Phenylethylamine: evidence for a direct, postsynaptic dopamine-receptor stimulating action

The trace amines are a structurally related group of amines and their isomers synthesized in mammalian brain and peripheral nervous tissues. They are closely associated metabolically with the dopamine, noradrenaline and serotonin neurotransmitter systems in mammalian brain. Like dopamine, noradrenaline and serotonin the trace amines have been implicated in a vast array of human disorders of affect and cognition. The trace amines are unique as they are present in trace concentrations, exhibit high rates of metabolism and are distributed heterogeneously in mammalian brain. While some are synthesized in their parent amine neurotransmitter systems, there is also evidence to suggest other trace amines may comprise their own independent neurotransmitter systems. A substantial body of evidence suggests that the trace amines may play very significant roles in the coordination of biogenic amine-based synaptic physiology. At high concentrations, they have well-characterized presynaptic “amphetamine-like” effects on catecholamine and indolamine release, reuptake and biosynthesis; at lower concentrations, they possess postsynaptic modulatory effects that potentiate the activity of other neurotransmitters, particularly dopamine and serotonin. The trace amines also possess electrophysiological effects that are in opposition to these neurotransmitters, indicating to some researchers the existence of receptors specific for the trace amines. While binding sites or receptors for a few of the trace amines have been advanced, the absence of cloned receptor protein has impeded significant development of their detailed mechanistic roles in the coordination of catecholamine and indolamine synaptic physiology. The recent discovery and characterization of a family of mammalian G protein-coupled receptors responsive to trace amines such as β-phenylethylamine, tyramine, and octopamine, including socially ingested psychotropic drugs such as amphetamine, 3,4-methylenedioxymethamphetamine, N,N-dimethyltryptamine, and lysergic acid diethylamide, have revitalized the field of scientific studies investigating trace amine synaptic physiology, and its association with major human disorders of affect and cognition.

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

To assess the role of β-phenylethylamine in aspects of dopamine release, we measured the level of β-phenylethylamine in the rat striatum after killing the rats by microwave irradiation. We then investigated the effect of β-phenylethylamine on electrically evoked dopamine release from rat striatal slices in vitro. The striatal β-phenylethylamine level was 46.5±3.5 ng/g wet tissue, equivalent to 0.3 μmol/l. Superfusion with low concentrations of β-phenylethylamine up to 1 μmol/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 μmol/l β-phenylethylamine. Moreover, the (−)-sulpiride (0.1 μmol/l)-induced increase in evoked dopamine release was also attenuated by superfusion with 0.3 μmol/l β-phenylethylamine. These data indicate that submicromolar levels of β-phenylethylamine could modify the dopamine autoreceptor mediated changes in evoked dopamine release from rat striatal slices.

Despite continued research, the influences that promote or exacerbate tardive dyskinesia (TD) symptoms remain incompletely understood. Recent findings (Gardos et al. 1992; Richardson et al. 1989) suggest that ingestion of the dietary constituent, phenylalanine, might exacerbate TD symptoms, but a double-blind, placebo-controlled challenge had not previously been conducted in schizophrenic patients. On two different mornings, in counterbalanced order, 18 male schizophrenic patients with TD were challenged with either WO mg/kg phenylalanine or placebo. Effects on abnormal involuntary movements, recall memory, and plasma phenylalanine were measured 90 minutes post-challenge. The results supported the hypothesis in that involuntary movements increased to a statistically and clinically meaningful degree after the phenylalanine challenge, but not after placebo. No effects on memory were detected. Significant order effects characterized the plasma findings but not the behavioral data. Results indicate that a dietary constituent, the amino acid phenylalanine, can potentially exacerbate tardive dyskinesia symptoms in schizophrenic patients. The influence of phenylalanine and other ingested substances on clinical symptomatology warrants further investigation.

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  1. Young and aged dogs were tested on a spatial memory task using a delayed non matching to sample technique. Dogs were tested with 20, 70 and 110 second delay intervals. Animals were pretrained to a stable level of performance prior to treatment.

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  2. During treatment periods, dogs were orally administered a placebo or l-deprenyl in doses of 0.5 and 1.0 mg/kg in a repeated measures design.

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  3. Young dogs did not show any significant effects of l-deprenyl, however the sample size was limited.

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  4. L-deprenyl administration improved spatial memory in aged dogs.

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  5. The optimal dose or length of treatment time of l-deprenyl varied among individual dogs.

The present paper describes the effect of β-phenylethylamine and its metabolites phenylethanolamine, tyramine, acetyl-phenylethylamine and phenylacetaldehyde on the dopaminergic nigrostriatal system. The rotational behavioural response to the i.v. injection of these drugs was quantified in animals with a unilateral 6-hydroxydopamine lesion of the nigrostriatal dopamine system. Only β-phenylethylamine and acetyl-phenylethylamine induced rotations ipsilateral to the side of the brain lesion. None of the compounds under study stimulated contralateral rotations. Acetyl-phenylethylamine was 90% less active than β-phenylethylamine. After β-phenylethylamine injection all animals ($\text{16}\text{16}$) showed ipsilateral rotations. The dose-response curve showed that at doses as low as 1.75 mg/kg ipsilateral turns increase, with a dose-related rotational response between 1.75 mg/kg and 11.66 mg/kg, no differences being found at doses between 11.66 and 29.16 mg/kg. Rotations began a few seconds after β-phenylethylamine injection. The highest response was found 30–60 s after the injection. The duration of the response was dose-related (4 min for the 3.5 mg/kg doses). The inhibition of dopamine-β-hydroxylase activity with [1–3,5-difluorobenzyl)imidazole-2-thiol (SKF102698) did not modify the rotational response to β-phenylethylamine. The inhibition of type B monoamine oxidase activity with l-deprenyl induced a slight increase in the ipsilateral rotational response to β-phenylethylamine. The inhibition of tyrosine hydroxylase activity with α-methyl-p-tyrosine decreased the rotational response to β-phenylethylamine. The dopamine receptor antagonist, haloperidol, completely blocked the ipsilateral rotational response to β-phenylethylamine. The blocking of dopamine uptake into storage vesicles with reserpine increased the rotational action of β-phenylethylamine. Taken together, the data suggest that, at low doses, β-phenylethylamine stimulates the release of dopamine from the cytoplasmic pool and behaves as a dopamine receptor agonist with a very rapid and brief action.