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PubMed1987

Effect of tryptamine on the mutagenic activity of 2-amino-3-methylimidazo(4,5-f) quinoline (IQ) and related azaarenes in the Ames test.

The bioactivation of the azaarenes 2-amino-3-methylimidazo(4,5-f) quinoline (IQ), 2-amino-3,4-dimethylimidazo(4,5-f) quinoline (MeIQ) and 2-amino-3,8-dimethylimidazo(4,5-f) quinoxaline (MeIQx) to mutagens by hepatic S9 preparations derived from Aroclor-pretreated Wistar rats was inhibited by tryptamine (2-50 microM). However, with similar preparations derived from Sprague-Dawley rats, bioactivation of IQ and MeIQx was less markedly inhibited by tryptamine while metabolic activation of MeIQ was enhanced. In the absence of cytosol, activation of IQ by microsomal preparations of both rat strains was inhibited by tryptamine. Cytosolic fractions from both rat strains were incapable of activation of IQ per se but increased the mutagenicity of the microsomal metabolite(s). This potentiation of the mutagenic activity by cytosol derived from Wistar rats was also inhibited by tryptamine whereas no significant inhibition was observed with cytosolic preparations from Sprague-Dawley rats. There appear to be two alternative pathways of microsomal metabolism of IQ: a tryptamine-sensitive pathway, probably involving the formation of the N-hydroxymetabolite; and a tryptamine-insensitive pathway producing weakly mutagenic or non-mutagenic metabolites which are activated to a potent mutagen by the cytosol. The tryptamine-insensitive pathway appears to be the major route of activation of the azaarenes in microsomal preparations from Sprague-Dawley rats and the principal activation route for MeIQ in both rat strains.

Animals↗
PubMed2002

Role of 5-HT(2) receptors in the tryptamine-induced 5-HT syndrome in rats.

We distinguished the functions of the different 5-hydroxytryptamine-2 (5-HT(2)) receptor (5-HT(2)R) subtypes in the tryptamine-induced 5-HT syndrome in rats using (1) the 5-HT(2A)R antagonist R93274 (N-[(3-p-fluorophenyl-1-propyl)-4-methyl-4-piperidinyl]-4-amino-5-iodo-2-methoxybenzamide), the 5-HT(2A/C)R antagonist R99647 (2-(dimethylaminomethyl)2,3,3a,8-tetrahydrodibenzo[c,f]isoxazolo[2,3-a]azepine), the 5-HT(2B/C)R antagonist SB-242084 (6-chloro-5-methyl-1-[[2-[(2-methyl-3-pyridyl)oxy]-5-pyridyl]carbamoyl]-indoline), and several 5-HT(2)R antagonists (ketanserin, risperidone, pipamperone and mianserin); and (2) chronic 5-HT(2)R activation by 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM). In contrast to SB-242084, the selective 5-HT(2A)R antagonist R93274 as well as the non-selective 5-HT(2A)R antagonists (R99647, ketanserin, risperidone, pipamperone and mianserin) significantly inhibited tryptamine-induced forepaw treading and tremors, and reversed peripherally mediated cyanosis into hyperaemia; only the 5-HT(2A/C)R antagonists R99647 and mianserin inhibited the tryptamine-induced hunched back. Intermittent DOM administration (intravenously every 48 h for 12 days) did not change the centrally mediated tryptamine-induced forepaw treading, tremors and hunched back at 1, 4 or 7 days after the last DOM pretreatment. The DOM-induced head twitch response, measured immediately after every DOM injection, was not affected. In contrast, peripherally mediated cyanosis was reversed into hyperaemia in 75, 11 and 20% of all pretreated rats at 1, 4 and 7 days, respectively, after the last DOM administration. Taken together, these finding suggest that central 5-HT(2A)Rs mediate tryptamine-induced forepaw treading and tremors, that peripheral 5-HT Rs mediate tryptamine-induced cyanosis, and that 5-HT(2A)Rs mediate tryptamine-induced hunched back. Peripheral 5-HT(2C)Rs are more sensitive to desensitization after intermittent treatment with an agonist than central 5-HT(2A)Rs.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗
PubMed1985

Tryptamine, a substrate for the serotonin transporter in human platelets, modifies the dissociation kinetics of [3H]imipramine binding: possible allosteric interaction.

Tricyclic antidepressants and nontricyclic serotonin (5-hydroxytryptamine) uptake blockers monophasically inhibit [3H]imipramine binding in human platelets. Similarly, serotonin and tryptamine inhibit the binding of [3H]imipramine in the low micromolar range and with a pseudo-Hill coefficient near unity. Dissociation of the [3H]imipramine receptor complex in the presence of uptake inhibitors follows first-order kinetics with a half-life of approximately 60 min. Although serotonin and tryptamine do not decrease [3H]imipramine binding when added under equilibrium conditions, simultaneous addition of serotonin or tryptamine with serotonin uptake inhibitors decreases the rate of ligand-receptor dissociation in a concentration-dependent manner. These data suggest a common site of action for serotonin, which is the substrate of the transporter system, and of tryptamine, its nonhydroxylated analog. This hypothesis is supported by the identification of a high-affinity (Km = 0.55 microM), saturable, and temperature-dependent uptake of [3H]tryptamine in human platelets. Uptake of [3H]tryptamine was inhibited potently by imipramine and nontricyclic serotonin uptake inhibitors with a potency similar to that observed for [3H]serotonin uptake. These data support the hypothesis that in platelets, [3H]imipramine, tricyclic, and nontricyclic serotonin uptake inhibitors bind to a common recognition site that is associated with the serotonin transporter but that differs from the substrate recognition site of the carrier through which serotonin and tryptamine exert a heterotropic allosteric modulation on [3H]imipramine binding.

Allosteric Regulation↗
PubMed1988

[3H]tryptamine binding sites are not identical to monoamine oxidase in rat brain.

Competition binding studies, subcellular distribution, and in vitro autoradiography were employed to compare the binding in rat brain of [3H]tryptamine with two radioligands for monoamine oxidase (MAO), [3H]pargyline, and [3H]1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine ([3H]MPTP). The MAO inhibitors pargyline, clorgyline, and deprenyl all yielded biphasic competition curves versus [3H]tryptamine. At low concentrations, these drugs stimulated binding by protecting the radioligand from MAO oxidation; at considerably higher concentrations, they inhibited binding by direct competition at the [3H]tryptamine binding site. In subcellular distribution studies, [3H]tryptamine was localized preferentially to the synaptosomal fraction, whereas [3H]pargyline showed greater binding to the mitochondrial fraction. Equilibrium binding studies revealed that the potencies of a series of seven compounds at inhibiting [3H]tryptamine binding were completely different from their potencies at inhibiting [3H]MPTP binding. Finally, the autoradiographic distribution of [3H]tryptamine binding in rat brain was different from that of [3H]MPTP and [3H]pargyline. We conclude that the [3H]tryptamine binding site in rat brain is not equivalent to MAO.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1981

Different hypothalamic receptors mediate 5-hydroxytryptamine- and tryptamine-induced core temperature changes in the rat.

1 Unilateral intrahypothalamic injection of 5-hydroxytryptamine (5-HT) caused a dose-related fall in core temperature in rats, whereas injection of tryptamine into the same site caused a dose-related rise in core temperature. 2 The core temperature changes induced by 5-HT or tryptamine were inhibited by intrahypothalamic pretreatment with indoleamine receptor antagonists in a dose-related manner. 3 Other neurotransmitter antagonists, haloperidol, atropine, phentolamine and (-)-propranolol, had no significant effect on core temperature changes induced by 5-HT or tryptamine. 4 A differential antagonism was observed for the indoleamine receptor antagonists against 5-HT and tryptamine-induced core temperature changes. Methergoline and triflupromazine were more selective against tryptamine-induced hyperthermia, while cyproheptadine was more selective against 5-HT-induced hypothermia. 5 Intrahypothalamic pretreatment with 5,-7-dihydroxytryptamine (5,7-DHT) 42 nmol in 2 microliter inhibited tryptamine-induced hyperthermia, but was without effect on 5-HT-induced hypothermia. 6 These results suggest the possible existence of two different receptor populations within the preoptic anterior hypothalamus in rats; one specific for 5-HT and the other for tryptamine.

5,7-Dihydroxytryptamine↗
PubMed1978

Tryptamine-induced drug effects insensitive to serotoninergic antagonists: evidence of specific tryptaminergic receptor stimulation?

The drug effects of tryptamine and 5-hydroxytryptopham (5-HTP) in the rabbit were compared following monoamine oxidase inhibition and various drug pretreatments. Both agents evoked hyperthermia and behavioural excitation; tryptamine but not 5-HTP also produced forepaw clonic activity. Serotoninergic receptor blockers abolished the effects of 5-HTP but only weakly influenced tryptamine responses. Both tryptamine and 5-HTP effects were potentiated by fluoxetine. Methergoline, a putative tryptaminergic receptor blocker, antagonized tryptamine-induced hyperthermia and forepaw clonus but did not influence 5-HTP responses. It is postulated that while 5-HTP produces its effects through a serotoninergic mechanism, some of the responses to tryptamine result from activation of a specific tryptamine-sensitive mechanism.

5-Hydroxytryptophan↗
PubMed1982

The effects of some antipsychotic drugs, D-amphetamine, and reserpine on the concentration and rate of accumulation of tryptamine and 5-hydroxytryptamine in the mouse striatum.

The mouse striatum contains about 2 ng/g of tryptamine and 600 ng/g of 5-hydroxytryptamine. No significant changes in mouse striatal tryptamine were observed after the administration of chlorpromazine, haloperidol, spiperone, or alpha-flupenthixol. The levels of 5-hydroxytryptamine were moderately reduced by chlorpromazine, spiperone, and alpha-flupenthixol but not by haloperidol. The administration of antipsychotic drugs to mice pretreated with a monoamine oxidase inhibitor (pargyline) produced an increase in the rate of accumulation of striatal tryptamine compared with that of pargyline-treated mice. In contrast, the rate of accumulation of 5-hydroxytryptamine after monoamine oxidase inhibition was reduced by chlorpromazine, spiperone, and alpha-flupenthixol but not haloperidol. D-Amphetamine administration did not change either tryptamine or its 5-hydroxyderivative while reserpine increased tryptamine and reduced 5-hydroxytryptamine. The results suggest that changes in striatal tryptamine may be controlled by the availability of tryptophan, the amino acid precursor of tryptamine.

Animals↗
PubMed1983

Butanol extracts from myelin fragments: tryptamine binding to lipid fractions.

To investigate the nature of the tryptamine binding components that originated from myelin butanol extracts (i.e., myelin proteolipids), the lipid mixtures obtained from these extracts were further fractionated by silicic acid column chromatography, and binding assays of 14C-tryptamine to those fractions were carried out by Sephadex LH20 column chromatography. Among several lipid fractions, only the F-C fraction retained the tryptamine binding properties of the original myelin butanol extracts, i.e., binding capacity, chromatographic profile and interaction with indoleamine analogues and other neurotransmitters. Since the quantitative TLC analysis indicated that this fraction contained a considerable amount of phosphatidylserine (PS) and phosphatidylinositol (PI), recombination experiments with these two acidic lipids were planned. The recombination system with PI did not show a tryptamine binding capacity, while the PS fraction possessed a tryptamine binding capacity similar to that of the myelin butanol extracts. However, displacement studies revealed that the recombinant fraction with PS alone did not display the complete regeneration of the specificity which had been observed in the myelin extracts. All these observations infer that the tryptamine binding components from myelin proteolipids are lipid in nature, and its binding entity is mainly PS. However, some specifically organized constitution with PS and other lipid molecule(s) may be necessary to regenerate the original tryptamine binding properties.

Animals↗
PubMed1982

The effect of tryptamine on serotonin release from hypothalamic slices is mediated by a cholinergic interneurone.

Tryptamine produced a concentration-related inhibition of potassium-evoked release of tritium from slices of rat hypothalamus preloaded with 3H-serotonin. This effect of tryptamine was blocked by a series of serotonin antagonists with a relative order of potency which suggested that tryptamine was acting on a post-junctional serotonin receptor. However, the response to tryptamine was also blocked by tetrodotoxin, indicating that tryptamine may be acting indirectly via the release of a second neurotransmitter. The finding that physostigmine enhanced, whilst atropine antagonised the effect of tryptamine suggests that the second neurotransmitter may be acetylcholine. This possibility is discussed.

Animals↗
PubMed1981

Histamine, theophylline and tryptamine transport through lipid bilayer membranes.

Diffusion of histamine, theophylline and tryptamine through planar lipid bilayer membranes was studied as a function of pH. Membranes were made of egg phosphatidylcholine plus cholesterol (1 : 1 mol ratio) in tetradecane. Tracer fluxes and electrical conductances were used to estimate the permeabilities to nonionic and ionic species. Only the nonionic forms crossed the membrane at a significant rate. The membrane permeabilities to the nonionic species were: histamine, 3.5 x 10(-5) cm x s-1; theophylline, 2.9 x 10(-4) cm x s-1; and tryptamine, 1.8 x 10(-1) cm x s-1. Chemical reactions in the unstirred layers are important in the transport of tryptamine and theophylline, but not histamine. For example, as pH decreased from 10.0 to 7.5 the ratio of nonionic (B) to ionic (BH+) tryptamine decreased by 300-fold, but the total tryptamine permeability decreased only 3-fold. The relative insensitivity of the total tryptamine permeability to the ratio, [B]/[BH+], is due to the rapid interconversion of B and BH+ in the instirred layers. Our model describing diffusion and reaction in the unstirred layers can explain some 'anomalous' relationships between pH and weak acid/base transport through lipid bilayer and biological membranes.

Biological Transport↗
PubMed1986

Characterization and quantitative autoradiography of [3H]tryptamine binding sites in rat brain.

[3H]Tryptamine binds with high affinity (Kd = 9.1 nM, Bmax = 54 fmol/mg wet wt.) to tissue sections of rat brain. The binding occurs rapidly and is reversible. Low concentrations of the beta-carbolines harmaline (IC50 = 25 nM) and tetrahydronorharman (tetrahydro-beta-carboline, IC50 = 50 nM) inhibit [3H]tryptamine binding. Serotonin (5-HT, IC50 = 2600 nM) as well as the 5-HT receptor antagonists methysergide and metergoline displace [3H]tryptamine at much higher concentrations from brain slices. The distribution of [3H]tryptamine binding sites in sections of rat brain has been analyzed by quantitative autoradiography. The highest density of binding sites is found in the nucleus (n.) interpeduncularis, a slightly lower one in the locus coeruleus. Moderately labelled are the n. accumbens septi, n. septi lateralis, n. medialis habenulae, n. tractus olfactorii lateralis, the central region of the amygdala, n. caudatus/putamen, n. reuniens and the hippocampal formation. A low density of binding sites is detected in the cerebral cortex and the subiculum. Even less binding sites are found in the n. dorsalis raphe and the substantia nigra. The pattern of distribution of [3H]tryptamine binding sites differs from that of [3H]5-HT (5-HT1), [3H]ketanserin (5-HT2) as well as [3H]imipramine binding sites. These data suggest unique tryptamine binding sites.

Animals↗
PubMed1984

Synergistic behavioral effects of serotonin and tryptamine injected intrathecally in mice.

The endogenous compounds, serotonin (5-HT) and tryptamine (TA), have been found to alter function in the CNS, supporting the hypothesis that they serve as neurotransmitters. It is reported here that intrathecal injections of either 5-HT or tryptamine elicited similar behavioral syndromes consisting of caudally-directed biting, or licking and scratching. Serotonin was found to be considerably more potent than tryptamine. However, administration of both indoleamines produced synergistic interactions with respect to this behavioral syndrome. Administration of fluoxetine with either 5-HT or tryptamine potentiated the scratching behavior produced by either indoleamine, but failed to enhance the effect of an injection of 5-HT plus tryptamine. Administration of methysergide blocked the effects of both indolamines. The results are discussed in terms of a possible mechanism of the synergism between 5-HT and tryptamine.

Animals↗
PubMed1985

Analysis of the cardiovascular responses to central injection of tryptamine in rats.

Tryptamine (2-20 micrograms), administered into the lateral cerebral ventricle of the rat, evoked a pressor response which was sometimes followed by a prolonged depressor response. The intracisternal administration of tryptamine (7-20 micrograms) caused a slow progressive and long-lasting depressor effect without or with an initial pressor effect. The pressor response was accompanied by variable changes in heart rate, whilst the pure depressor response was accompanied by a decrease in heart rate. After transection of the spinal cord between C1 and C2 the pressor response was substantially reduced or abolished. Methysergide, injected centrally, antagonized in a dose-dependent manner the pressor effect, whilst p-chlorophenylalanine, atropine and hexamethonium, administered by the same route, did not diminish this effect. It is concluded that tryptamine, injected centrally, causes both increases and decreases in arterial blood pressure and heart rate. The pressor response to tryptamine results from the activation of central noncholinergic, methysergide-sensitive, receptor sites and the depressor response to tryptamine may be due to a centrally-induced reduction in sympathetic nervous activity. It is tentatively suggested that tryptamine, like 5-hydroxytryptamine, participates in the physiological regulation of the cardiovascular system of the rat, as both a central excitatory and inhibitory regulator.

Animals↗
PubMed1989

Tryptamine impairs the acquisition of a one-way active avoidance task.

The effects of intraperitoneal administration of tryptamine to rats pretreated with iproniazid, on the acquisition of an unsignalled one-way active avoidance task, were examined. Tryptamine at 2.5 and 5 mg/kg significantly increased the number of trials required to perform this task to a 9/10 consecutive avoidances criterion, without affecting escape performance. The iproniazid pretreatment had no affect on acquisition, or any other performance variable, of the task. Tryptamine did not significantly affect the avoidance response, or escape response latencies; further tryptamine did not alter gross locomotor activity measured as photocell counts. These results suggest that the acquisition deficit was not the result of nonassociative effects such as changes in response capability, general activity level or nociception. The acquisition deficit induced by tryptamine may involve a direct stimulation of central 5-HT receptors since it was not induced by systemically administered 5-HT, was reversed by the 5-HT antagonists methysergide and metergoline, but was not affected by depletion of brain 5-HT, with PCPA, or by the dopamine antagonist haloperidol. Possible behavioural mechanisms for the action of tryptamine are discussed.

Animals↗
PubMed1988

Interaction of spin-labeled tryptamine with monoamine oxidase: probing the microenvironment of the active site by spin probe-spin label techniques.

The spin-labeled substrate, tryptamine, was used as a structural probe of the active site of bovine liver monoamine oxidase B (amine:oxygen oxidoreductase (deaminating) (flavin-containing), EC 1.4.3.4). When the reaction was monitored by electron spin resonance (ESR), line broadening effects indicative of binding with an apparent relation to substrate specificity of the highly purified enzyme were observed. The spectrum indicated that the bound tryptamine was 'partially immobilized' with a dissociation constant of 39 microM and 2.2 mol bound per enzyme dimer. The correlation time, reflecting the environment of the tryptamine binding site, was determined to be 6.2 ns. The topology of the active site was investigated by using dual spin-label methodology in which the spin-labeled substrate, tryptamine, and the 15N-substituted and deuterated maleimide spin label covalently bound to the essential sulfhydryl groups were used. The ESR spectral data suggested that the essential sulfhydryl groups are at least 14 A away from the tryptamine-binding site. The environment surrounding both spin-labeled substrates, tryptamine and [2H,15N]MSL, and the motional properties of the enzyme are discussed.

Binding Sites↗
PubMed1982

Tryptamine: a neuromodulator or neurotransmitter in mammalian brain?

Tryptamine synthesized by decarboxylation of L-tryptophan occurs as an endogenous constituent of mammalian brain albeit at very low concentrations (low ng/g range). It is primarily metabolized by oxidative deamination by MAO and possesses an extremely rapid turnover and half-life. Subcellular localization appears to be in nerve terminals and it is releasable by electrical or potassium evoked depolarization. Neuropharmacological and electrophysiological data strongly suggest the existence of post-synaptic receptors for tryptamine independent of those for 5HT. There may exist a rostrally projecting neuronal tryptamine containing system arising from cell bodies in or close to the nucleus raphé medianus. The demonstration of specific receptors for tryptamine in the CNS strongly indicates a transmitter role, although a strong case can be made for a role as a modifier of central 5HT systems. The possibility also exists that 5HT and tryptamine may be mediators of functionally opposite neuronal pathways. Whatever the role of tryptamine in the CNS it is clear that it not simply present as an accident of metabolism or a "biological artefact." The indications are that it possesses important functions in central neurotransmission.

Animals↗
PubMed1984

The possible site of action of 5-hydroxytryptamine, 6-hydroxytryptamine, tryptamine and dopamine on identified neurons in the central nervous system of the snail, Helix aspersa.

Intracellular recordings were made from identified neurons in the right parietal ganglion of the snail, Helix aspersa. Cells F 4, 5 and 6 were excited by 5-hydroxytryptamine (5-HT) and inhibited by dopamine while cells in the F 30 area were inhibited by both compounds. Low doses of both tryptamine and 6-HT produced weak excitation of cells F 4, 5 and 6 while higher doses of both compounds inhibit the activity of these cells. In terms of the inhibitory responses, tryptamine and 6-HT are approximately equipotent but between 10 and 100 times less potent than dopamine. d-Tubocurarine reversibly antagonized the excitatory action of 5-HT on cells F 4, 5 and 6 and converted tryptamine and 6-HT excitation to inhibition. In the presence of the antagonist, ergometrine, the dopamine inhibitory response was almost completely abolished while the inhibitory responses to tryptamine and 6-HT were converted to weak excitation. All four agonists inhibited cells in the F 30 area with the following potency ratios: dopamine much greater than tryptamine/6-HT greater than 5-HT. Tubocurarine had no antagonist effects on these responses while ergometrine reduced or blocked all four, often irreversibly. In potassium-free Ringer the inhibitory responses to all four agonists were enhanced. It is concluded that on cells F 4, 5 and 6, low concentrations of tryptamine and 6-HT act on 5-HT receptors while higher concentrations of both agonists act on dopamine receptors. On cells in the F 30 area, 5-HT, 6-HT and tryptamine all act on a dopamine receptor.

Animals↗
PubMed1961

Effects on amine oxidase of substances which antagonize 5-hydroxytryptamine more than tryptamine on the rat fundus strip.

Certain substances, 2-bromolysergic acid diethylamide, dimethyltryptamine (3-(2-dimethylaminoethyl)indole), 2-methyldimethyltryptamine (3-(2-dimethylaminoethyl)-2-methylindole), and 5-benzyloxydimethyltryptamine (5-benzyloxy-3-(2-dimethylaminoethyl)indole), antagonize the effects of 5-hydroxytryptamine on the rat fundus strip more than those of tryptamine. These substances have been tested for their ability to inhibit the oxidation of tryptamine and 5-hydroxytryptamine by suspensions of guinea-pig liver and rat fundus. 2-Bromolysergic acid diethylamide has virtually no inhibitory activity and it is doubtful if the others produce any significant inhibition of amine oxidase in the concentrations which antagonize the effects of 5-hydroxytryptamine more than those of tryptamine. It seems that the differential character of the blocking action of these compounds should be ascribed either to interference with the transport of tryptamine (but not 5-hydroxytryptamine) through the cell wall, coupled with the block of a receptor common to both tryptamine and 5-hydroxytryptamine, or to the existence of separate tryptamine and 5-hydroxytryptamine receptors.The amine oxidases of the guinea-pig liver and rat fundus appear to be a mixture of at least two types of enzyme, one of which has a higher affinity for 5-hydroxytryptamine than the other and is more susceptible to inhibition by 2-methyldimethyltryptamine.

Animals↗