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

doi:10.1016/0028-3908(83)90203-4

Neuropharmacology

Volume 22, Issue 11, November 1983, Pages 1297-1301

https://doi.org/10.1016/0028-3908(83)90203-4 Get rights and content

Abstract

The in vivo release of endogenous dopamine (DA) from the rat caudate nucleus has been measured in the presence and absence of β-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 × 10⁻³ to 5 × 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 × 10⁻³ to 5 × 10⁻⁵ M; 5 × 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 × 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.

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Cited by (39)

Selegiline induces a wake promoting effect in rats which is related to formation of its active metabolites
2016, Pharmacology Biochemistry and Behavior
Citation Excerpt :
Increased levels of extracellular DA have been observed in the rat striatum following chronic selegiline administration (Lamensdorf et al., 1996). In addition, MAO-B inhibitors have been shown pre-clinically to block the breakdown of the MAO-B substrate, phenylethylamine (PEA), a biogenic amine that stimulates the release and inhibits the re-uptake of DA in the brain (Baker et al., 1976; Perlow et al., 1980; Philips and Robson, 1983; Nielsen et al., 1983). Selegiline is rapidly metabolized in vivo, mainly in the liver through the microsomal P450 system (Yoshida et al., 1986; Reynolds et al., 1978), to form l-desmethylselegiline and l-methamphetamine, which are further metabolized to l-amphetamine (Heinonen et al., 1994).
The goal of the present work was to characterise the effects of selegiline on the rat sleep pattern. Furthermore, for comparative purposes, the pharmacokinetics of selegiline and its metabolites in brain and plasma were investigated, and microdialysis experiments were performed to examine the resulting effect on dopamine, noradrenaline and serotonin levels. Selegiline (1, 5, 10 and 30 mg/kg) was found to dose-dependently increase the time spent awake following acute dosing. The pharmacokinetic assessment of selegiline showed that, following an oral dose of 5 mg/kg, low circulating levels of the parent compound were found relative to those of biotransformed l-methamphetamine and l-amphetamine. The time course of selegiline-induced wakefulness was shown to follow the time course of l-methamphetamine and l-amphetamine in brain, suggesting that these metabolites are responsible for the modulation of sleep architecture. Furthermore, selegiline (5 mg/kg) caused a significant increase of extracellular levels of DA (250%) and NA (200%), but not of 5-HT, in the rat prefrontal cortex. In summary, an integrated experimental approach was undertaken here to evaluate selegiline's effect on sleep architecture in rats in relation to its pharmacokinetics and changes in monoaminergic neurotransmitter levels in the brain. The effect of selegiline on sleep was likely mediated by an increase of dopamine and noradrenaline levels in the brain caused by the formed metabolites.
β-Phenylethylamine Requires the Dopamine Transporter to Release Dopamine in Caenorhabditis elegans
2016, Trace Amines and Neurological Disorders: Potential Mechanisms and Risk Factors
Previous data showed that β-phenylethylamine (βPEA) causes short-lasting behavioral effects in mammals likely by increasing the concentration of extracellular dopamine. However, the mechanism through which βPEA releases dopamine has not been completely elucidated yet. Recent data showed that βPEA causes behavioral and in vitro effects in Caenorhabditis elegans (C. elegans) as well. In cells transfected with the C. elegans dopamine transporter, βPEA-induced increase of extracellular dopamine is completely blocked by RTI-55, a cocaine homolog and dopamine transporter inhibitor. Interestingly, in C. elegans neuronal cultures, RTI-55 only partly inhibits the effect of βPEA, suggesting that in native systems other mechanisms are required by βPEA to increase extracellular dopamine. Amperometric recordings demonstrated that βPEA causes oxidative currents, that is, dopamine release, only in a subset of dopaminergic neurons. βPEA, however, did not generate oxidative currents in neurons isolated from mutants that do not express the dopamine transporter. Moreover, the increase in extracellular dopamine by βPEA does not involve the monoamine vesicles as genetic ablation of cat-1, the C. elegans homolog of the vesicular monoamine transporter, had no effect on the ability of βPEA to increase extracellular dopamine. Taken together, these data suggest that βPEA releases dopamine in the synaptic cleft via the dopamine transporter.
Effects of Trace Amines on the Dopaminergic Mesencephalic System
2016, Trace Amines and Neurological Disorders: Potential Mechanisms and Risk Factors
Trace amines (TAs) are a class of endogenous compounds, which are heterogeneously distributed throughout the mammalian brain and peripheral nervous tissues, despite being at relatively low levels. It is now largely accepted that TAs are not pure inactive byproducts of amino acid metabolism but, instead, are considered important neuromodulators involved in the regulation of key brain physiological functions.
This chapter presents an overview of the close interplay between TAs and dopamine, also discussing recent experimental evidence on the neuromodulatory effects of TAs on the activity of mesencephalic dopaminergic (DAergic) system, supporting the potential involvement of TAs in several physiological and pathological conditions associated with the activity of the DAergic mesencephalic system.
Rat striatal monoamine oxidase-B inhibition by l-deprenyl and rasagiline: Its relationship to 2-phenylethylamine-induced stereotypy and Parkinson's disease
2002, Parkinsonism and Related Disorders
Rats were injected intraperitoneally with varying doses of l-deprenyl (selegiline) followed 2 h later by 30 mg kg⁻¹ 2-phenylethylamine (PEA), administered in the same way, and the stereotypic behavioural response elicited was assessed. l-Deprenyl alone at doses of up to 5 mg kg⁻¹ caused no significant behavioural response. Administration of PEA without prior l-deprenyl treatment resulted in only a modest increase in stereotypic behaviour and this was not significantly enhanced by the prior administration 1 mg kg⁻¹ l-deprenyl. When the administered dose of l-deprenyl was increased to 2.5 or 5 mg kg⁻¹, however, the stereotypic behavioural response to PEA was greatly potentiated and in the latter case persisted for 60 min. A dose of 2.5 mg kg⁻¹ l-deprenyl and 1 mg kg⁻¹ rasagiline was shown to result in over 90% inhibition of the monoamine oxidase (MAO)-B from rat liver and striatum, whereas the inhibition of MAO-A was about 60 and 40% in liver and striatum, respectively. The recovery of MAO-B activity in rat striatum and liver following a single i.p. injection of 5 mg kg⁻¹ l-deprenyl gave first-order rate constants of 1.80 and 7.15 h⁻¹, respectively, which corresponded to half-lives of 9.23 and 2.33 days. Similar results were obtained with rasagiline. The corresponding indices of stereotypic response to PEA (30 mg kg⁻¹; i.p.) during recovery from the single dose of l-deprenyl were initially high, but had started to decline by the third day after l-deprenyl treatment and was not significant after day 4. At that time, less than 20% of the striatal monoamine oxidase-B activity had been regained, whereas the recovery of the liver enzyme was about 65%. These data are discussed in terms of the suggested involvement of PEA potentiation in the anti-parkinsonian actions of l-deprenyl and rasagiline and the duration of the ‘wash-out’ period used in studies on the effects of l-deprenyl on patients with Parkinson's disease. The longer duration of the recovery of brain monoamine oxidase B after its selective inhibition and the corresponding behavioural responses of the animals to PEA at same time points, indicate that PEA may have a major pharmacological role in the mechanism of the antiParkinson action of l-deprenyl and rasagiline. Brain monoamine oxidase B inhibition has previously been shown to significantly increases brain PEA and which is capable of releasing dopamine endogeously or that formed from l-dopa.
β-Phenylethylamine modulates acetylcholine release in the rat striatum: Involvement of a dopamine D<inf>2</inf> receptor mechanism
2001, European Journal of Pharmacology
We examined the effects of β-phenylethylamine on striatal acetylcholine release in freely moving rats using in vivo microdialysis. β-Phenylethylamine at 12.5 mg/kg, i.p. did not affect acetylcholine release in the striatum, whereas 25 and 50 mg/kg, i.p. immediately induced an increase in acetylcholine release in the striatum at 15–45 min. This increase following intraperitoneal administration of β-phenylethylamine (25 mg/kg) was not affected by locally applied SCH-23390 (R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine, 10 μM), a dopamine D₁ receptor antagonist, nor by raclopride (10 μM), a dopamine D₂ receptor antagonist. The increased release of acetylcholine induced by β-phenylethylamine was suppressed by local infusion of tetrodotoxin (1 μM). In contrast, the extracellular acetylcholine level in the striatum was significantly decreased by local application of β-phenylethylamine (10 and 100 μM) in the striatum via a microdialysis probe. The decrease was completely blocked by local co-application of raclopride (10 μM). The β-phenylethylamine-induced decrease in striatal acetylcholine release was not affected by co-perfusion with SCH-23390 (10 μM). These results indicate that systemic administration of β-phenylethylamine increases acetylcholine release, whereas locally applied β-phenylethylamine decreases striatal acetylcholine release in freely moving rats. Furthermore, the dopaminergic system, through the dopamine D₂ receptor, is involved in the locally applied β-phenylethylamine-induced decrease in acetylcholine in the striatum.
The reverse transport of DA, what physiological significance?
2001, Neurochemistry International
It is well established that midbrain dopamine neurons innervating the striatum, release their neurotransmitter through an exocytotic process triggered by the neural firing and involving a transient calcium entry in the terminals. Long ago, it had been proposed, however, that another mechanism of release could co-exist with classical exocytosis, involving the reverse-transport of the cytosolic amine by the carrier, ordinarily responsible for uptake function. This atypical mode of release could be evoked directly at the preterminal level by multiple environmental endogenous factors involving transient alterations of the sodium gradient. It cannot be excluded that this mode of release participates in the firing-induced release. In contrast with the classical exocytosis of a preformed DA pool, the reverse-transport of DA requires simultaneous alterations of intraterminal amine metabolism including synthesis and displacement from storage compartment. The concept of a reverse-transport of dopamine is coming from the observations that releasing substances, such as amphetamine-related molecules, actually induce this type of transport. A large set of arguments advocates that reverse-transport plays a role in the maintenance of basal extracellular DA concentration in striatum. It was also often evoked in physiopathological situations including ischemia, neurodegenerative processes, etc. The most recent studies suggest that this release could occur mainly outside the synapses, and thus could constitute a major feature in the paracrine transmission, sometimes evoked for DA.

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Neuropharmacology

Abstract

References (26)

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

Brain Res.

Interactions of trace amines with dopamine in rat striatum

Prog. NeuroPsychopharmac.

The effect of β-phenylethylamine on central and peripheral monoamine containing neurons

Eur. J. Pharmac.

The distribution of β-phenylethylamine in discrete regions of the rat brain and its effect on brain noradrenaline, dopamine and 5-hydroxytryptamine levels

Neuropharmacology

Increased dopamine and norepinephrine concentrations in primate CSF following amphetamine and phenylethylamine administration

Brain Res.

Interaction of β-phenylethylamine with dopamine and noradrenaline in the central nervous system of the rat

J. Pharm. Pharmac.

Stereotyped behavior in rats induced by phenylethylamine, dependence on dopamine and noradrenaline, and possible relation to psychoses

d-Amphetamine-induced release of “newly synthesized” and “stored” dopamine from the caudate nucleus in vivo

J. Pharmac. exp. Ther.

Kinetic measurements of the turnover rates of phenylethylamine and tryptamine in vivo in the rat brain

J. Neurochem.

Identification and distribution of β-phenylethylamine in the rat

Can. J. Biochem.

Chemical release of dopamine from striatal homogenates: evidence for an exchange diffusion model

J. Pharmac. exp. Ther.

Amphetamine-like activity of β-phenylethylamine after a monoamine oxidase inhibitor in vivo

J. Pharm. Pharmac.

Dose-response effects of β-phenylethylamine on stereotyped behavior in pargyline-pretreated rats

Biol. Psychiat.

Cited by (39)

Selegiline induces a wake promoting effect in rats which is related to formation of its active metabolites

β-Phenylethylamine Requires the Dopamine Transporter to Release Dopamine in Caenorhabditis elegans

Effects of Trace Amines on the Dopaminergic Mesencephalic System

Rat striatal monoamine oxidase-B inhibition by l-deprenyl and rasagiline: Its relationship to 2-phenylethylamine-induced stereotypy and Parkinson's disease

β-Phenylethylamine modulates acetylcholine release in the rat striatum: Involvement of a dopamine D<inf>2</inf> receptor mechanism

The reverse transport of DA, what physiological significance?