Does phenylethylamine act as an endogenous amphetamine in some patients?

Janßen, Paul; Leysen, Josée E.; Megens, Anton; Awouters, F.

doi:10.1017/s1461145799001522

Cited by 76 publications

(59 citation statements)

References 69 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Like all the other GRK mutants available, mice lacking GRK6 under basal conditions do not demonstrate any obvious behavioral phenotype. However, GRK6-deficient mice, unlike other GRK mutants, are remarkably supersensitive to the locomotor-stimulating effect of psychostimulants (Gainetdinov et al 2003a), including cocaine, amphetamine (Figure 6), and endogenous "trace amine" β-phenylethylamine (β-PEA) (Janssen et al 1999, Premont et al 2001. In biochemical experiments, these mice demonstrated an enhanced coupling of striatal D2-like DA receptors to G proteins and increased affinity for D2 but not D1 DA receptors.…”

Section: Figurementioning

confidence: 99%

Desensitization of G Protein–coupled Receptors and Neuronal Functions

Gainetdinov

Premont

Bohn

et al. 2004

Annu. Rev. Neurosci.

769

692

View full text Add to dashboard Cite

I Abstract G protein-coupled receptors (GPCRs) have proven to be the most highly favorable class of drug targets in modern pharmacology. Over 90% of nonsensory GPCRs are expressed in the brain, where they play important roles in numerous neuronal functions. GPCRs can be desensitized following activation by agonists by becoming phosphorylated by members of the family of G protein-coupled receptor kinases (GRKs). Phosphorylated receptors are then bound by arrestins, which prevent further stimulation of G proteins and downstream signaling pathways. Discussed in this review are recent progress in understanding basics of GPCR desensitization, novel functional roles, patterns of brain expression, and receptor specificity of GRKs and βarrestins in major brain functions. In particular, screening of genetically modified mice lacking individual GRKs or βarrestins for alterations in behavioral and biochemical responses to cocaine and morphine has revealed a functional specificity in dopamine and µ-opioid receptor regulation of locomotion and analgesia. An important and specific role of GRKs and βarrestins in regulating physiological responsiveness to psychostimulants and morphine suggests potential involvement of these molecules in certain brain disorders, such as addiction, Parkinson's disease, mood disorders, and schizophrenia. Furthermore, the utility of a pharmacological strategy aimed at targeting this GPCR desensitization machinery to regulate brain functions can be envisaged.

show abstract

Section: Figurementioning

confidence: 99%

Desensitization of G Protein–coupled Receptors and Neuronal Functions

Gainetdinov

Premont

Bohn

et al. 2004

Annu. Rev. Neurosci.

769

692

View full text Add to dashboard Cite

show abstract

“…Additional studies suggest that at high concentrations TAs interact and interfere with biogenic amine transporter function in ways similar to AMPH and METH but different from DA, NE, cocaine, and methylphenidate (Hirano et al, 1989;Janssen et al, 1999;Mundorf et al, 1999;Berry, 2004;Sulzer et al, 2005). Classically then, the TAs have been shown to inhibit DA uptake and to a lesser extent NE and 5-HT (Horn & Snyder, 1972;Raiteri et all., 1977;Dyck, 1983;Bailey et al, 1987), as well as exert an AMPH-like effect (Janssen et al, 1999) on presynaptic monoamine transporters causing them to reverse their normal direction of transport (Stamford et al, 1986;Parker & Cubeddu, 1988).…”

Section: 42mentioning

confidence: 99%

“…Classically then, the TAs have been shown to inhibit DA uptake and to a lesser extent NE and 5-HT (Horn & Snyder, 1972;Raiteri et all., 1977;Dyck, 1983;Bailey et al, 1987), as well as exert an AMPH-like effect (Janssen et al, 1999) on presynaptic monoamine transporters causing them to reverse their normal direction of transport (Stamford et al, 1986;Parker & Cubeddu, 1988). This results in the displacement of DA from intracellular vesicles elevating cytoplasmic concentrations, and ultimately elevating neurotransmitter concentrations in the synaptic space (Amara & Sonders, 1998;Sulzer et al, 2005).…”

Section: 42mentioning

confidence: 99%

“…In rodents PEA elicits AMPH-like behavior (Hirano et al, 1989;Janssen et al, 1999) at doses of ∼50 mg/kg (intraperitoneal) characterized by hyperactivity, occasional walking backward, rearing, sniffing, gnawing, and licking (Dourish, 1982;Boulton, 1982;Lapin, 1996). At higher doses (75-100 mg/kg) repetitive, stereotypical behaviors, predominate including 'wet dog' shaking, excessive grooming and head movement, seizures, labored breathing, salivation, and straub tail.…”

Section: 43mentioning

confidence: 99%

See 1 more Smart Citation

Trace amine-associated receptor 1—Family archetype or iconoclast?

Grandy

2007

Pharmacology & Therapeutics

178

211

View full text Add to dashboard Cite

Interest has recently been rekindled in receptors that are activated by low molecular weight, noncatecholic, biogenic amines that are typically found as trace constituents of various vertebrate and invertebrate tissues and fluids. The timing of this resurgent focus on receptors activated by the 'trace amines' (TAs) β-phenylethylamine (PEA), tyramine (TYR), octopamine (OCT), synephrine (SYN), and tryptamine (TRYP) is the direct result of two publications that appeared in 2001 describing the cloning of a novel G protein-coupled receptor (GPCR) referred to by their discoverers as TA1 (Borowsky et al., 2001) and TAR1 (Bunzow et al., 2001). When heterologously expressed in Xenopus laevis oocytes and various eukaryotic cell lines recombinant rodent and human TA receptors dosedependently couple to the stimulation of cAMP production. Structure-activity profiling based on this functional response has revealed that in addition to the TAs, other biologically active compounds containing a 2 carbon aliphatic side chain linking an amino group to at least one benzene ring are potent and efficacious TA receptor agonists with amphetamine, methamphetamine, 3-iodothyronamine, thyronamine, and dopamine among the most notable. Almost 100 years after the search for TA receptors began numerous TA1/TAR1-related sequences, now called Trace AmineAssociated Receptors (TAARs), have been identified in the genome of every species of vertebrate examined to date. Consequently, even though heterologously expressed TAAR1 fits the pharmacological criteria established for a bona fide TA receptor a major challenge for those working in the field is to discern the in vivo pharmacology and physiology of each purported member of this extended family of GPCRs. Only then will it be possible to establish whether TAAR1 is the family archetype or an iconoclast.

show abstract

“…Med., 2008, 215 (4), 333-340. © 2008 Tohoku University Medical Press β -Phenylethylamine (β -PEA), an endogenous monoamine, is distributed in the mammalian central nervous system (CNS) and serves as a neuromodulator (Janssen et al 1999). The level of β -PEA in the human CNS differs in various neuropsychiatric disorders such as depression, schizophrenia, and attention-deficit hyperactivity disorder, suggesting that β -PEA is involved in the pathophysiology of these diseases (Branchek and Blackburn 2003).…”

mentioning

confidence: 99%

.BETA.-Phenylethylamine Inhibits K+ Currents in Neocortical Neurons of the Rat: A Possible Mechanism of .BETA.-phenylethylamine-induced Seizures

Kitamura

Munakata

Haginoya

et al. 2008

Tohoku J. Exp. Med.

View full text Add to dashboard Cite

β -Phenylethylamine (β -PEA), an endogenous amine synthesized in the brain, serves as a neuromodulator and is involved in the pathophysiology of various neurological disorders such as depression, schizophrenia, and attention-deficit hyperactivity disorder. β -PEA fully exerts the physiological effects within the nanomolar concentration range via the trace amine receptors, but β -PEA also causes convulsions at much higher concentrations via an as yet unknown mechanism. To investigate the electrophysiological mechanism by which β -PEA induces convulsions, we examined the effect of β -PEA on ionic currents passing through the cell membrane of dissociated rat cerebral cortical neurons, using a patch-clamp technique. The external application of β -PEA suppressed ionic currents which continuously flowed when the membrane potential was held at -25 mV. The suppression was in a concentration-dependent manner and a half-maximal effective concentration was 540 μ M. These currents suppressed by β -PEA consisted of two K + currents: a time-and voltagedependent K + current (M-current) and a leakage K + current. The suppression of the M-current reduces the efficacy of the current in limiting excessive neuronal firing, and the suppression of the leakage K + current can cause membrane depolarization and thus promote neuronal excitation. Reducing both of these currents in concert may produce neuronal seizing activity, which could conceivably underlie the convulsions induced by high-dose β -PEA.β -phenylethylamine; M-current; patch-clamp; seizure.

show abstract

Does phenylethylamine act as an endogenous amphetamine in some patients?

Cited by 76 publications

References 69 publications

Desensitization of G Protein–coupled Receptors and Neuronal Functions

Desensitization of G Protein–coupled Receptors and Neuronal Functions

Trace amine-associated receptor 1—Family archetype or iconoclast?

.BETA.-Phenylethylamine Inhibits K+ Currents in Neocortical Neurons of the Rat: A Possible Mechanism of .BETA.-phenylethylamine-induced Seizures

Contact Info

Product

Resources

About