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Elevated serum prolactin concentrations occur in inherited disorders of biogenic amine metabolism because dopamine deficiency leads to insufficient inhibition of prolactin secretion. This work from the International Working Group on Neurotransmitter Related Disorders (iNTD) presents the results of the first standardized study on levodopa-refractory hyperprolactinemia (LRHP; >1000 mU/L) and pituitary magnetic resonance imaging (MRI) abnormalities in patients with inherited disorders of biogenic amine metabolism. Twenty-six individuals had LRHP or abnormal pituitary findings on MRI. Tetrahydrobiopterin deficiencies were the most common diagnoses (n = 22). The median age at diagnosis of LRHP was 16 years (range: 2.5-30, 1st-3rd quartiles: 12.25-17 years). Twelve individuals (nine females) had symptoms attributed to hyperprolactinemia: menstruation-related abnormalities (n = 7), pubertal delay or arrest (n = 5), galactorrhea (n = 3), and decreased sexual functions (n = 2). MRI of the pituitary gland was obtained in 21 individuals; six had heterogeneity/hyperplasia of the gland, five had adenoma, and 10 had normal findings. Eleven individuals were treated with the dopamine agonist cabergoline, ameliorating the hyperprolactinemia-related symptoms in all those assessed. Routine monitoring of these symptoms together with prolactin concentrations, especially after the first decade of life, should be taken into consideration during follow-up evaluations. The potential of slow-release levodopa formulations and low-dose dopamine agonists as part of first-line therapy in the prevention and treatment of hyperprolactinemia should be investigated further in animal studies and human trials. This work adds hyperprolactinemia-related findings to the current knowledge of the phenotypic spectrum of inherited disorders of biogenic amine metabolism., (© 2023 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

Biogenic amines (BAs), such as octopamine, tyramine, dopamine, serotonin, and acetylcholine regulate various behaviors and physiological functions in insects. Here, we identified seven genes encoding BA biosynthetic enzymes and 16 genes encoding BA G protein-coupled receptors in the genome of the endoparasitoid wasp, Pteromalus puparum. We compared the genes with their orthologs in its host Pieris rapae and the related ectoparasitic wasp Nasonia vitripennis. All the genes show high (>90%) identity to orthologs in N. vitripennis. P. puparum and N. vitripennis have the smallest number of BA receptor genes among the insect species we investigated. We then analyzed the expression profiles of the genes, finding those acting in BA biosynthesis were highly expressed in adults and larvae and those encoding BA receptors are highly expressed in adults than immatures. Octα1R and 5-HT 7 genes were highly expressed in salivary glands, and a high messenger RNA level of 5-HT 1A was found in venom apparatuses. We infer that BA signaling is a fundamental component of the organismal organization, homeostasis and operation in parasitoids, some of the smallest insects., (© 2019 Wiley Periodicals, Inc.)

In order to study the effect of cinnamon essential oil (CEO) on the microbiological and physiochemical characters of fresh Italian style sausage, CEO (0%, 0.1%, and 0.5%, v/w) was added into ground meat, cased, and stored at 4°C. Lipid oxidation, instrument color, total viable aerobic counts, Enterobacteriaceae, biogenic amines, and total volatile basic nitrogen (TVB-N) were investigated during 10 days (day). Results showed that CEO treatments had lower thiobarbituric acid reactive substances (TBARS), b* value, aerobic and Enterobacteriaceae counts, biogenic amine contents, and TVB-N and higher a* values at 4, 6, 8, and 10 days compared to the control, whereas 0.5% CEO treatment had better effect than 0.1% CEO. CEO improved color shelf-life by inhibiting lipid oxidation and prevented the increase in biogenic amines and TVB-N by reducing microbial counts of fresh sausage during storage. This study suggested that CEO could be applied in the food industry to improve the shelf-life of meat products., (© 2019 Japanese Society of Animal Science.)

Calcineurin inhibitor nephrotoxicity, especially for the widely used tacrolimus, has become a major concern in post-transplant immunosuppression. Multiparametric amino acid metabolomics is useful for biomarker identification of tacrolimus nephrotoxicity, for which specific quantitative methods are highlighted as a premise. This article presents a targeted metabolomic assay to quantify 33 amino acids and biogenic amines in human urine by high-performance liquid chromatography coupled with tandem mass spectrometry. Chromatographic separation was carried out on an Agilent Zorbax SB-C 18 column (3.0 × 150 mm, 5 μm) with addition of an ion-pairing agent in the mobile phase, and MS/MS detection was achieved in both the positive and negative multiple reaction monitoring modes. Good correlation coefficients (r 2 > 0.98) were obtained for most analytes. Intra- and inter-day precision, stability, carryover and incurred sample reanalysis met with the acceptance criteria of the guidance of the US Food and Drug Administration. Analysis on urine from healthy volunteers and renal transplantation patients with tacrolimus nephrotoxicity confirmed symmetric dimethylarginine and serine as biomarkers for kidney injury, with AUC values of 0.95 and 0.81 in receiver operating characteristic analysis, respectively. Additionally, symmetric dimethylarginine exhibited a tight correlation with serum creatinine, and was therefore indicative of renal function. The targeted metabolomic assay was time and cost prohibitive for amino acid analysis in human urine, facilitating the biomarker identification of tacrolimus nephrotoxicity., (Copyright © 2018 John Wiley & Sons, Ltd.)

Plasma membrane monoamine transporter (PMAT) is a new polyspecific organic cation transporter that transports a variety of biogenic amines and xenobiotic cations. Highly expressed in the brain, PMAT represents a major uptake 2 transporter for monoamine neurotransmitters. At the blood-cerebrospinal fluid (CSF) barrier, PMAT is the principal organic cation transporter for removing neurotoxins and drugs from the CSF. Here I summarize our latest understanding of PMAT and its roles in monoamine uptake and xenobiotic disposition., Competing Interests: I have no conflicts of interest to declare., (© 2016 American Society for Clinical Pharmacology and Therapeutics.)

During the last decade, the use of innovative yeast cultures of both Saccharomyces cerevisiae and non-Saccharomyces yeasts as alternative tools to manage the winemaking process have turned the oenology industry. Although the contribution of different yeast species to wine quality during fermentation is increasingly understood, information about their role in wine ageing over lees is really scarce. This work aims to analyse the incidence of three non-Saccharomyces yeast species of oenological interest (Torulaspora delbrueckii, Lachancea thermotolerans and Metschnikowia pulcherrima) and of a commercial mannoprotein-overproducer S. cerevisiae strain compared with a conventional industrial yeast strain during wine ageing over lees. To evaluate their incidence in mouthfeel properties of wine after 4 months of ageing, the mannoprotein content of wines was evaluated, together with other wine analytic parameters, such as colour and aroma, biogenic amines and amino acids profile. Some differences among the studied parameters were observed during the study, especially regarding the mannoprotein concentration of wines. Our results suggest that the use of T. delbrueckii lees in wine ageing is a useful tool for the improvement of overall wine quality by notably increasing mannoproteins, reaching values higher than obtained using a S. cerevisiae overproducer strain. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

Sepiapterin reductase (SR) catalyses the last step in the tetrahydrobiopterin biosynthesis pathway; it converts 6-pyruvoyl-tetrahydropterin (6-PTP) to BH(4) in an NADPH-dependent reaction. SR deficiency is a very rare autosomal recessive disorder with normal phenylalanine (Phe) concentration in blood and diagnostic abnormalities are detected in CSF. We present a 16-month-old girl with SR deficiency. From the newborn period she presented with an adaptation regulatory disorder. At the age of 3 months, abnormal eye movements with dystonic signs and at 4.5 months psychomotor retardation were noticed. Since that time axial hypotonia with limb spasticity (or rather delayed reflex development), gastro-oesophageal reflux and fatigue at the end of the day has been observed. Brain MRI was normal; EEG was without epileptiform discharges. Analysis of biogenic amine metabolites in CSF at the age of 16 months showed very low HVA and 5-HIAA concentrations. Analysis of CSF pterins revealed strongly elevated dihydrobiopterin (BH(2)), slightly elevated neopterin and elevated sepiapterin levels. Plasma and CSF amino acids concentrations were normal. A phenylalanine loading test showed increased Phe after 1 h, 2 h and 4 h and very high Phe/Tyr ratios. SR deficiency was confirmed in fibroblasts and a novel homozygous g.1330C>G (p.N127K) SPR mutation was identified. On L-dopa and then additionally 5-hydroxytryptophan, the girl showed slow but remarkable progress in motor and intellectual ability. Now, at the age of 3 years, she is able to sit; expressive speech is delayed (to 1 1/2 years), passive speech is well developed. Her visual-motor skills, eye-hand coordination and social development correspond to the age of 2 1/2 years.

Kynuramines represent their own class of biogenic amines. They are formed either by decarboxylation of kynurenines or pyrrole ring cleavage of indoleamines. N(2)-formylated compounds formed in this last reaction can be deformylated either enzymatically by arylamine formamidases or hemoperoxidases, or photochemically. The earlier literature mainly focussed on cardiovascular effects of kynuramine, 5-hydroxykynuramine and their N(1),N(1)-dimethylated analogs, including indirect effects via release of catecholamines or acetylcholine and interference with serotonin receptors. After the discovery of N(1)-acetyl-N(2)-formyl-5-methoxykynuramine (AFMK) and N(1)-acetyl-5-methoxykynuramine (AMK) as major brain metabolites of melatonin, these compounds became of particular interest. They were shown to be produced enzymatically, pseudoenzymatically, by various free radical-mediated and via photochemical processes. In recent years, AFMK and AMK were shown to scavenge reactive oxygen and nitrogen species, thereby forming several newly discovered 3-indolinone, cinnolinone and quinazoline compounds, and to protect tissues from damage by reactive intermediates in various models. AMK is of special interest due to its properties as a potent cyclooxygenase inhibitor, NO scavenger forming a stable nitrosation product, inhibitor and/or downregulator of neuronal and inducible NO synthases, and a mitochondrial metabolism modulator. AMK easily interacts with aromates, forms adducts with tyrosyl and tryptophanyl residues, and may modify proteins.

Paediatric neurotransmitter diseases are a group of inherited disorders attributable to a disturbance of neurotransmitter metabolism. The monoamines, catecholamines and serotonin, also called biogenic amines, are neurotransmitters with multiple roles including psychomotor function, hormone secretion, cardiovascular, respiratory and gastrointestinal control, sleep mechanisms, body temperature and pain. Given the multiple functions of monoamines, disorders of their metabolism comprise a wide spectrum of manifestations, with motor dysfunction being the most prominent clinical feature. The severity of the clinical manifestations ranges from mild to severe. Patients with severe and intermediate phenotypes may present with infantile parkinsonism that differs in a number of aspects from the parkinsonism in nigrostriatal degeneration. Analysis of monoamine metabolites and pterins in spinal fluid assists in the diagnosis of these disorders. Treatment options include tetrahydrobiopterin supplementation, L: -dopa, 5-hydroxytryptophan, and medications that potentiate monoamine transmission. Response to treatment is variable.

Three different stress treatments, CO2 anesthesia, chilling anesthesia, and vertical spin, were applied to test whether honeybee (Apis mellifera) workers express stress responses in rewarding behaviors. In the present work, we defined the rewarding behaviors as the bees flying between the hive and feeder. The results from behavioral observation show that the flight time interval of the rewarding behavior of bee workers, flying between hive and feeder, was longer when they were stressed, suggesting that the stress treatments affected the workers' rewarding behavior. The biogenic amine levels in the workers' brains were measured to examine the rapid biochemical brain response to the stressors. After the chilling anesthesia, the dopamine (DA) and octopamine (OA) levels were significantly decreased; with the CO2 anesthesia for durations of both 2 min and 4 min, only DA showed a significant decrease. In the non-anesthesia treatments, the vertical spin with a velocity of 50 and 60 rpm for 90 s, the DA and OA levels were significantly decreased. Our results suggest that when the bees were under stress, the brain levels of OA and DA were depressed, and this may have caused latency in the rewarding behavior. The serotonin (5-HT) levels under these stress treatments were not changed., (Copyright 2008 Wiley-Liss, Inc.)

The acinar salivary glands of cockroaches receive a dual innervation from the subesophageal ganglion and the stomatogastric nervous system. Acinar cells are surrounded by a plexus of dopaminergic and serotonergic varicose fibers. In addition, serotonergic terminals lie deep in the extracellular spaces between acinar cells. Excitation-secretion coupling in cockroach salivary glands is stimulated by both dopamine and serotonin. These monoamines cause increases in the intracellular concentrations of cAMP and Ca(2+). Stimulation of the glands by serotonin results in the production of a protein-rich saliva, whereas stimulation by dopamine results in saliva that is protein-free. Thus, two elementary secretory processes, namely electrolyte/water secretion and protein secretion, are triggered by different aminergic transmitters. Because of its simplicity and experimental accessibility, cockroach salivary glands have been used extensively as a model system to study the cellular actions of biogenic amines and to examine the pharmacological properties of biogenic amine receptors. In this review, we summarize current knowledge concerning the aminergic control of cockroach salivary glands and discuss our efforts to characterize Periplaneta biogenic amine receptors molecularly.

Biogenic amines are an important class of primary messengers in the central (CNS) and peripheral nervous systems and in peripheral organs. These substances regulate and modulate many physiological and behavioral processes. Various inactivation mechanisms for these substances exist to terminate biogenic amine-mediated signal transduction. In vertebrates, the enzymes monoamine oxidase and/or catechol-O-methyl-transferase are involved in these processes. In insects, however, in which both enzymes are low in abundance or absent, biogenic amines are inactivated mainly by N-acetylation or O-sulphation. In Drosophila, beta-alanyl conjugation mediated by the Ebony protein has recently been shown to be a novel and alternative pathway for biogenic amine inactivation. Here, we report the cloning of ebony cDNA (Peaebony) from a brain-specific cDNA library of the cockroach Periplaneta americana. The open reading frame encodes a protein of 860 amino acid residues (PeaEbony). The PeaEbony polypeptide shares homology to Ebony sequences from Anopheles gambiae, Apis mellifera, and Drosophila melanogaster. In addition, PeaEbony exhibits sequence similarity to a family of microbial non-ribosomal peptide synthetases. The mRNA encoding PeaEbony is highly expressed in the cockroach brain and to a lesser extent in the salivary glands. PeaEbony is, therefore, probably involved in the inactivation of various biogenic amines through beta-alanyl conjugation in the cockroach CNS. Since the salivary glands in Periplaneta are innervated by dopaminergic and serotonergic neurons, PeaEbony probably also biochemically modifies dopamine and serotonin in these acinar glands., (Copyright 2005 Wiley-Liss, Inc)

5-Hydroxytryptamine (5-HT) plays a role in the regulation of 3, 4-dihydroxyphenylethylamine (dopamine) neurons in the brain, but the precise mechanism of regulation by 5-HT(1A) receptors of dopamine release has not been defined. The present study describes the effect of 5-¿3-[[(2S)-1,4-benzodioxan-2ylmethyl]amino]propoxy¿-1, 3-benzodioxole HCl (MKC-242), a highly potent and selective 5-HT(1A) receptor agonist, on dopamine release in the prefrontal cortex using microdialysis in the freely moving rat. Subcutaneous injection of MKC-242 (0.3 - 1.0 mg kg(-1)) increased extracellular levels of dopamine in the prefrontal cortex. The effect of MKC-242 in the prefrontal cortex was antagonized by pretreatment with the selective 5-HT(1A) receptor antagonist, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohe xanecarboxamide (WAY100635; 1 mg kg(-1), i.p.). Local application of WAY100635 (10 microM) via a microdialysis probe antagonized the effect of systemic MKC-242 in an increasing dopamine release, and locally infused 8-hydroxy-2-(di-n-propylamino)tetralin (10 microM) increased dopamine release in the prefrontal cortex. MKC-242 increased cortical dopamine release in the rats pretreated with 5, 7-dihydroxytryptamine (150 microgram, i.c.v.) that caused an almost complete reduction in cortical 5-HT content. The effect of MKC-242 to increase dopamine release was also observed in the hippocampus, but not in the striatum or nucleus accumbens. Fluoxetine, a selective serotonin reuptake inhibitor, increased dopamine release in the prefrontal cortex, but not in the nucleus accumbens, while buspirone, a 5-HT(1A) receptor agonist, increased dopamine release in both brain regions. The present results indicate that activation of postsynaptic 5-HT(1A) receptors increases dopamine release in a brain region-specific manner.

In vivo exposure of Lymnaea acuminata to thymol and [6]-gingerol (active molluscicidal components of Trachyspermum ammi and Zingiber officinale, respectively) indicates that they significantly alter acetylcholinesterase, lactic dehydrogenase, succinic dehydrogenase and cyto-oxidase activity in the nervous -tissue of snails. In vitro exposure showed that, except for acetylcholinesterase and lactic dehydrogenase, no significant changes were observed in cyto-oxidase and succinic dehydrogenase activity in the nervous tissue of L. acuminata. Sublethal exposure to thymol and [6]-gingerol reduced the levels of 5-hydroxytryptamine (5-HT) and dopamine (DA) in the nervous tissue of L. acuminata. There was, however, no significant change in the level of 5-hydroxy indol acetic acid (5-HIAA). Thymol and [6]-gingerol thus affects all the known neurotransmission mechanisms in the snail either separately or through a complex interaction between the different neurotransmitters. This may account for their toxicity to snails., (Copyright 1999 John Wiley & Sons, Ltd.)

The purpose of the current review is to present a brief background examining the mechanisms controlling synthesis, storage, release and action of the biogenic amine neurotransmitters and to provide examples of newly defined conditions that expand our awareness of the diversity and complexity of the inherited diseases that affect these important regulators of central and peripheral homeostasis.

The synthesis of the enantiomers of bupropion, (rac)-2-tert-butylamino-3'-chloropropiophenone 1 (Wellbutrin) is described. The enantiomers were compared with the racemate in both the tetrabenazine-induced sedation model and the inhibition of uptake of biogenic amine assay. No significant differences were found in their potencies to reverse tetrabenazine-induced sedation in mice or in their IC50 values as inhibitors of biogenic amine uptake into nerve endings obtained from mouse brain.

1. The purpose of the present study was to investigate the acute (single injection), direct (chronic treatment) and the long-lasting effects after exposure to the alpha 1/beta-adrenoceptor antagonist labetalol during rat brain development on adrenoceptors and monoamine metabolism. 2. In 10-day-old rat pups, subcutaneously administered labetalol (10 mg kg-1) passed the blood-brain barrier, reaching a level of 2.1 micrograms g-1 tissue in the brain 90 min after injection. 3. Chronic labetalol treatment (10 mg kg-1, s.c., twice daily) during the first 10 days of life significantly increased alpha 1-adrenoceptor binding in the hypothalamus (+39%), but not in the occipital cortex. 4. This chronic postnatal labetalol treatment did not result in long-lasting changes in alpha 1- and beta-receptors measured on day 60. 5. A single labetalol injection (10 mg kg-1, s.c.) on postnatal day 10 significantly increased noradrenaline (NA) metabolism in all brain regions tested (+25 to 105%), but had no effects on 5-hydroxytryptamine (5-HT) or dopamine metabolism. 6. Chronic labetalol treatment between postnatal (PN) days 1 and 10 also increased NA metabolism on PN 10 (3-methoxy-4-hydroxyphenylglycol (MHPG)/NA, +20 to 100%), suggesting that tolerance to the acute effect of labetalol did not occur. A slight increase in 5-HT metabolism (20%) was induced by the chronic labetalol treatment in the hippocampus and meso-limbic system. 7. In general, long-lasting effects on NA metabolism could not be detected on day 60 more than one month after the treatment. However, 5-HT metabolism was significantly increased in all four brain regions measured (+20 to 70%). 8. We conclude that chronic labetalol exposure during early postnatal rat brain development does not cause long-lasting changes in beta-receptor number or NA metabolism, but appears to be critical for the rate of 5-HT metabolism in later life.

1 Infusion of large doses of (+)-amphetamine continuously for 7 days by means of osmotic minipumps caused a long-lasting reduction of endogenous dopamine levels, dopamine nerve terminals demonstrated histochemically and [3H]-noradrenaline uptake in vitro in the striatum of mice. 2 The effect was dose-dependent, fully developed after 4 days and selective for striatal dopamine up to a dose of (+)-amphetamine of 25 microgram/h. Higher doses, which produced increased mortality, also affected dopamine levels in the olfactory tubercle as well as noradrenaline in several regions. 3 Fluorescence histochemical studies using the Falck-Hillarp technique disclosed catecholamine accumulations in the striatum after (+)-amphetamine; a sign of neurotoxic damage. No effects on the dopamine cell bodies were noted. There were also no indications of neurotoxic damage to noradrenaline or 5-hydroxytryptamine neurones induced by (+)-amphetamine. 4 Large doses of (-)-amphetamine were without effect, demonstrating that the long-lasting impairment of transmitter uptake-storage mechanism in striatal dopamine nerve terminals is selective for (+)-amphetamine. 5 There was a slow gradual recovery of endogenous dopamine and [3H]-noradrenaline uptake in the striatum with time, which was almost complete 6 months after the (+)-amphetamine administration. 6 The results give further evidence for the view that (+)-amphetamine in large doses can have a selective neurotoxic action on a vulnerable population of a dopamine nerve terminals in the striatum. The results suggest in addition that there is a slow regrowth and regeneration with time of damaged dopamine nerve terminals.

1. Pargyline (100 mg/kg) increased the concentration of cerebral noradrenaline dopamine and 5-hydroxytryptamine in the mouse. Amphetamine (5 mg/kg) reduced the concentration of noradrenaline and increased the concentrations of 5-hydroxytryptamine and dopamine. 2. When amphetamine was administered 4 h after an injection of pargyline, the effect of the sympathomimetic drug on the concentrations of noradrenaline and 5-hydroxytryptamine was not altered. The effect on the dopamine content was reversed, amphetamine causing a decrease instead of an increase. 3. Pargyline increased the concentration of cerebral glycogen, whereas amphetamine caused a decrease. 4. The administration of amphetamine 4 h after pargyline resulted in a decrease in brain glycogen similar to that seen after amphetamine alone. 5. These results suggest that the potentiation of the effect of amphetamine on animal behaviour by pretreatment with an inhibitor of monoamine oxidase is not mediated through a central action on noradrenaline release. 6. Amphetamine-induced glycogenolysis was antagonized by 71% by desmethylimipramine (10 mg/kg). 7. The change in glycogen concentration as a function of time after an injection of amphetamine was not modified when 2 consecutive doses of amphetamine were given with an interval between doses of 30 minutes.

1 The effects have been investigated of various reserpine-like, neuroleptic, antidepressant and other compounds on the adenosine-5'-triphosphate (ATP)-dependent uptake of noradrenaline (NA) (reserpine-sensitive) and tryptamine (reserpine-resistant) by membranes of isolated chromaffin granules of bovine adrenal medulla. 2 Reserpine and Ro 4-1284 (2-hydroxy-2-ethyl-3-isobutyl-9,10-dimethoxy-hexahydro-11bH-benzo(a)quinolizine) as well as neuroleptics (e.g. chlorpromazine and haloperidol) inhibited the NA uptake, but the reserpine-like drugs were more potent. In contrast, Ro 4-1284 showed a considerably weaker effect thatn the neuroleptics in interfering with tryptamine uptake. Chlorpromazine had about the same potency in inhibiting NA and tryptamine uptake, whereas the action of haloperidol was more pronounced on the uptake of NA than of tryptamine. 3 The relative potencies of neuroleptic drugs in inhibiting NA uptake by granule membranes in vitro corresponded only partly to their relative potencies in enhancing dopamine turnover in vivo. 4 The inhibition of NA uptake by chloropromazine and Ro 4-1284 appeared to be of the noncompetitive type. 5 Chlorpromazine did not influence the decrease in ATP induced by granule membranes in the incubation medium. 6 Other basic, but not acidic compounds also inhibited NA uptake by granule membranes; their potency was of the order of that of chlorpromazine (antidepressants) or weaker (e.g. benzodiazepines). 7 In conclusion, the mechanism of action of neuroleptics probably differs from that of reserpine-like drugs in the inhibition of monoamine uptake by membranes of catecholamine storage organelles. While interference with the granular storage of dopamine at the granule membrane level may contribute to the in vivo action of neuroleptics (e.g. in enhancing dopamine turnover), additional effects of these drugs must be involved in vivo, e.g. blockade of pre- and postsynaptic dopamine receptors.

1 Rabbit anti-guinea-pig lymphocytic serum was fractionated by gel filtration to obtain partially purified materials possessing anti-inflammatory activity. The pharmacological properties of these materials were then studied. 2 Two fractions were found which reproducibly contained significant activity. One of these activities caused inflammation at the site of injection and was associated with high molecular weight protein (2008000). The other activity was found in low molecular weight fraction but was shown to be due to small amounts of endotoxin from Gram negative bacteria. These organisms contaminated the fractions in spite of the recommended precautions for gel filtration having been taken. 3 The endotoxin-containing fraction completely abolished leucocyte infiltration into the rat foot which had been injected with kaolin. It had no apparent effect on circulating haemolytic complement. It caused maximal elevation of serum 11-hydroxycorticosteroid concentrations and was found to cause the release of pharmacologically active amines. Many of the previously reported naturally occurring anti-inflammatory substances have similar pharmacological properties to those of the endotoxin-containing fraction. 4 It was concluded that doubt will exist about the presence of anti-inflammatory factors in mammalian body fluids unless stringent precautions are taken to exclude measurable bacterial contamination. 5 These experiments also cast doubt on the validity of accepted procedures for excluding microbial growth from columns used in the fractionation of serum.

1 The effects of intraperitoneally administered melatonin on sleep and brain neurochemistry in the rat were studied by use of EEG recording and standard fluorescence techniques. 2 Melatonin, 10 mg/kg, reduced time to sleep onset and time spent awake but increased both slow wave and paradoxical sleep. Qualitatively similar but smaller effects were produced by a dose of 2.5 mg/kg. 3 Neither dose of melatonin altered normal EEG patterns or disrupted normal sleep behaviour. 4 Melatonin, 20 mg/Kg, did not significantly alter concentrations of tryptophan, 5-hydroxytryptamine, 5-hydroxyindoleacetic acid, noradrenaline or dopamine in any part of the brain. 5 it is concluded that the sleep promoting activity of melatonin cannot be related to gross changes in brain indoleamine and catecholamine levels.

1. Oral doses of 10-100 mg/kg of BRL 13776 lowered the blood pressure of both deoxycorticosterone acetate (DOCA)/NaCl-treated hypertensive rats and untreated normotensive rats. 2. BRL 13776 (100 mg/kg, orally) also reduced the blood pressure of renal hypertensive cats (cellophane perinephritis model). 3. No tolerance developed to the blood-pressure lowering action of BRL 13776 when an oral daily dose of 100 mg/kg was administered repeatedly for up to 15 days to hypertensive rats and cats. 4. The fall in blood pressure to BRL 13776 in rats was associated with a reduction of tissue catecholamines. 5. The catecholamine depletion occurred in all the peripheral tissues examined but in the brain was restricted to certain regions, these being the hind-brain on single dosing and the hind-brain, hypothalamus and mid-brain on repeated dosing. Catecholamine levels in the cerebral hemispheres were not affected by either single or repeated doses of BRL 13776. 6. BRL 13776 caused some reduction of the 5-hydroxytryptamine content of the heart but not of whole brain or any brain region. 7. Neither single doses (up to 900 mg/kg orally) nor repeated doses (100-300 mg/kg orally) of BRL 13776 produced any significant behavioural effects in animals. 8. BRL 13776 is a new type of agent to display both antihypertensive and monoamine-depleting properties. The reduction of noradrenaline in certain brain regions may be a cause of the antihypertensive response but depletion in the periphery could contribute in a major or minor way. The differential action on noradrenaline in the brain together with the lack of effect on 5-hydroxytryptamine might also explain the apparent absence of behavioural effects.

1. The dose-related effects of the selective alpha 2-adrenoceptor agonists clonidine, UK-14,304 and B-HT 933 on the body temperature of untreated and reserpine-treated mice were investigated. 2. In untreated mice all three agonists induced a dose-related hypothermia. The highest doses of UK-14,304 and B-HT 933, 3 and 100 mg kg-1 respectively, elicited a marked (10 degrees C) hypothermia, whereas the maximal hypothermic effect of clonidine (5.5 degrees C) was less pronounced and reached a plateau at a dose of 0.5 mg kg-1 i.p. 3. Reserpine (2.5 mg kg-1, s.c.) induced a marked hypothermia in the mouse; 18 h after injection body temperature had decreased to only slightly (0.5-1.5 degrees C) above ambient (19 degrees C). 4. All three alpha 2-agonists produced a partial dose-related reversal of reserpine-induced hypothermia; maximal thermogenic responses (9-10 degrees C increases in body temperature) were elicited by doses of 0.2, 0.5 and 16 mg kg-1 i.p. of clonidine, UK-14,304 and B-HT 933 respectively, and the log dose-response curves for all 3 agonists were bell-shaped. 5. Following intracerebroventricular administration to reserpine-treated mice, the thermogenic response to clonidine was more rapid in onset, and the agonist was 20 fold more potent than when injected i.p. 6. The selective alpha 2-adrenoceptor antagonists, idazoxan (0.05-0.5 mg kg-1), Wy 26392 (0.3-5.0 mg kg-1) and yohimbine (0.1-1.6 mg kg-1) given orally attenuated the thermogenic responses to all 3 agonists in reserpinized mice in a dose-related manner. Pretreatment with a single dose of idazoxan (0.3 mg kg-1, orally) elicited a 6 fold parallel shift to the right in the dose-response curve to clonidine. 7. The selective alpha 1-adrenoceptor antagonists, prazosin (10 mg kg-1) and indoramin (3-10 mg kg-1), and the beta-adrenoceptor antagonist, propranolol (10 mg kg-1), only partially attenuated the thermogenic responses to the alpha 2-agonists in reserpinized mice. These effects were variable and not clearly dose-related. 8. Pretreatment of reserpinized mice with the catecholamine synthesis inhibitor, alpha-methyl-p-tyrosine, markedly attenuated (60-95%) the thermogenic response to the noradrenaline uptake inhibitor, desipramine (0.13-12.5 mg kg-1, i.p.), but only slightly reduced (10-35%) that to clonidine (0.032-0.5 mg kg-1, i.p.). 9. These results suggest that alpha2-adrenoceptor agonists reverse reserpine-induced hypothermia via a central mechanism involving activation of postsynaptic alpha 2-adrenoceptors.

After chronic administration of ethanol to mice by the intragastric route head twitches occur as part of the ethanol withdrawal syndrome. Treatments which reduce brain 5-hydroxytryptamine or increase brain noradrenaline inhibited ethanol withdrawal head twitches, whereas treatments which increase brain 5-hydroxytryptamine or reduce brain noradrenaline were capable of inducing head twitches in control animals.

In most patients with deficiency of tetrahydrobiopterin (BH4) continuous administration of BH4 or of a synthetic analogue such as 6-methyltetrahydropterin (6-MPH4) lowers plasma phenylalanine concentrations to the therapeutic range. The effective dose of BH4 varies from 1 to 2 mg kg-1 daily in patients with defective biopterin synthesis, to 5 mg kg-1 or more in patients with dihydropteridine reductase (DHPR) deficiency. The cost of 2 mg kg-1 day-1 of BH4 is comparable to the cost of a low phenylalanine diet. Higher doses of pterins given orally (20 mg kg-1) raise the levels of tetrahydropterin in cerebrospinal fluid (CSF) to normal in patients with defective biopterin synthesis in whom initial concentration of biopterin species are low. In some, but not all, such patients pterin therapy also raises CSF amine metabolite concentrations and ameliorates symptoms. High dose therapy does not appear to be effective in raising CSF pterin levels in patients with DHPR deficiency who already accumulate dihydrobiopterin (BH2) in CSF. Central folate deficiency is an additional cause of neurological deterioration in patients with DHPR deficiency who require supplementation with folate as folinic acid. It is suggested that the accumulation of BH2 in such patients competitively interferes with folate metabolism.

1 The effects of K(+), NaCN and the ionophores monensin, nonactin and carbonyl-cyanide-p-trifluoro-methoxyphenylhydrazone (FCCP) on the contents of [(3)H]-5-hydroxytryptamine ([(3)H]-5-HT), [(3)H]-dopamine and [(3)H]-noradrenaline ([(3)H]-NA) in guinea-pig synaptosomes preloaded with these amines were measured.2 In the presence of Ca(2+), K(+) markedly reduced the amine content of the synaptosomes, indicating an acceleration of spontaneous amine release. In the absence of Ca(2+), K(+) had much less effect.3 Monensin, nonactin and FCCP caused a release of all the three labelled amines. This release was considerably faster and more marked than that induced by K(+) and showed no dependence on Ca(2+). The ionophores did not release lactate-dehydrogenase from synaptosomes.4 NaCN, a blocker of oxidative energy production, did not enhance the spontaneous release of [(3)H]-5-HT nor did it influence the monensin-induced release of [(3)H]-5-HT.5 It is concluded that (a) the intragranular storage of 5-HT, dopamine and NA is dependent on the maintenance of a pH-gradient across the granular membrane as well as on the granular membrane potential; (b) the ionophores cause a non-exocytotic release of granular amines, and (c) blood platelets are partial models for aminergic brain neurones as far as intragranular amine storage is concerned.

1 The effects of mianserin and of selected tricyclic antidepressants were compared in a number of monoamine uptake models. 2 The ability of mianserin to block the noradrenergic neurone membrane amine pump of rabbit brain stem slices was comparable to that of imipramine and amitriptyline and less than that of desipramine and nortriptyline. Both mianserin and desipramine were competitive inhibitors of noradrenaline uptake in vitro. The effect of mianserin on noradrenaline uptake in vivo was studied both peripherally and centrally. The ability of 6-hydroxydopamine to lower rat heart noradrenaline levels was found to be very sensitive to inhibition by tricyclic antidepressants. Mianserin was active in this model. However, its ability to block the 6-hydroxydopamine-induced fall in rat heart noradrenaline concentration was appreciably less than that of the tricyclics studied. 3 Mianserin, like tricyclic antidepressants, was essentially devoid of effect on dopamine uptake both in vitro and in vivo. 4 The ability of mianserin to inhibit [3H]-5-hydroxytryptamine uptake by rat hypothalamic synaptosomes was appreciably less than that of the tricyclic antidepressants studied. Mianserin was essentially devoid of effect on rat brain 5-hydroxytryptamine uptake in vivo. 5 It is concluded that in certain situations large doses of mianserin may block noradrenaline uptake in vivo. However, in no way does mianserin rival tricyclic antidepressants in blocking monoamine uptake in vivo. The clinical efficacy of mianserin cannot be attributed to inhibition of monoamine uptake.

1 The effect of pretreatment with clomipramine hydrochloride (15 mg/kg, i.p.) on the (--)-trans-delta9-tetrahydrocannabinol (delta9-THC)-induced changes in body temperature and brain amines of the rat was investigated. 2 A dose of 0.05 mg/kg of delta9-THC produced hyperthermia and a decrease in whole brain concentration of 5-hydroxyindoleacetic acid (5-HIAA). Doses of 2 and 5 mg/kg produced hypothermia and increases in brain 5-HIAA whereas 0.5 mg/kg did not affect either parameter. delta9-THC, at any of the doses, did not affect the whole brain concentrations of dopamine, noradrenaline or 5-hydroxytryptamine. 3 Clomipramine modified these responses of delta9-THC in that the dose-response curves appeared to be shifted to the right. 4 It is concluded that clomipramine acts as an antagonist to these actions of delta9-THC by interfering with entry of delta9-THC into tryptaminergic neurones.

1 The cataleptic and monoamine-depleting effects of a butyrophenone derivative (4'-fluoro-4-[[4-(p-fluorophenyl)-3-cyclohexen-1-yl]-amino]-butyrophenone hydrochloride, U-32, 802A) were studied in rats and mice and compared with those of tetrabenazine. 2 Catalepsy was evaluated by means of a modified grid test which allowed the repetition of the test in the same animal several times without affecting the results. Both drugs produced a dose-related cataleptic state of similar time course. 3 Like tetrabenazine, U-32, 802A induced a large reduction in the content of 5-hydroxytryptamine, dopamine and noradrenaline in different parts of the brain, with a concomitant elevation in the metabolites 5-hydroxyindol-3-yl acetic acid and homovanillic acid. The time courses of the catalepsy and the reduction in brain monoamines were very similar. 4 The activity of U-32, 802A suggested that the drug, although chemically a butyrophenone, might act primarily at the presynaptic organelle for storage of monoamines in a way similar to tetrabenazine.

The authors review four "second generation" antidepressants (maprotiline, amoxapine, trazodone, and nomifensine) in terms of action on biogenic amines and receptors, antidepressive efficacy, and adverse effects. Doxepin is used as a comparative agent and is similar to the prototypical tricyclic agents in all the above categories. Maprotiline is a selective noradrenergic agent, but shares a similar adverse effect profile with doxepin and may be associated with a high frequency of seizures in overdose. Amoxapine is a mixed action antidepressant with significant neuroleptic activity in vivo. Its adverse effect profile is highlighted by symptoms related to its neuroleptic activity, and seizures and acute renal failure in overdose. Trazodone is a selective serotonergic agent with low anticholinergic activity, and minimal morbidity/mortality in overdose. Reports of priapism, leading to impotence in some men, however, is of concern. Nomifensine is a potent noradrenergic and dopaminergic agent with low anticholinergic activity, and minimum cardiotoxicity and low morbidity/mortality in overdose. Its most important adverse effects include overstimulation and infrequent, usually reversible, immunologic hypersensitivity reactions. Trazodone and nomifensine have favorable profiles for use in the elderly. Trazodone may be more favorable in the anxious/agitated patient due to its sedative effects, whereas nomifensine may be more beneficial in the retarded, apathetic patient.

1. Rats were injected intravenously with 2 mg/kg (-)-trans-delta9-tetrahydrocannabinol (delta9-THC) at ambient temperatures of 4 degrees, 21 degrees, 31 degrees and 37 degrees C. 2. The general behavior exhibited by rats treated with delta9-THC was similar at all four ambient temperatures. 3. Body temperatures were recorded continuously before and after drug administration. At 4 degrees and 21 degrees C, delta9-THC caused hypothermia whereas no change in body temperature occurred at 31 degrees and 37 degrees C. 4. The concentrations in the whole brain of noradrenaline (NA), dopamine, 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were determined spectrophotofluorimetrically 1 h after drug administration. At 4 degrees C delta9-THC caused an increase of 5-HT, at 21 degrees C an increase of 5-HIAA, at 21 degrees C an increase of 5-HIAA AND A decrease of NA, and at 37 degrees C an increase of 5-HT and 5-HIAA. 5. At all ambient temperatures, delta9-THC increased the brain levels of 5-HT and/or 5-HIAA. A correlation between the delta9-THC-induced hypothermic response and the possible alteration of brain 5-HT metabolism cannot be excluded.

Pain is not an electrical impulse derived from tissue injury but an emotional experience arising when a nervous input is interpreted in the light of experience and emotional context as being 'painful'. Pain may thus signify tissue damage, vivid sensory experience or inner turmoil. Pain may be distressing but it can also be pleasurable. Whether a given stimulus provokes pain and whether that emotional feeling causes distress varies from individual to individual and from moment to moment. The brain possesses chemically mediated mechanisms that can exert control over the experience of 'pain'. An understanding of such mechanisms suggests new approaches to the relief of distressing pain (and to the artificial production of pleasurable pain).

The practical value of measuring plasma concentrations is to optimize treatment in order to attain the best balance in each particular patient between wanted clinical therapeutic effects and unwanted adverse and side-effects. This increase in treatment efficacy can be concurrent--that is, the treatment is monitored and the dosage changed as necessary--or predictive, where the results of a test dose can be used to calculate the appropriate dosage. Wanted effects include: (1) the attainment of adequate drug concentrations for the minimum period of time necessary, as in the use of antibiotics; (2) the suppression of symptoms, as in the use of the benzodiazepines in anxiety states; (3) the use of drugs to improve function, e.g. levodopa in Parkinsonism; (4) drugs are used to prevent episodes of illness; and (5) complex suppression of symptoms, as with the antidepressives and antipsychotics. The biological alternatives to plasma level monitoring depend on establishing an empirical relationship between the putative monitor and the clinical response. Such measures avoid the problem of estimation of drug concentration at the receptor. Examples include monoamine oxidase activity in platelets, the uptake of amines into platelets, neuroendocrine measures such as prolactin concentrations, the electroencephalogram, and peripheral measures such as pulse rate, pupil size and tremor.

1 Catalepsy was produced in rats and mice by the subcutaneous injection of either tetrabenazine or the butyrophenone U-32,802A (4'-fluoro-4-{[4-(p-fluorophenyl)-3-cyclohexen-1-yl]amino} butyrophenone hydrochloride). Catalepsy was evaluated by the duration of total immobility on a vertical grid.2 Pretreatment with p-chlorophenylalanine (PCPA) reduced the intensity of catalepsy by 50% or more, whereas its time course remained the same.3 5-Hydroxytryptophan (5-HTP), 10 mg/kg, enhanced the catalepsy induced by U-32,802A or tetrabenazine, provided it was administered soon (45 min) after the neuroleptic; injections at 90 min had no effect. Otherwise untreated rats given this dose of 5-HTP behaved normally on the grid.4 The anticataleptic effect of PCPA was reversed by 5-HTP.5 Measurable changes in 5-hydroxytryptamine (5-HT) metabolism in the rat forebrain accompanied the modification of catalepsy by 5-HTP and PCPA.6 Methysergide (5 mg/kg) given 30 min before the neuroleptics to either mice or rats reduced the catalepsy, assessed 2.5 h after the methysergide. It also prevented the increase in neuroleptic-induced catalepsy following 5-HTP, 10 mg/kg.7 Tryptophan, like 5-HTP, increased the catalepsy seen in mice after U-32,802A and tetrabenazine, and increased the production of 5-hydroxyindol-3-ylacetic acid in the forebrain.8 In the rat, intracerebroventricular injection of physostigmine produced catalepsy which was not modified by methysergide or PCPA but was abolished by atropine. Similarly, in the mouse, catalepsy induced by the subcutaneous injection of pilocarpine was abolished by atropine but not affected by either methysergide or 5-HTP.9 Atropine greatly reduced the catalepsy induced by U-32,802A and tetrabenazine but lowered striatal homovanillic acid (HVA) only after U-32,802A. D,L-DOPA, 20 mg/kg, diminished the cataleptogenic effect of both neuroleptics and raised striatal HVA.10 The results support the view that there is a facilitating or permissive action of 5-HT-containing neurones on neuroleptic-induced catalepsy.

1. The release of 5-hydroxytryptamine (5-HT), dopamine and noradrenaline (NA) from the rat isolated vas deferens was estimated by high performance liquid chromatography with electrochemical detection. 2. Compound 48/80, which is known to release 5-HT and histamine from mast cells, induced a concentration-related, rapid overflow of 5-HT from the rat isolated vas deferens, releasing about 50% of the 5-HT present in the tissue at a concentration of 300 micrograms ml-1. The drug did not induce the release of either dopamine or NA. 3. The depolarizing agents veratridine (10 microM) or K+ (100 mM) induced the release of 5-10% of the 5-HT present in the vas deferens, but did not evoke the overflow of 5-HT from isolated mast cells. 4. Veratridine induced the release of a greater proportion of the dopamine than of the NA contained in the vas deferens (41.0 +/- 5.5 vs 17.9 +/- 2.0%, after 20 min of exposure to the drug, n = 6). In contrast, K+ evoked the release of both amines equally. 5. It is concluded that in the rat vas deferens 5-HT is stored in mast cells and also in cells responsive to depolarizing stimuli. It is suggested that 5-HT could be a neuromodulator or a neurotransmitter in this organ. Veratridine and K+ induce the release of dopamine in addition to NA.

1 The effects of low-dose lithium administration (2 mEq/kg, daily) and its subsequent withdrawal have been examined with reference to changes in biogenic amine systems in several discrete regions of rat brain. 2 Increased levels of striatal tyrosine and midbrain tryptophan were found following lithium administration together with slight decreases in striatal tyrosine hydroxylase and midbrain tryptophan hydroxylase activities. Withdrawal resulted in a decrease in tyrosine content with increased tyrosine hydroxylase activity, whilst tryptophan levels and tryptophan hydroxylase activity were increased. 3 Lithium treatment and withdrawal resulted in altered levels of noradrenaline and dopamine, these changes being regionally variable. 3-Methoxy-4-hydroxyphenylglycol content was depressed in both treated and withdrawal rats as were 3,4-dihydroxyphenylacetic acid levels. Homovanillic acid decreased as a result of lithium treatment, but was greatly elevated in the withdrawal group. 4 5-Hydroxytryptamine content decreased in some brain regions following lithium treatment with return towards control values in withdrawal rats. 5-Hydroxyindoleacetic acid levels also displayed a regional variation as a result of lithium treatment and withdrawal. 5 The implications of these observations in elucidating the pharmacological effect of lithium treatment and its subsequent withdrawal are discussed.

In an effort to explore the contribution of the metabolites of pargyline towards the in vivo inhibition of monoamine oxidase (MAO), the effects of pargyline and its major metabolites on the production and metabolism of a number of biogenic amines were studied in rats. The administration of pargyline gave rise to three major ethyl acetate extractable metabolites: benzylamine, N-methylbenzylamine and N-propargylbenzylamine (NPB). Only NPB demonstrated in vivo monoamine oxidase inhibitory properties at an acute dose of 30 mg kg-1. The acute effects of pargyline, NPB, and deprenyl on urine and brain concentrations of a number of biogenic amines (phenylethylamine (PEA), m- and p-tyramine, noradrenaline (NA), dopamine, and 5-hydroxytryptamine (5-HT) and their metabolites were evaluated. Increased urine and brain concentrations of PEA were considered to represent in vivo inhibition of type B MAO while decreased concentrations of NA and 5-HT metabolites were regarded as indicators of an in vivo inhibition of MAO type A. NPB, like deprenyl and pargyline, significantly increased urine and brain PEA while only pargyline reduced 5-HT metabolism, suggesting that the metabolism of pargyline to NPB may contribute towards the MAO type B inhibitory effects of pargyline in vivo. Since the therapeutic benefits of MAO inhibitors in clinical practice usually require some period of chronic treatment, the chronic effects of repeated 14 daily doses of the above MAO inhibitors on central and peripheral biogenic amines were evaluated at the following times: during treatment, one day and five days after termination of treatment. The biochemical changes observed during the course of chronic NPB, pargyline and deprenyl treatments generally follow the expected in vitro characteristics of these drugs, but the detailed changes observed suggest clear differences. For example, the in vivo effect of pargyline on urine 5-hydroxyindoleacetic acid excretion was considerably weaker than its effect on the excretion of NA and dopamine metabolites. These changes are opposite to the in vitro effects of pargyline on 5-HT, dopamine and NA oxidative deamination. Inhibitions of the metabolism of all the amines studied were clearly observed during chronic MAOI treatments, but these effects were less evident five days after the end of treatment, suggesting an almost normal metabolism of biogenic amines. It is concluded that while MAO inhibitors may be the primary compound responsible for MAO inhibition, the effects of their metabolites in some cases may also play equally important roles in the regulation of monoamines both in the periphery and the brain. Thus, as demonstrated here, NPB was found to be as potent as pargyline and deprenyl with regard to its in vivo MAO type B inhibitory properties.

1 The concentrations of p- and m-tyramine, dopamine, 3,4-dihydroxyphenylacetic acid and homo-vanillic acid were measured in the mouse or rat striatum following the subcutaneous injection of molindone or fluphenazine. The mouse hypothalamic levels of the m- or p-isomers of octopamine were also analysed. 2 Endogenous concentrations of p- and m-tyramine in the mouse striatum and p- and m-octopamine in the mouse hypothalamus were 20.6, 5.7, 9.4 and 1.2 ng/g respectively. The rat striatum concentrations of p- and m-tyramine were 12.8 and 3.8 ng/g. 3 The administration of low doses of molindone (1 to 10 mg/kg) produced a reduction in striatal p-tyramine, an increase in m-tyramine and an increase in dopamine turnover. Similar effects were produced by all doses of fluphenazine (0.1 to 5 mg/kg) employed. These findings are consistent with those observed after blockade of dopamine postsynaptic receptors. 4 With high doses of molindone (100 mg/kg) the effects on both tyramines and on dopamine metabolism were reversed. These results can be interpreted as molindone acting as a partial agonist. 5 The concentrations of hypothalamic p- and m-octopamine were increased by the higher doses of molindone (20 to 100 mg/kg) employed while lower doses produced no significant effects. All doses of fluphenazine reduced hypothalamic p-octopamine. These changes seem to depend on differences in the availability of p-tyramine to be converted into p-octopamine. 6 These results suggest that molindone acts as a blocker or a partial agonist of dopamine receptor sites and fit well with the proposal of a reciprocal relation between dopamine and tyramine. It is not possible yet to ascertain whether tyramine controls dopamine or vice versa or if it is a direct or a more remote relation.

Ceruloplasmin is a blue copper protein found in the alpha 2-globulin fraction of vertebrate plasma. It is a single-chain glycoprotein of molecular weight 132 000. It contains six copper atoms per molecule, comprising three or possibly four different types of copper. Its many functions may be related to the heterogeneous nature of these six copper atoms and to the various catalytic activities which they provide. Caeruloplasmin resembles albumin and transferrin in that all three serum proteins are regarded primarily as transport proteins. However, each has numerous other action as important as this transport function. Caeruloplasmin directly mobilizes iron into the serum and provides the major molecular link between copper and iron metabolism; it is the most prominent serum antioxidant, preventing deleterious oxidation of polyenoic acids and other substrates; it scavenges superoxide radicals; it serves as an acute-phase reactant (an endogenous modulator) of the inflammatory response; finally, caeruloplasmin may regulate the serum concentration of the biogenic amines, adrenaline (epinephrine) and serotonin (5-HT).

The hepatic phenylalanine hydroxylating system consists of three essential components, phenylalanine hydroxylase, dihydropteridine reductase and the non-protein coenzyme, tetrahydrobiopterin. The reductase and the pterin coenzyme are also essential components of the tyrosine and tryptophan hydroxylating systems. Recent studies have shown that there are three distinct forms of phenylketonuria or hyperphenylalaninaemia, each caused by the lack of one of these essential components. The variant forms of the disease that are caused by the lack of dihydropteridine reductase or tetrahydrobiopterin are characterized by severe neurological deterioration, impaired functioning of tyrosine and tryptophan hydroxylases and the resultant deficiency of tyrosine- and tryptophan-derived monoamine neurotransmitters in brain.

Amine oxidases have been classified in the past on the basis of either (a) the structural requirements in the substrate or (b) the tissue (or species) of origin, or both. As knowledge about the chemistry of these enzymes grows, their classification on the basis of chemical structure is becoming possible. Currently, many amine oxidases can be categorized according to whether they contain riboflavin (e.g. the monoamine oxidases -- EC 1.4.3.4) or copper (e.g. the amine oxidases of plasma and the diamine oxidases EC 1.4.3.6 -- found prominently in pig kidney cortex, placenta, and pea seedlings). The copper-linked oxidases are inhibited by cyanide and by semicarbazide. The nature of the carbonyl compound(s) in the various enzyme molecules is not yet known. Nutritional deficiencies of copper and treatment of animals with copper-chelating agents are reflected in reduced activity of one or more of these enzymes. The ultimate effects of copper deficiency and copper excess on amine metabolism in vivo are described.

1 Mazindol is a new anorexigenic agent which possesses a different chemical structure from that of phenylethylamines, but shows a pharmacological profile similar to that of (+)-amphetamine. 2 Mazindol neither altered whole brain monoamine levels (noradrenaline (NA), dopamine, 5-hydroxytryptamine (5-HT)) nor changed NA levels in the hypothalamus or dopamine levels in the caudate nucleus. 3 Mazindol enhanced dopamine turnover rate in the caudate nucleus, as shown by the increased rate of dopamine decline after blockade of catecholamine synthesis by alpha-methyl-p-tyrosine and decreased the conversion index of (3H)-tyrosine into brain NA. 4 Mazindol administration did not modify pargyline-induced decline of 5-hydroxyindoleacetic acid suggesting that 5-HT turnover is not altered by this drug.