Monoamine Transmitters Research Articles

The chromaffin granule and synaptic vesicle amine transporters differ in substrate recognition and sensitivity to inhibitors.

Classical studies using bovine chromaffin granules have defined the physiologic and pharmacologic properties of the vesicular amine transporter that packages monoamine transmitters into intracellular vesicles for subsequent regulated release. The recent isolation of two distinct but closely related cDNA clones encoding vesicular amine transport suggests that the activity expressed in the brain (synaptic vesicle amine transporter or SVAT) may differ significantly from the previously described adrenal gland activity (chromaffin granule amine transporter or CGAT). A direct comparison of the two transporters now shows that SVAT has a higher affinity than CGAT for monoamine substrates, in particular for histamine. In addition, SVAT shows approximately 10-fold greater sensitivity to tetrabenazine than CGAT. [3H]Dihydrotetrabenazine shows no detectable binding to CGAT but does bind to SVAT, accounting for the differential sensitivity. Furthermore, methamphetamine preferentially inhibits transport by SVAT relative to CGAT, apparently by competing at the site of amine recognition rather than by disrupting the vesicular pH gradient. These previously unsuspected differences in the storage of monoamine transmitter in the central nervous system and the adrenal gland may help to account for several classic pharmacological observations.

Synaptic vesicular monoamine transporter expression: distribution and pharmacologic profile

The human vesicular monoamine transporter (hSVMT) cDNA predicts a protein of 515 amino acids that shares 92% amino acid identity with the rat cDNA. Northern analyses reveal expression of 4.3 kb SVMT mRNAs in rat hypothalamus, midbrain and brainstem, a 3 kb hSVMT mRNA in human brainstem and a 4.8 kb hSVMT mRNA in human hypothalamus. In situ hybridization documents significant SVMT expression in human nigra compacta neurons and in rat hypothalamic neurons whose distribution patterns are identical to those previously reported to display histaminergic markers. COS cell hSVMT expression yielded nanomolar affinities for tetrabenazine and reserpine, micromolar affinities for haloperidol, GBR12909, serotonin, mazindol, nomifensin and d-amphetamine, while dopamine, epinephrine, norepinephrine and histamine each displayed millimolar affinities. These observations extend the pharmacological characterization of hSVMT and studies of its distribution, and indicate likely physiological roles for SVMT in packaging monoamine transmitters including histamine.

Signalling Effect of Elevated Potassium Concentrations and Monoamines on Brain Energy Metabolism at the Cellular Level (Part 1 of 2)

The effects of elevated K+ concentrations and monoamine transmitters on different cell types in the CNS and on different subcellular structures in these cells are reviewed. Pronounced differences exist in the metabolic processes that are stimulated by excess K+ and by adrenergic agonists, e.g., noradrenaline. An elevation in the extracellular K+ concentration appears to enhance neuronal-astrocytic interaction by stimulating metabolic processes involved in (1) the promotion of supply of precursors for transmitter glutamate, and (2) reestablishment of resting ion distribution following neuronal excitation. The monoamine transmitters stimulate energy production and Na+,K(+)-ATPase activity in astrocytes in a complex manner and, in so doing, facilitate their role in ion regulation. However, in contrast to excess K+, they do not enhance the production of astrocytic precursors for neuronal glutamate production. Emphasis is placed on possible profound differences in metabolic effects on excitatory and inhibitory neurotransmission and on the importance of stimulation of glycolytic metabolism in astrocytes versus oxidative metabolism in neurons.

Pka mediates the effects of monoamine transmitters on the K + current underlying the slow spike frequency adaptation in hippocampal neurons

The Ca 2+-activated K + current I AHP , which underlies spike frequency adaptation in cortical pyramidal cells, can be modulated by multiple transmitters and probably contributes to state control of the forebrain by ascending monoaminergic fibers. Here, we show that the modulation of this current by norepinephrine, serotonin, and histamine is mediated by protein kinase A in hippocampal CA1 neurons. Two specific protein kinase A inhibitors, Rp-cAMPS and Walsh peptide, suppressed the effects of these transmitters on I AHP and spike frequency adaptation. The effects of the cyclic AMP analog 8CPT-cAMP were also inhibited, whereas muscarinic and metabotropic glutamate receptor agonists had full effect. Intracellular application of protein kinase A catalytic subunit or a phosphatase inhibitor mimicked the effects of monoamines or 8CPT-CAMP. These results demonstrate that monoaminergic modulation of neuronal excitability in the mammalian CNS is mediated by protein phosphorylation.

The relationship between changes in monoamine transmitters and edema of the central nervous system after thermal burns in rats. (Chinese)

The relationship between changes in monoamine transmitters and edema of the central nervous system after thermal burns in rats. (Chinese)

Interactions of methylenedioxymethamphetamine with monoamine transmitter release mechanisms in rat brain slices.

This study investigates the effects of methylenedioxymethamphetamine (MDMA) and amphetamine on monoamine release from rat superfused brain slices in both the presence and absence of vesicular stores of transmitter. MDMA caused the release of radioactivity from slices incubated with [3H]5-hydroxytryptamine, [3H]noradrenaline or [3H]dopamine with EC50 values of 1.9 mumol/l (95% confidence limits 1.5-2.3 mumol/l), 4.5 mumol/l (2.3-8.7 mumol/l), and greater than 30 mumol/l, respectively. In contrast, amphetamine (0.1-300 mumol/l) was more effective in releasing radioactivity from slices incubated with [3H]dopamine than [3H]noradrenaline or [3H]5-hydroxytryptamine. When Ca2+ was excluded from the superfusion fluid, the MDMA-induced release of radioactivity from slices incubated with [3H]dopamine was unaltered, but that from slices incubated with [3H]noradrenaline or [3H]5-hydroxytryptamine was enhanced. MDMA (10 mumol/l) facilitated the stimulation-induced (5 Hz, 1 min) outflow of radioactivity from slices incubated with [3H]noradrenaline or [3H]5-hydroxytryptamine to 7.5-fold and 2.1-fold of control values, respectively, but had no effect on that from slices incubated with [3H]dopamine. Amphetamine (1 mumol/l) increased the stimulation-induced outflow from slices incubated with [3H]noradrenaline, but not that from slices incubated with [3H]5-hydroxytryptamine or [3H]dopamine. Inhibition of monoamine oxidase by a 30-min incubation with pargyline (100 mumol/l) enhanced the releasing action of MDMA on all three monoamines. Pargyline (100 mumol/l) also enhanced the facilitation caused by MDMA, of the stimulation-induced outflow of radioactivity from slices incubated with [3H]noradrenaline, [3H]5-hydroxytryptamine or [3H]dopamine. In some experiments, slices were obtained from reserpinised rats (2.5 mg/kg s.c. 24 h prior) and pre-exposed for 30 min to the monoamine oxidase inhibitor parglyine (100 mumol/l). Under these conditions, electrical stimulation evoked a small residual stimulation-induced outflow of radioactivity from slices incubated with [3H]noradrenaline, and failed to evoke an outflow of radioactivity from slices incubated with [3H]5-hydroxytryptamine or [3H]dopamine. However, a Ca(2+)-dependent stimulation-induced outflow of radioactivity was evoked in the presence of either MDMA (10 mumol/l) or amphetamine (1 mumol/l) from slices incubated with either [3H]dopamine or [3H]noradrenaline, but not from slices incubated with [3H]5-hydroxytryptamine. The stimulation-induced outflow of radioactivity from slices incubated with [3H]noradrenaline was enhanced in the presence of desipramine (1 mumol/l), however this enhancement was less than that caused by 10 mumol/l MDMA or 1 mumol/l amphetamine. The Ca(2+)-dependent response to electrical stimulation in the presence of MDMA from slices incubated with [3H]noradrenaline was greatly reduced when rats were pretreated with a higher dose of reserpine (10 mg/kg s.c.).(ABSTRACT TRUNCATED AT 400 WORDS)

Changes in monoamine transmitter concentration in freshwater mussel tissues

Freshwater mussels were analyzed for biogenic amine transmitter substances in gill tissue, suprabranchial nerve and blood. Gill tissue from normal pondwater-acclimated mussels contained significant amounts of monoamine neurotransmitter substances. In comparison with the suprabranchial nerve the gill tissue contained 42% of the dopamine, 7% of the serotonin and 490% of norepinephrine. Exposing the animals to deionized water (salt-depleted) resulted in a loss of transmitter substances from gill tissue, but serotonin reduction was modest. The mussel gill tissue content of serotonin and the precursor tryptophan was regulated at nearly constant levels. Serotonin is an important transmitter substance in mussels and the many functions it controls, including sodium transport regulation, would depend on its continued presence.

Chronic neonatal NMDA receptor blockade with MK-801 alters monoamine metabolism in the adult rat

Administration of non-competitive N- methly- d-aspartate (NMDA) antagonists in rodents leads to a characteristic motor syndrome which has been related to changes in monoamine metabolism in a variety of brain regions. We examined the question whether chronic MK-801 treatment in neonatal rats from postnatal day 8 through 19, which has been shown previously to alter NMDA receptor function, would also affect monoamine metabolism in striatum and frontal cortex of adult rats. Monoamines and their metabolites were determined 5 months after the treatment using high-performance liquid chromatography with electrochemical detection. Dihydroxyphenylacetic acid (DOPAC) concentration was elevated (>40%) in both regions tested, while 5-hydroxyindoleacetic acid (5-HIAA) concentration was significantly elevated only in the cortex (19%), and 3-methoxy-4-hydroxyphenylglycol (MHPG) only in the striatum (47%). These results demonstrate that the long-lasting effects of chronic neonatal MK-801 treatment are not restricted to glutamate transmission, but include monoamine transmission as well.

Chapter 24: Effects of monoamine transmitters on neurons and astrocytes: correlation between energy metabolism and intracellular messengers

In the central nervous system (CNS), monoaminergic transmitters act on both neurons and glial cells, affecting energy metabolism, turnover of transmitter-related amino acids, potassium homeostasis, and/or calcium signaling. The typical glial cell of the brain cortex is the astrocyte. In the brain, monoaminergic transmitters are released mainly from noradrenergic, serotonergic and dopaminergic fibers, extending from the brainstem over the entire cerebrum and cerebellum. The transmitters released from neurons, show effects on glial cells, especially on astrocytes, and represent a neuronal-astrocytic interaction. Functional alterations induced in astrocytes, in turn, affect mainly energy metabolism, glutamatergic, or GABAergic impulse transmission, and potassium homeostasis. The chapter discusses the effects of monoamines on astrocytic metabolism, on turnover of glutamate and its precursors and metabolites, and on ion homeostasis. Normal functional interactions are described and effects by drugs that interact with binding sites for monoaminergic transmitters are also included. Few examples are given of pathological conditions where monoaminergic dysfunction appears to play a major role. Thereafter, some of the possible mechanisms by which these compounds affect cell function are also discussed.

Biochemical Assessment of Preoperative Stress

Diazepam 5 mg or an inert placebo tablet was given as preoperative hypnotic on the night before operation to two groups (n = 18 in each of healthy women having elective Caesarean section under spinal analgesia. A third group (n = 18) received no hypnotic. The quality of the preoperative night's sleep assessed subjectively was significantly better in the diazepam-treated patients compared with those receiving no drug. The diazepam-treated patients had also smaller CSF concentrations of noradrenaline (NA) and of the dopamine metabolite, 3, 4-dihydroxy phenylacetic acid (DOPAC). In comparison with the two other patient groups, in the diazepan group there was no correlation between demo-graphic, physiological or subjectively estimated variables and CSF or plasma measurements of monoamine transmitters and their metabolites. Preoperative fear and apprehension correlated most strongly with preoperative heart rate and with the increase in heart rate from the previous day. The monoamine neurotransmitters or their metabolites were of limited use in monitoring the intensity of preoperative fear and anxiety.

Neurotransmitters in neocortex of aged rhesus monkeys

The effects of aging on levels of neurotransmitters were determined in two regions of the cerebral cortex in rhesus monkeys ( Macaca mulatta). Choline acetyltransferase (ChAT) activity as well as somatostatin, neuropeptide Y, and substance P immunoreactivities were analyzed in the right caudal cingulate gyrus and in the left and right inferior occipital poles in five age groups: 4–6 years; 8–11 years; 20–25 years; 26–29 years; and 31–34 years. Neuroactive amino acids and markers for monoamine transmitters were analyzed only in the youngest (4–6 years) and oldest (31–34 years) animals. Across the five age groups studied, ChAT activity as well as somatostatin and neuropeptide Y immunoreactivities were significantly decreased bilaterally in occipital poles of the 31- to 34-year-old group. There were no significant age-related differences in substance P immunoreactivity. In 4–6-year-old vs. 31–34-year-old monkeys, levels of amino acid neurotransmitters were unchanged. However, there were significant reductions in norepinephrine, serotonin and its metabolites, kynurenine, and 4-hydroxyphenyllactic acid in occipital poles of the 31- to 34-year-old monkeys. No significant neurochemical changes were detected in the cingulate cortex. These findings demonstrate that aged nonhuman primates show reductions in cortical markers for a variety of neurotransmitters, including acetylcholine, somatostatin, neuropeptide Y, norepinephrine, and serotonin but that these changes do not occur uniformly in the neocortex.

BIOCHEMICAL ASSESSMENT OF PREOPERATIVE STRESS: A STUDY WITH DIAZEPAM AND MEASUREMENT OF MONOAMINE METABOLITES AND CATECHOLAMINES IN CEREBROSPINAL FLUID AND PLASMA

Diazepam 5 mg or an inert placebo tablet was given as preoperative hypnotic on the night before operation to two groups (n = 18 in each) of healthy women having elective Caesarean section under spinal analgesia. A third group (n = 18) received no hypnotic. The quality of the preoperative night's sleep assessed subjectively was significantly better in the diazepam-treated patients compared with those receiving no drug. The diazepam-treated patients had also smaller CSF concentrations of noradrenaline (NA) and of the dopamine metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC). In comparison with the two other patient groups, in the diazepam group there was no correlation between demographic, physiological or subjectively estimated variables and CSF or plasma measurements of monoamine transmitters and their metabolites. Preoperative fear and apprehension correlated most strongly with preoperative heart rate and with the increase in heart rate from the previous day. The monoamine neurotransmitters or their metabolites were of limited use in monitoring the intensity of preoperative fear and anxiety.

Aspects Cliniques et Neurobiologiques de L'Administration à Long Terme des Psychotropes*

In neuroleptic therapy for psychotic illnesses, clinical improvement occurs much later than central dopamine blockade, and its time course varies widely among patients. A hypothesis explaining neuroleptic-responsive illness cannot be explained by dopamine blockade alone. Nevertheless, experimental data suggest that this mechanism may be a step in the therapeutic process for schizophrenia. Explanations are suggested for the time lag in therapeutic response for neuroleptics, including the hypothesis of delayed inactivation of mid-brain dopamine neurones. Chronic benzodiazepine treatment elicits adaptive responses in the CNS that are manifested as functional tolerance and physical dependence. Possible mechanisms involved in such a profound alteration of neuronal functioning are suggested. Down regulation of benzodiazepine receptors has been shown to be related to functional tolerance under certain conditions. The effect of repeated treatment with antidepressants is compatible with the hypothesis that changes in central monoamine transmission are involved in the activity of these drugs. Beta-adrenergic receptors are desensitized and their density is decreased; alpha-2 adrenoreceptors sensitivity is reduced, and post-synaptic serotoninergic receptors sensitivity is increased. It remains to be clarified whether some of the changes have larger role than others or whether they all contribute to the psychotropic drug activity in the therapeutic process.

Hypothalamic-pituitary-adrenal axis and monoamine transmitter activity in depression: A pilot study of central and peripheral effects of electroconvulsive therapy

Central and peripheral measures of hypothalamic-pituitary-adrenal (HPA) axis and monoamine neurotransmitter activity were assessed in 8 depressed patients during a medication-free period and again after completion of a course of electroconvulsive therapy (ECT). Seven patients responded fully to ECT. At baseline there was corresponding activation of the HPA and noradrenergic systems, with apparent elevation in cerebrospinal fluid (CSF) concentrations of corticotropin-releasing hormone (CRH) in some patients. Neither CRH nor adrenocorticotropin (ACTH) in CSF changed significantly after ECT, with a mean 10% decline in CSF CRH. Urinary free cortisol (UFC) excretion was high both before and after treatment. Although peripheral noradrenergic hyperractivity at baseline appeared to normalize with ECT, CSF concentrations of the principal norepinephrine metabolite, 3-methoxy-4-hydroxyphenyl-glycol (MHPG) were unaffected and remained correlated with CSF CRH. In contrast, there increases in the CSF levels of the main metabolite of serotonin in half the patients.

覚醒剤後遺症の慢性化に関する神経化学的検討

覚醒剤後遺症の慢性化に関する神経化学的検討

Central monoamine metabolism in the male brown-Norway rat in relation to aging and testosterone

Concentrations of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), noradrenaline (NA). free 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were determined in brain regions of 5-, 20-, and 32-month-old male Brown-Norway rats using high pressure liquid chromatography. In view of the activating effects of sex steroids on peptide and monoamine transmitter systems and the declining plasma testosterone levels with aging, the effects of testosterone supplementation on age-related changes in central monoamine metabolism were also studied. Age-related decreases in monoamine metabolism were observed in nigrostriatal, mesocortical and coeruleohippocampal systems. Marked reductions in DOPAC (35%) and HVA (50%) occurred in the ventral tegmental area between 20 and 32 months of age. 5-HT and 5-HIAA levels showed reductions and increases depending on the brain region. Testosterone administration resulted in elevations of HVA in the substantia nigra and MHPG in the locus coeruleus and hippocampus, which were most pronounced in young animals. It is concluded that there are marked differences in age-related changes between nigrostriatal, mesocortical and coeruleohippocampal systems and that testosterone exerts a stimulatory influence on some aspects of monoamine metabolism in young but not in aged animals.

Widespread alterations in central noradrenaline, dopamine, and serotonin systems in the Brattleboro rat not related to the local absence of vasopressin

A comprehensive study of monoamine transmitter and metabolite concentrations measured by HPLC was undertaken in female (vasopressin-deficient) Brattleboro rats as compared to Long Evans rats. Noradrenaline was significantly increased in 8 out of 13 dissected brain regions, whereas concentrations of the metabolite 3-methoxy-4-hydroxyphenylglycol were not altered. The increases were not restricted to areas which are normally innervated by vasopressin-containing neurons. Serotonin was increased in 6 and dopamine in 4 regions and this was accompanied in some areas by increases in the metabolites 5-hydroxyindolacetic acid and dihydroxyphenylacetic acid. Only in the striatum, cerebellum, and the medulla-pons no changes could be detected in any of the compounds of interest. These results show that the long term absence of vasopressin in Brattleboro rats appears to be associated with increases in monoamine transmitter contents and decreased metabolite/transmitter ratios. The regional distribution of these changes does not bear any relationship to the regional distribution of vasopressin cell bodies or nerve endings.

Facilitatory and inhibitory transmitters modulate spontaneous transmitter release at cultured Aplysia sensorimotor synapses.

1. The monoamine transmitter 5-hydroxytryptamine (5-HT) and the peptide Phe-Met-Arg-Phe-amide (FMRFa), which appear to contribute to presynaptic facilitation and inhibition of the sensorimotor synapse in the abdominal ganglion of Aplysia, can modulate the frequency of spontaneous transmitter release at synapses formed between dissociated Aplysia sensory neurones and motoneurones in vitro. 2. 5-HT caused a decrease in the mean time interval between consecutive miniature EPSPs (mEPSPs), while FMRFa, applied either by itself or together with 5-HT, caused an increase in the mean time interval between consecutive mEPSPs. 3. Depolarization of the presynaptic neurone caused a decrease in the mean time interval between consecutive mEPSPs. This modulation required external Ca2+. 4. 5-HT and FMRFa were able to modulate spontaneous release when applied in saline solutions lacking Ca2+ and containing Ca2(+)-chelating agents, suggesting that the modulation of spontaneous release by 5-HT and FMRFa did not require a Ca2+ influx. Similarly, spontaneous release could still be modulated by 5-HT and FMRFa in saline solutions containing 1 mM-Cd2+, which blocked both the voltage-gated Ca2+ channels and the evoked transmitter release. 5. To prevent a rise in intracellular Ca2+, we buffered the concentration of Ca2+ in the presynaptic terminals by injecting into the sensory neurone the Ca2+ chelator 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA). The injection of BAPTA blocked evoked transmitter release, suggesting that it acted as an effective buffer of Ca2+ in the terminals. However, spontaneous release could still be observed and was still modulated by 5-HT and FMRFa. This suggests that the modulation of spontaneous release does not require an elevation of intracellular Ca2+. 6. We propose that 5-HT and FMRFa can modulate the rate of spontaneous release directly by mechanisms that do not require changes in the intracellular concentration of Ca2+. These mechanisms might contribute an additional component to the presynaptic inhibition and facilitation of evoked transmitter release.

Interleukin-1 β and muramyl dipeptide can prevent decreased antibody response associated with sleep deprivation

A single, brief (8 h) period of sleep deprivation (DEP) was found to suppress secondary antibody response to sheep red blood cells in rats. This decrease could be totally prevented if either interleukin-1 β (IL-1) or muramyl dipeptide (MDP) was administered at the beginning of the DEP vigil. Twenty-five units of IL-1 or 250 μg/kg MDP was found to be immunosuppressive in sleeping rats but, paradoxically, the combination of such doses with DEP alleviated this effect. Increased colonic temperatures associated with antigen and/or adjuvant administration were not related to the differences in antibody levels between sleeping and DEP animals. Activation of hypothalamic dopamine in IL-1-treated rats following DEP suggests that this monoamine transmitter system may participate in the observed protective activity of IL-1. The present findings extend the immune adjuvant effects of both IL-1 and MDP to protection of the host against behaviorally induced immunosuppression.

Studies of dioxole ring substituted 3,4-methylenedioxyamphetamine (MDA) analogues.

The 3,4-ethylidenedioxy and 3,4-isopropylidenedioxy analogues, EDA and IDA, respectively, of 3, 4-methylenedioxyamphetamine (MDA) were compared to MDA in drug-stimulated [3H]-serotonin overflow from prelabelled rat hippocampal slices, [3H]-dopamine overflow from prelabelled rat caudate slices, in their ability to displace the 5-HT2 agonist R-[125I]-DOI from rat brain cortical binding sites. They were also compared in the two-lever drug discrimination assay in rats, utilizing d-LSD tartrate (0.08 mg/kg) or MDMA.HCl (1.75 mg/kg) as the training stimulus. MDA and EDA were nearly equipotent in inducing release of both [3H]-monoamine transmitters, while IDA was considerably less potent. Pretreatment of hippocampal slices with the 5-HT-uptake inhibitor fluoxetine (3.2 microM) blocked the [3H]-5-HT overflow induced by MDA. In the drug discrimination experiments, complete substitution occurred with all three drugs in both LSD- and MDMA-trained rats. The ED50 values indicated that MDA had about twice the potency of EDA, and five times the potency of IDA in MDMA-trained rats. In the LSD-trained animals, MDA was about three times more potent than EDA and about seven times more potent than IDA. The KI values for displacement of R-[125I]-DOI generally parallel the results of the LSD transfer tests.