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PubMed1996

Pharmacology of cloned human 5-HT1D receptor-mediated functional responses in stably transfected rat C6-glial cell lines: further evidence differentiating human 5-HT1D and 5-HT1B receptors.

This study was undertaken to investigate the pharmacology of human serotonin (5-HT)1D receptor sites by measuring two functional cellular responses, inhibition of forskolin-stimulated cAMP formation and promotion of cell growth, using transfected rat C6-glial cell lines and a broad series of 5-HT receptor agonists. Stable and separate transfection of a pcDNA3 or pRcRSV plasmid, each containing a cloned human 5-HT1D receptor gene, in rat C6-glial cells was confirmed with RT-PCR of 5-HT1D receptor mRNA and radioligand binding with [3H] 5-carboxamidotryptamine (5-CT) and [3H] sumatriptan. The 5-HT1D receptor density was 350 and 1050 fmol/mg protein for the C6-glial/pcDNA3/5-HT1D and C6-glial/pRcRSV/5-HT1D cell line, and forskolin (100 microM)-induced cAMP formation was inhibited by 45 and 78% in the presence of 1 microM 5-HT, respectively. A comparison of the intrinsic agonist activities for sixteen 5-HT receptor ligands with their corresponding binding affinities for the human 5-HT1D receptor site showed similar results for both cell lines with the exception of the partial agonist m-trifluoro-phenyl-piperazine (TFMPP). Three classes of compounds were observed: 1) efficacious agonists, such as 5-CT, 5-methoxytryptamine, 5-HT, sumatriptan, bufotenine, 5-methoxy-3(1,2,3,6-tetrahydro-4-pyridinyl)1H-indole (RU 24,969), tryptamine and 8-hydroxy-2(di-n-propilamino)tetralin (8-OH-DPAT), with agonist potency close to their binding affinity; 2) the partial agonists metergoline, 7-trifluoromethyl-4(4-methyl-1-piperazinyl)-pyrolo-(1,2-a) quinoxaline (CGS 12066B), 1-naphthylpiperazine and 2'-methyl-4-(5-methyl-[1,2,4]oxadiazol-3-yl)-biphenyl-4-carboxylic acid [4-methoxy-3-(4-methylpiperazin-1-yl)-phenyl]-amide (GR 127,935) with marked intrinsic agonist activity but at concentrations higher than their binding affinity; and 3) the silent antagonists ritanserin, ketanserin and methiothepin, apparently free of intrinsic agonist activity, with antagonist potency close to their binding affinity. The cAMP data were further supported by the observed promotion of cell growth by stimulation of both transfected cell lines with sumatriptan under serum-free conditions; half-maximal stimulation was obtained at 4.4 nM (C6-glial/pcDNA3/5-HT1D) fully in agreement with its EC50-value (5.7 nM) for inhibition of cAMP formation. This growth promoting effect was antagonised by 1 microM methiothepin and not observed in pcDNA3-plasmid-transfected and non-transfected C6-glial cells. A comparative study with a C6-glial/pcDNA3/5-HT1B cell line expressing a similar amount of cloned human 5-HT1B receptors (Bmax: 360 fmol/mg protein) showed almost no intrinsic agonist activity for metergoline, 1-naphtylpiperazine and GR 127,935. Together with the 5-HT1D receptor binding selectivity and antagonist activity of ketanserin and ritanserin, the findings define important pharmacological differences between cloned human 5-HT1D and 5-HT1B receptor sites.

Animals↗
PubMed1988

Effect of chronic deuterated and non-deuterated phenelzine on rat brain monoamines and monoamine oxidase.

The effects of phenelzine and 1,1-dideuterophenelzine (0.5 or 2.5 mg/kg/day) administered s.c. via miniosmotic pumps for 13 days were compared. Striatal levels of p-tryrosine and tryptophan were unaffected by either treatment. The concentrations of DOPAC, HVA and 5-HIAA were dose-dependently decreased by phenelzine and deuterated phenelzine; furthermore, the deuterated compound decreased the amounts of these acids more than the same dose of phenelzine. Dopamine levels were increased by a rather small amount by all drug treatments; no effects of drug dose or drug type (deuterated or nondeuterated) were observed. With the exception of phenylethylamine, qualitatively similar effects were found with all other amines measured; their amounts were increased dose-dependently and the effects of deuterated phenelzine were greater than those of phenelzine. Rat cerebral MAO activity was inhibited dose-dependently by phenelzine and by deuterated phenelzine. Type A MAO was inhibited more than type B, and deuterated phenelzine inhibited both types more than did phenelzine. The present study shows that the efficacy of phenelzine was increased about 5-fold by deuteration, that deuterated phenelzine increased tryptamine, m-tyramine and p-tyramine levels much more than it did the other monoamines, that phenylethylamine levels were least affected by the drug treatments, and that deuterated phenelzine inhibited MAO more than did phenelzine.

Animals↗
PubMed1990

Inhibition of noradrenaline release from the sympathetic nerves of the human saphenous vein via presynaptic 5-HT receptors similar to the 5-HT 1D subtype.

The human saphenous vein preincubated with [3H]noradrenaline was used to determine the pharmacological properties of the release-inhibiting presynaptic serotonin (5-HT) receptor on the sympathetic nerves. The overflow of tritium evoked by transmural electrical stimulation (2 Hz) was concentration-dependently inhibited by drugs known to stimulate 5-HT receptors in the following rank order: oxymetazoline greater than or equal to 5-HT greater than 5-carboxamidotryptamine = 5-methoxytryptamine = sumatriptan greater than tryptamine greater than N,N(CH3)2-5-HT = yohimbine = 8-hydroxy-2-(di-n-propylamino)-tetraline. The potencies of these agonists in inhibiting overflow were significantly correlated with their affinities for 5-HT1B and 5-HT1D binding sites, but not with those for 5-HT1A or 5-HT1C binding sites. 5-Aminotryptamine, methysergide, ipsapirone, cyanopindolol, SDZ 21009 and metergoline dit not produce a significant inhibition. Metitepine and methysergide antagonized the inhibitory effect of 5-HT, whereas spiroxatrine, propranolol, ketanserin and ICS 205-930 did not. These data exclude the idea that the inhibitory presynaptic 5-HT receptor on the sympathetic nerves belongs to the 5-HT2 and 5-HT3 receptor class; the pattern of agonist potencies suggests that the receptor is very similar to the 5-HT1D receptor subtype.

Adult↗
PubMed1987

Interaction between 5-HT uptake inhibition and activation of 5-HT autoreceptors by exogenous agonists in rat cerebral cortex slices and synaptosomes.

Rat cerebral cortex slices or synaptosomes were labelled with 3H-5-hydroxytryptamine (3H-5-HT) and subsequently superfused. They were depolarized by electrical stimulation (slices) or with high K+ (slices and synaptosomes). Continuous electrical stimulation (2 Hz, 24 mA, 2 ms) and continuous or discontinuous K+ depolarization (15-25 mM) were used. 1. Continuous electrical stimulation or continuous K+-depolarization of slices evoked a steady overflow of tritium that slowly decayed with time. 2. Exposure to increasing concentrations of 5-methoxy-3(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole succinate (RU 24969) (0.001-0.1 microM) during continuous electrical stimulation produced a concentration-dependent decrease in tritium overflow. Citalopram (1 microM) counteracted the effect of RU 24969. 3. RU 24969 inhibited the evoked 3H-overflow and citalopram reduced the effect of RU 24969 also during continuous depolarization of slices with 20 mM K+. Similar results were obtained by using 5-methoxytryptamine or LSD. 4. In slices 1 microM citalopram increased significantly the tritium overflow evoked by electrical stimulation or by 20 mM K+-depolarization. 5. Increasing the K+ concentration from 20 mM to 25 mM mimicked the effects of 1 microM citalopram both on the RU 24969 activity and on the evoked tritium overflow. 6. RU 24969 (0.001-0.1 microM) decreased in a concentration-dependent way the release of tritium from cortical synaptosomes depolarized with K+ (15-20 mM). The presence of 1 microM citalopram did not modify significantly the effect of the agonist. Citalopram was ineffective also when the serotonin uptake carrier in superfused synaptosomes was activated by tryptamine.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

"5-HT1R" or 5-HT1D sites? Evidence for 5-HT1D binding sites in rabbit brain.

Radioligand binding studies were performed in membranes of rabbit whole brain and striatum using the novel iodinated radioligand for 5-hydroxytryptamine 5-HT1B and 5-HT1D sites, Serotonin-5-O-Carboxymethyl-Glycyl[125I]Tyrosinamide ([125I]GTI). [125I]GTI labelled a finite number of high affinity sites in rabbit brain membranes, Bmax = 191 +/- 47 fmol/mg protein, pKD (-log mol/l) = 8.50 +/- 0.13, n = 5. The pharmacological profile of [125I]GTI binding was fully comparable to that reported previously in human and other brain preparations known to possess 5-HT1D sites (using either [3H]5-HT or [125I]GTI) and displayed a characteristic rank order of affinity: 5-carboxamido-tryptamine greater than 5-HT = dihydroergotamine greater than or equal to ergotamine greater than or equal to sumatriptan greater than or equal to CGS 12066 greater than or equal to metergoline greater than yohimbine greater than or equal to methysergide greater than ICYP greater than 8-OH-DPAT greater than or equal to CP 93129 greater than (-)pindolol greater than ketanserin greater than isamoltane greater than mesulergine greater than corynanthine greater than buspirone greater than MDL 72222. Autoradiographic studies were performed on rabbit brain slices using [3H]5-HT in the presence of 100 nmol/l 8-OH-DPAT and mesulergine (in order to mask 5-HT1A and 5-HT1C binding sites) and [125I]CYP (iodocyanopindolol) in the presence of 3 mumol/l isoprenaline and 100 nmol/l 8-OH-DPAT (in order to mask beta adrenoceptor and 5-HT1A binding sites). There was no detectable specific binding of [125I]CYP through the brain, thus excluding the presence of 5-HT1B sites in rabbit brain.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Urinary excretion of the enantiomers of 1-methyl-1,2,3,4-tetrahydro-beta-carboline in unequal abundance implies enzymatic metabolism in man.

1-Methyl-1,2,3,4-tetrahydro-beta-carboline, a condensation product of tryptamine and acetaldehyde, is one of the neuropharmacologically active alkaloids in mammals. Its enantiomers excreted in human urine were independently analyzed by gas chromatography-negative ion chemical ionization mass spectrometry. Mass fragmentograms of the racemic 1-methyl-1,2,3,4-tetrahydro-beta-carboline offered two peaks with (S)-(-)- and (R)-(+)-configurations which were eluted in this retention order. When the racemic tetradeuterated 1-methyl-1,2,3,4-tetrahydro-beta-carboline was orally administered to a human subject, the urinary tetradeuterated enantiomers were found to be of unequal abundance. The deuterated (R)-(+)-1-methyl-1,2,3,4-tetrahydro-beta-carboline was predominantly excreted in human urine about 3-times over the deuterated (S)-(-)-one. The stereoselective difference in the urinary excretion of 1-methyl-1,2,3,4-tetrahydro-beta-carboline administered exogenously implies that it is enzymatically metabolized, but not that its biosynthesis is associated with an enzymatic reaction.

Administration, Oral↗
PubMed1996

Serotonin-induced changes in the excitability of cultured antennal-lobe neurons of the sphinx moth Manduca sexta.

The modulatory actions of 5-hydroxy-tryptamine (5HT or serotonin) on a morphologically identifiable class of neurons dissociated from antennal lobes of Manduca sexta at stages 9-15 of the 18 stages of metamorphic adult development were examined in vitro with whole-cell patch-clamp recording techniques. Action potentials could be elicited from approximately 20% of the cells. These cells were used to examine effects of 5HT (5 x 10(-6) to 5 x 10(-4) M) on cell excitability and action-potential waveform. 5HT increased the number of spikes elicited by a constant depolarizing current pulse and reduced the latency of responses. 5HT also led to broadening of action potentials in these neurons and increased cell input resistance. Modulation of potassium channels by 5HT is likely to contribute to these responses. 5HT causes reversible reduction of at least 3 distinct potassium currents, one of which is described for the first time in this study. Because effects of 5HT on antennal-lobe neurons in culture mimic those observed in situ in the brain of the adult moth, in vitro analysis should contribute to elucidation of the cellular mechanisms that underlie the modulatory effects of 5HT on central olfactory neurons in the moth.

Action Potentials↗
PubMed1994

Modulation of swimming in Tritonia: excitatory and inhibitory effects of serotonin.

1. In the mollusc Tritonia escape swimming is produced by a network of central pattern generator (CPG) neurons. The purpose of this study was to determine which neurotransmitters might be involved in the swim system. 2. Injection of serotonin (5HT) into whole animals elicited swimming followed by a long-lasting inhibition of swimming. In isolated brain preparations, bath-applied 5HT elicited a swim pattern at short latency and also caused a long-lasting inhibition of the swim pattern. The activation of swimming by 5HT was associated with a tonic depolarization of cerebral cell 2 (C2) and the dorsal swim interneurons (DSI) which form part of the swim CPG network. 3. In isolated brain preparations, bath applied glycine, histamine, proctolin, and FMFRamide had no effect on the swim motor pattern elicited by electrical stimulation of a peripheral nerve. Aspartate, carbacol, dopamine, glutamate, octopamine, pilocarpine, and small cardioactive peptide-B (SCPB) inhibited the activation of swimming by nerve stimulation. 4. The 5HT antagonists cyproheptidine, tryptamine, and 7-methyltryptamine had no effect on swimming, but methysergide and fenfluramine inhibited swimming to both normal sensory stimuli and exogenously applied 5HT. 5. Staining with a polyclonal antibody indicated that one class of CPG neurons, the dorsal swim interneurons (DSI), was immunoreactive for 5HT.

Animals↗
PubMed1989

Chlorpromazine-induced alterations in hypothalamic amine metabolism and stress responses in severe cold.

To investigate the effects on the central nervous system of severe cold stress with and without chlorpromazine, guinea pigs were treated with chlorpromazine or 0.9% NaCl and exposed to -20 degrees C or +23 degrees C for 1 h. Hypothalamic noradrenaline (NA), dopamine (DA), 5-hydroxy-tryptamine (5-HT), 3-methoxy-4-hydroxyphenyl ethylene glycol (MHPG), homovanillinic acid (HVA) and 5-hydroxy-indoleacetic acid (5-HIAA) were determined by high-performance liquid chromatography. Serum, urinary and vitreous fluid catecholamines, muscle and liver glycogen, and blood glucose were also measured. Chlorpromazine caused distinct hypothermia at -20 degrees C and slight hypothermia at +23 degrees C. The rise in hypothalamic MHPG, 5-HIAA and MHPG/NA and in 5-HIAA/5-HT ratios in the cold indicate increased noradrenergic and serotonergic activity. The latter was inhibited by chlorpromazine and a drug-induced inhibition of noradrenergic neurons could not be ruled out. Chlorpromazine increased the turnover of DA at room temperature and the same tendency was seen in the cold. The hypothermic animals had low serum catecholamines, indicating diminished sympathetic activity. The chlorpromazine-treated cold-exposed animals did not react to the environmental stress by sympathetic activation, as urinary NA and adrenaline were not elevated, but DA was excreted by all the drug-treated animals. Vitreous fluid NA and DA were elevated as an indicator of cold stress, and no drug effect was seen in this fluid.

Animals↗
PubMed1991

Coincidence of "ladder-like patterns" in distributions of monoaminergic terminals and sympathetic preganglionic neurons in the rat spinal cord.

A ladder-like pattern of distribution of sympathetic preganglionic neurons (SPNs) was compared with that of monoaminergic terminals in the upper thoracic spinal cord of the rat. SPNs were identified by a retrograde labeling with cholera toxin subunit B (CTb) injected into the superior cervical ganglia of both sides. Monoaminergic terminals were stained immunohistochemically by using antisera raised against 5-hydroxy-tryptamine (5-HT) or dopamine-beta-hydroxylase (DBH). SPNs showing full dendritic arbors were found in all of the sympathetic preganglionic nuclei. They formed a ladder in the horizontal plane. The nucleus intermediolateralis was connected with the central autonomic nucleus by many transverse dendritic bundles. Photomontages of serial sections of material stained alternatively with antisera against CTb and 5-HT or DBH clearly showed a close correlation between SPNs and monoaminergic terminals. There is no transverse dendritic bundle of SPNs without the accompaniment of monoaminergic terminals.

Animals↗
PubMed1995

The paracellular channel for water secretion in the upper segment of the Malpighian tubule of Rhodnius prolixus.

Lumen to bath J12/C1 and bath to lumen J21/C2 fluxes per unit concentration of 19 probes with diameters (dm) ranging from 3.0-30.0 A (water, urea, erythritol, mannitol, sucrose, raffinose and 13 dextrans with dm 9.1-30.0 A) were measured during volume secretion (Jv) in the upper segment of the Malpighian Tubule of Rhodnius by perfusing lumen and bath with 14C or 3H-labeled probes. Jnet = (J12/C1-J21/C2) was studied as a function of Jv.Jv was varied by using different concentrations of 5-hydroxy tryptamine. Jnet for 3H-water was not different from Jv. We found: (i) A strong correlation between Jnet and Jv for 8 probes dm = 3.0-11.8 A (group a probes), indicating that the convective component of Jnet is more important than its diffusive component and than unstirred layers effects which are negligible. Therefore group a probes are solvent dragged as they cross the epithelium. (ii) There is no correlation between Jnet and Jv for 11 probes with dm = 11.8-30 A (group b). Therefore these probes must cross the epithelium by diffusion and not by solvent drag. (iii) In a plot of Jnet/Jv vs. dm group a probes show a steep linear relation with a slope = -0.111, while for group b probes the slope is -0.002. Thus there is a break between groups a and b in this plot. We tried to fit the data with models for restricted diffusion and convention through cylindrical or parallel slit pathways. We conclude that (i) group a probes are dragged by water through an 11.0 A-wide slit. (ii) Most of Jv must follow an extracellular noncytosolic pathway. (iii) Group b probes must diffuse through a 42 A-wide slit. (iv) A cylindrical pathway does not fit the data.

Animals↗
PubMed1981

Electrical responses of pineal cells to melatonin and putative transmitters. Evidence for circadian changes in sensitivity.

The effects of microelectrophoretically applied melatonin (N-acetyl-5-methoxy-tryptamine), noradrenaline (NOR) or acetylcholine (ACH) on the electrical activity of pineal cells during both the day- and night-time were studied in urethane anesthetised guinea-pigs. A total of 288 cells were tested with melatonin, and in addition with either NOR (120 cells) or ACH (138 cells). Of the 206 cells responding to melatonin application, 139 were excited and 67 inhibited. A total of 85 cells responded to the application of NOR, 45 being excited and 40 inhibited. Responses to ACH application were observed in 75 pineal cells, 49 units being inhibited and 26 excited. It was possible to observe excitation in 18 units following electrical stimulation of the lateral habenular nucleus, and of these cells, nine units were additionally tested with ACH. Application of the cholinergic transmitter caused enhanced activity in eight of these cells, the remaining unit being inhibited. The responses to melatonin and NOR varied significantly depending on whether the cells were tested during the day or night. It is apparent from these studies that (1) melatonin, noradrenaline and acetylcholine can bring about direct changes in the firing frequency of pineals cells, and (2) pineal cells do not respond to these substances in the same way. Furthermore, since melatonin application had no effect when nerve cells in brain regions surrounding the pineal organ were tested, the results suggest that melatonin, either produced in the pineal or reaching the gland in the general circulation may be capable of directly influencing the cells engaged in its own synthesis.

Acetylcholine↗
PubMed1988

Dopamine and serotonin in cat retina: electroretinography and histology.

Anatomical structures of the cat retina were related to functional changes induced by the application of dopaminergic and serotonergic substances. We report on the contribution of dopaminergic and serotonin accumulating retinal neurones to retinal activity as reflected by the electroretinogram. The effect of dopaminergic neurones was investigated by the application of the neurotoxin 6-hydroxy-dopamine (6-OHDA) which is known to destroy dopaminergic neurones, and injections of either serotonin (5-HT) or the analogue 5,6-dihydroxy-tryptamine (5,6-DHT) were used to monitor the effects of indoleamines. In control experiments aminophosphonobutyric acid (APB), an agonist of glutamate transmission, was injected. Conventional immunohistochemical methods identified dopaminergic and serotonin accumulating neurones, and the electrophysiological data obtained from the same animals were related to the anatomical structures influenced by the respective substances. Destruction of dopaminergic amacrine cells by 6-OHDA increased the ERG b-wave amplitude. Accumulation of indoleamines by certain amacrine cells also caused an increase of the ERG b-wave. However, intra-vitreal injection of APB completely blocked the b-wave. The data show that ERG mass responses can be used to monitor transmitter-specific effects on retinal circuitry.

5,6-Dihydroxytryptamine↗
PubMed1996

Conclusive evidence for distinct transporters for 5-hydroxytryptamine and noradrenaline in pulmonary endothelial cells of the rat.

The aims of this study were to obtain conclusive evidence about the roles of a 5-hydroxytryptamine [5-HT] transporter and uptake1 in the dissipation of 5-HT in the lungs of the rat and to compare the properties of the 5-HT transporter in rat lungs with that in other tissues, including brain and platelets. In the first part of the study, the IC50 values of a range of selective inhibitors and substrates of the 5-HT transporter or uptake1 were determined for inhibition of uptake of 5-HT or noradrenaline in intact perfused lungs of rats. Monoamine oxidase was inhibited and, in experiments with noradrenaline, catechol-O-methyltransferase was also inhibited. Initial rates of uptake of 5-HT or noradrenaline were measured in lungs perfused with 2 nmol/l 3H-5-HT or 3H-noradrenaline for 2 min, in the absence or presence of at least three concentrations of paroxetine, citalopram, fluoxetine, 7-methyltryptamine, tryptamine, nisoxetine, imipramine, 5-HT, desipramine, (+)-oxaprotiline, cocaine or tyramine. The results showed that pharmacologically distinct transporters are involved in the uptake of 5-HT and noradrenaline in rat lungs, since there was no significant correlation between the IC50 values for inhibition of 5-HT and noradrenaline uptake in the lungs. However, there were significant correlations between the IC50 values for (a) inhibition of 5-HT uptake in rat lungs and of uptake by the 5-HT transporter in rat brain and (b) inhibition of noradrenaline uptake in rat lungs and of uptake1 in rat phaeochromocytoma PC-12 cells. The results support the conclusion that 5-HT uptake in rat lungs occurs, at least predominantly, by a 5-HT transporter which is very similar to or the same as that in other tissues, such as the brain, and provide further evidence for transport of noradrenaline by uptake1. Further experiments were carried out to determine whether there is any transport of 5-HT by uptake1 or of noradrenaline by the 5-HT transporter in rat lungs. Lungs were perfused with 2 nmol/l 3H-5-HT or 3H-noradrenaline for 2 min in the absence or presence of 1 mumol/l citalopram, desipramine, or citalopram and desipramine. The results showed that there was no evidence of any transport of 5-HT in the lungs by uptake1 or of noradrenaline by the 5-HT transporter, in that desipramine had no effect on 5-HT uptake (in the absence or presence of citalopram) and citalopram had no effect on noradrenaline uptake (in the absence or presence of desipramine). The final series of experiments was carried out to determine whether, at high concentrations of the amine, there is any interaction of 5-HT with uptake1 or of noradrenaline with the 5-HT transporter. Noradrenaline, at a concentration of 10 mumol/l, did not affect 5-HT uptake in lungs perfused with 2 nmol/l 3H-5-HT for 2 min (uptake1 inhibited), but 50 mumol/l 5-HT inhibited noradrenaline uptake by 56% in lungs perfused with 2 nmol/l 3H-noradrenaline for 2 min (5-HT transporter inhibited). These and the above results show that the 5-HT transporter appears to be exclusively responsible for 5-HT uptake in rat lungs, despite the possible interaction of 5-HT at high concentrations with the uptake1 transporter in the cells. On the other hand, noradrenaline is transported exclusively by uptake1 in the lungs, and there is no evidence that it interacts with the 5-HT transporter, even at high concentrations.

Adrenergic Uptake Inhibitors↗
PubMed1994

Nucleotide sequence of the tryptophan decarboxylase gene of Catharanthus roseus and expression of tdc-gusA gene fusions in Nicotiana tabacum.

The enzyme tryptophan decarboxylase (TDC; EC 4.1.1.28) converts tryptophan into tryptamine. In Catharanthus roseus and other plants capable of producing terpenoid indole alkaloids (TIAs) TDC links primary metabolism to the secondary metabolic pathway involved in the biosynthesis of these compounds. The accumulation of tdc mRNA in C. roseus cells is developmentally regulated and transcriptionally influenced by elicitors (induction) and auxins (repression). Here we report that TDC is encoded by a single copy gene in the C. roseus genome. No introns were observed upon isolation and sequencing of this gene. To study gene expression controlled by the tdc promoter, a 2 kb promoter fragment and a number of 5' deleted promoter derivatives were joined in translational fusion to a beta-D-glucuronidase reporter gene (gusA). Expression of the chimaeric constructs was monitored in stably transformed tobacco plants and in transiently transfected tobacco protoplasts. Histochemical and fluorimetric analysis of transgenic plants revealed that 1938 bp of the tdc promoter (with respect to the translational start codon) give rise to GUS activity in roots, stems and leaves. No tissue or cell type specificity was noted. Promoter deletions up to nucleotide -398 directed lower levels of gusA expression but conferred the same pattern of staining for GUS activity as the -1938 construct. Further deletion of the tdc promoter up to nucleotide -232 resulted in drastically reduced GUS activity levels and loss of GUS staining in all parts of the transgenic plants. In contrast to stable transformation, the -232 tdc-gusA construct gave rise to GUS activity levels comparable to those of the -398 construct in an assay system for transient expression in protoplasts.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1981

The role of the serotonergic system in foot shock-induced behavior in mice.

In a foot shock-induced fighting (FSIF) test, serotonergic and antiserotonergic agents were examined. Stimulation of the brain 5-hydroxytryptamine (5-HT) neurons with different serotonergic agents, such as l-tryptophan, 5-hydroxytryptophan, imipramine, fluoxetine, 5-methoxy-tryptamine, quipazine, and fenfluramine, showed the inhibiting role of the 5-HT system in FSIF. At the same time, following the results obtained in FSIF tests and locomotor activity tests, it can be inferred that the 5-HT antagonists used (methysergide, cyproheptadine, metergoline, cinnarizine, and pizotifen) do not act specifically in this model of aggression. P-Chlorophenylalanine effects on mice in FSIF also seem to be partly due to catecholaminolytic action.

Aggression↗
PubMed1978

High-affinity 3H-serotonin binding to caudate: inhibition by hallucinogens and serotoninergic drugs.

The specific binding of 3H-serotonin to calf caudate homogenate was studied. The dissociation constant was 2nM and the number of specific sites was 14fmoles/mg protein. Of many drugs tested, inhibition of specific 3H-serotonin binding occurred almost exclusively with serotonin agonists and antagonists. The concentrations for 50% inhibition of 3H-serotonin binding by serotonergic agonists follow: bufotenin, 6nM; 5-methoxytryptamine, 12 nM; psilocin, 35nM; dimethyltryptamine, 220 nM; and tryptamine, 270 nM. The concentrations for the antagonists were: LSD 9.5 nM; methysergide 16nM and metergoline 25nM.

Animals↗
PubMed1984

Evidence that 5-HT agonist-induced rotational behaviour in the rat is mediated via 5-HT1 receptors.

The rotational behaviour induced by 5-HT agonists has been investigated in rats with lesions of the dorsal raphe' nucleus (DRN). We have previously reported that 5-methyoxy-N,N-dimethyl-tryptamine (5-MeODMT) caused dose-related contralateral rotation in rats with 5,7-dihydroxytryptamine (5,7-DHT) lesions of the DRN. Similar findings are now presented for the 5-HT1 agonists 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and 5-methoxy-3 (1,2,3,6-tetrahydropyridin-4-yl) (1H indole) (RU24969). In this model, in agreement with the behavioural studies, both agonists were shown to have a greater affinity for the 5-HT1 binding site when compared with the 5-HT2 binding site. Antagonist studies using selective 5-HT2 antagonists (ketanserin and pirenperone) at non-sedative doses failed to inhibit this behaviour. In contrast, the classical 5-HT antagonist methysergide caused significant inhibition of the rotational behaviour. These results suggest that 5-HT agonist-induced rotation in the rat is mediated via 5-HT1 receptors, probably located in the substantia nigra.

8-Hydroxy-2-(di-n-propylamino)tetralin↗