Commentary

Trace amines and alternative neurotransmitters in the central nervous system☆

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” (TA) β-phenylethylamine (PEA), tyramine (TYR), octopamine (OCT), synephrine (SYN), and tryptamine (TRYP) is the direct result of 2 publications that appeared in 2001 describing the cloning of a novel G protein-coupled receptor (GPCR) referred to by their discoverers Borowsky et al. as TA1 and Bunzow et al. as TA receptor 1 (TAR1). When heterologously expressed in Xenopus laevis oocytes and various eukaryotic cell lines, recombinant rodent and human TAR dose-dependently couple to the stimulation of adenosine 3′,5′-monophosphate (cAMP) production. Structure–activity profiling based on this functional response has revealed that in addition to the TA, other biologically active compounds containing a 2-carbon aliphatic side chain linking an amino group to at least 1 benzene ring are potent and efficacious TA receptor agonists with amphetamine (AMPH), methamphetamine, 3-iodothyronamine, thyronamine, and dopamine (DA) among the most notable. Almost 100 years after the search for TAR began, numerous TA1/TAR1-related sequences, now called TA-associated receptors (TAAR), 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 TAR, 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 GPCR. Only then will it be possible to establish whether TAAR1 is the family archetype or an iconoclast.

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.

The most important manifestations of advanced liver disease are malnutrition, encephalopathy, and hepatorenal syndrome. Appropriate and optimal nutritional and metabolic support with specially formulated solutions enriched in branched-chain amino acids, together with other advanced treatments such as plasmapheresis, hemofiltration, and continuous arteriovenous hemodialysis, can correct the most important metabolic and clinical aberrations and temporarily improve the quality of life. However, the ultimately poor prognosis of patients with severe liver failure has not been altered significantly to date by the provision of nonspecific or specifically tailored nutrient regimens. The prognosis appears to depend on the arrest, correction, or reversal of the primary pathophysiologic process.

The effects of electrolytic lesions of the locus coeruleus (LC) on endogenous octopamine and noradrenaline levels were observed at various temporal intervals. Noradrenaline was assayed from halved tissue samples by high-performance liquid chromatography (HPLC) while octopamine was determined from the other halfs of the brain samples by radioenzymatic assay methods accompanied by chromatographic separation. Brains were dissected into 8 regions: cerebellum, anterior and posterior cortex, hippocampus, hypothalamus, medulla/pons, midbrain and striatum. Assays were performed at postlesion intervals of 4, 8, 13 and 18 days. The rates of depletion of noradrenaline at the tested intervals roughly matched those of octopamine in the anterior cortex, posterior cortex and striatum. In the cerebellum, hypothalamus, hippocampus and pons/medulla, levels of octopamine diminished later than those of noradrenaline, at times showing an initial increase within the first week after LC lesion. In the midbrain however, this pattern was reversed, octopamine levels initially decreasing in parallel with noradrenaline but subsequently recovering to significantly higher values. The results do not unequivocally support the hypothesis that octopamine is present in the brain solely as a ‘false transmitter’ in noradrenergic neurones. Neither, however, do they provide clear support for earlier contentions that octopamine is likely to play a role in central neurones as a synaptic transmitter, independent of the noradrenergic system.

The purpose of this study was to investigate modifications of 5-HT synthesis in a chronic pain model, the arthritic rat, at different times after the inoculation with Freund's adjuvant.

This study confirms our previous findings that experimental induced polyarthritis is associated with a marked increase in free tryptophan levels in serum. During the acute phase of the disease (15–21 days after the adjuvant), the general increase in 5-HT synthesis observed in the CNS appeared to be related to an increase in tryptophan availability due to the elevation of free tryptophan in serum. During the post-acute phase of the disease (28–42 days after the adjuvant), the level of free tryptophan in the serum remained markedly increased but the levels in the CNS tended to return to normal values in all areas examined. At 42 days, 5-HT synthesis in the brain had also returned to normal values but was further increased at the spinal level. In addition, although 5-HT levels and 5-HT synthesis were increased in the dorsal as well as in the ventral part of the cord, an increase in the rate of disappearance of the amine after blockade of the decarboxylase (benserazide) was only observed in the dorsal part. This result tends to suggest that the descending serotonergic system projecting to the dorsal horn is preferentially activated during chronic pain.