with ethanol prevented the effects of both PEA and AMPH.

Amphetamine↗

PubMed1996

Antagonism by CPP (+/-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid, of beta-phenylethylamine (PEA)-induced hypermotility in mice of different strains.

In male C57BL/6, BALB/c, and SHR (bred from Swiss) mice, pretreatment with (+/-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), a competitive antagonist of N-methyl-D-aspartate (NMDA) receptor, attenuated the hyperlocomotion induced by beta-phenylethylamine (PEA). This effect of CPP was blocked by intracerebroventricularly (ICV) administered NMDA (0.2 nM). CPP did not alter the hyperlocomotion induced by d-amphetamine. PEA rarely inhibited spontaneous motor activity in those strains. Two other competitive antagonists of NMDA, 2-amino-5-phosphonopentanoic acid (AP-5) and 2-amino-7-phosphonoheptanoic acid (AP-7), ICV at doses of 0.01-0.1 microgram, were ineffective. The noncompetitive antagonists of NMDA, dizocilpine (MK-801) and phencyclidine, at subthreshold doses of 0.1-0.5 mg/kg, potentiated the stimulant effect of PEA. In earlier studies we also observed antagonism between CPP and PEA in NIH-Swiss mice, a strain in which PEA inhibits locomotion. Relationships between the stimulant and the anxiogenic effects of PEA are discussed.

Animals↗