Signal transduction in guard cells.
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Abscisic Acid↗
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Renal metabolism of 5-hydroxyindolacetic acid.
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Hydroxyindoleacetic Acid↗
Serotonergic activity is depressed in the ventromedial hypothalamic nucleus of 12-day-old obese Zucker rats.
We previously reported lower ventromedial hypothalamic nucleus (VMN) serotonergic activity in 11-wk genetically obese vs. lean Zucker rats. To determine whether the activity was secondary to metabolic alterations associated with this established obesity (e.g., significant hyperphagia and hyperinsulinemia), we examined monoaminergic activity in various brain nuclei of 12-day lean (Fa/Fa and Fa/fa) and obese (fa/fa) rats early in the development of obesity. Obese pups had greater percent carcass fat than heterozygotes, both of which were fatter than homozygous lean rats. Obese, but not heterozygous lean, pups were hyperinsulinemic vs. Fa/Fa pups. VMN 5-hydroxy-3-indoleacetic acid levels, an index of serotonin release, were lower in obese and heterozygous than in homozygous lean pups and were not correlated with plasma insulin levels. Although monoamine differences also occurred in several other nuclei, for the most part they appeared to be unrelated to the obese genotype. We conclude that blunted VMN serotonergic activity is not secondary to the obese rat's hyperinsulinemia and may play a significant role in the development of obesity.
Adipose Tissue↗
Bromocriptine reduces obesity, glucose intolerance and extracellular monoamine metabolite levels in the ventromedial hypothalamus of Syrian hamsters.
We examined whether reductions in body fat stores and insulin resistance in Syrian hamsters induced by bromocriptine are associated with reductions in daily norepinephrine (NE) and serotonin activities as indicated by their extracellular metabolite levels in the ventromedial hypothalamus (VMH). High levels of these monoamines within the VMH have been suspected to induce obesity and insulin resistance. Microdialysate samples from the VMH of freely moving obese male hamsters (BW: 208 +/- 5 g) were collected hourly over a 25-hour period before bromocriptine treatment, during the first day of and after 2 weeks of bromocriptine treatment (800 microg/animal daily, i.p.), and body composition and glucose tolerance analyses were conducted before and after 2 weeks of treatments. The microdialysate samples were analyzed by HPLC for metabolites of serotonin: 5-hydroxy-indoleacetic acid (5-HIAA), NE: 3-methoxy-4-hydroxy-phenylglycol (MHPG), and dopamine: homovanillic acid (HVA). Bromocriptine treatment for 14 days significantly reduced body fat by 60% and areas under the glucose and insulin curves during a glucose tolerance test by 50 and 46%, respectively. Concurrently, extracellular VMH contents of 5-HIAA, MHPG, and HVA were reduced by 50, 29 and 66%, respectively (p < 0.05). Similarly, VMH 5-HIAA and MHPG contents were 48 and 44% less, respectively (p < 0.05), in naturally glucose-tolerant hamsters compared with naturally glucose-intolerant hamsters. Bromocriptine induced reductions of body fat, and improvements in glucose intolerance may result in part from its ability to decrease serotonin and NE activities in the VMH.
Adipose Tissue↗
Activation of central biogenic amines following aggressive interaction in male lizards, Anolis carolinensis.
Many stimuli, including social aggression, activate endocrine stress mechanisms, presumably mediated or modulated by central neurotransmitters. To determine the effects of aggression on central neurochemistry, reproductively active male Anolis carolinensis were paired and allowed to establish social dominance relationships. While combatants cohabited, the fight losers invariably became socially subordinate and displayed darker color, selection of lower perch sites, and lower body posture than the winners. After one hour, one day, one week, or one month of cohabitation animals were sacrificed. Each member of a pair was killed at approximately the same time, along with animals kept isolated as controls. Diencephalon, non-optic lobe midbrain and hindbrain were analyzed for indoleamines, catecholamines and metabolites by coulochem electrode array HPLC. Early activation (by one hour) of the serotonergic system in subordinate male lizards was indicated by decreased serotonin (5-HT), increased 5-hydroxy-indoleacetic acid (5-HIAA) levels and 5-HIAA/5-HT ratio. Substrate 5-hydroxy-tryptophan (5-HTP) also increased in losing males, suggesting enhanced production as well as turnover. Significant 5-HTP and 5-HIAA/5-HT increases for subordinate males, compared with levels in control and dominant males, were greatest at one hour and diminished thereafter. This pattern of indoleamine system activation is consistent with stress-induced stimulation of the serotonergic system and prolonged activation of the stress response in subordinate animals, as well as serotonergic inhibition of aggression. In contrast with serotonin, subordinate males did not have increased catecholamine system activation following one hour of interaction. The ratio of DOPAC/dopamine was lower following one hour of interaction in subordinate males. Adrenergic system activation, indicated by metanephrine/epinephrine ratio, increased with time in losing males, except that after one month of cohabitation, turnover returned to levels that equaled those of control animals. Noradrenergic metabolite MHPG, as well as MHPG/NE ratio, were significantly reduced in dominant males at one hour and one week. Changes in adrenergic system activation, not seen in or registered by noradrenergic systems, indicate a possible role for central epinephrine in social stress accommodation.
Aggression↗
Preclinical studies on the anti-migraine drug, sumatriptan.
Sumatriptan is believed to constrict selectively the cranial vessels that are distended and inflamed during migraine. The action is mediated by activation of a 5-HT1 receptor subtype which has been shown in animals to be localized in cranial vessels. Further studies to elaborate sumatriptan's precise clinical mode of action have focused on the human meningeal circulation and should lead to a better understanding of the pathogenesis of migraine. Administering [14C]sumatriptan, drug-related material was shown to be well absorbed. Following absorption there was some first-pass metabolism resulting in oral bioavailabilities of 37, 58 and 23% in rat, dog and rabbit, respectively. In all species, circulating sumatriptan was cleared rapidly by metabolic and renal clearance with a half-life of 1-2 h. The indoleacetic acid metabolite is the primary metabolic product; however, rats, mice and rabbits also N-demethylate the methylaminosulphonylmethyl side-chain. The passage of sumatriptan and its metabolites across the blood-brain barrier appeared to be very limited, although some drug could be detected in the cerebrospinal fluid after administration of high intravenous doses. Safety studies in various animal species showed that sumatriptan produced few adverse pharmacodynamic effects when administered acutely, except at high doses, although it was less well tolerated in dogs. No findings of toxicological significance were observed in rats and dogs after chronic dosing for 1 year or more.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
The clinical pharmacology, pharmacokinetics and metabolism of sumatriptan.
Clinical pharmacology studies were undertaken in young healthy volunteers, in a small number of elderly subjects and in migraine subjects during and between attacks. Absorption after subcutaneous and oral administration was rapid. Bioavailability was nearly 100% after subcutaneous administration and averaged 14% after oral administration. Elimination was predominantly by metabolism to a non-active indoleacetic acid analogue. The plasma half-lives of sumatriptan and the metabolite were about 2 h. Pharmacokinetic and pharmacodynamic variables were similar in all groups studied and were not altered by the presence of food, alcohol, dihydroergotamine or prophylactic migraine treatments. Sumatriptan produced a number of minor adverse events, but had no clinically significant effect on routine haematological or biochemical investigations using the intravenous, subcutaneous or oral routes. Transient rises in blood pressure were observed which were no greater than those that would be anticipated during moderate exercise. The physician-administered subcutaneous injection resulted in transient stinging at the site of injection in many subjects; administration using the auto-injector was better tolerated.
Aged↗
Diurnal rhythms of plasma cortisol, beta-endorphin and prolactin, and cerebrospinal fluid amine metabolite levels before suicide. Case report.
There are indications to suggest a relationship between low levels of 5-hydroxy-indoleacetic acid (5HIAA) in the cerebrospinal fluid and suicidal behavior. Many depressed patients show an elevated cortisol secretion. As beta-endorphin is derived from the same precursor as ACTH, it is expected that plasma beta-endorphin levels will also rise in depressed patients. We report here a case of severe depression with diurnal variation who showed low CSF 5HIAA prior to his suicide. In contrast, his catecholamine metabolites were 50% above the mean values of other depressed patients. Hormonal measurements, however, showed low cortisol, prolactin and beta-endorphin levels.
Catecholamines↗
Effect of serotoninergic system on FSH secretion in male and female rats: evidence for stimulatory and inhibitory actions.
The present experiments were designed to assess the effect of the serotoninergic system on FSH secretion in prepubertal (16-, 18-, 20-, 26- and 30-day-old) and adult (60-day-old) male and female rats. The intraperitoneal administration of 5-hydroxytryptophan (5-HTP), a serotonin (5-HT) precursor, induced a significant increase of FSH levels in male rats at 16, 26, 30 and 60 days of age (p less than 0.01) but not at 18 and 20 days. In the females, no modifications in FSH concentrations in prepubertal and adult rats were observed after 5-HTP injection. These results indicate that there are sexual differences in the effect of the serotoninergic system on FSH secretion. Orchidectomy performed in prepubertal (30-day-old) and adult rats (60 days) besides increasing FSH levels, reversed the response of this hormone to 5-HTP administration, since in castrated rats the 5-HT precursor induced a significant decrease in serum FSH concentrations. The administration of 5-HTP to 30 day-old castrated rats treated with testosterone induced FSH release as it did in control animals of this age. In the adult castrated rats the administration of testosterone abolished the inhibitory effect of 5-HTP observed in castrated rats but did not invoke the stimulatory action of 5-HTP observed in the controls. This difference between prepubertal and adult rats appears to be related to a decrease in the sensitivity to testosterone of the central mechanism which controls FSH secretion. These results indicate that 5-HTP stimulates FSH release in normal rats and inhibits FSH release in castrated rats, testosterone concentration being a relevant factor in determining the 'type' of effect produced. The hypothalamic concentrations of 5-HT and 5-hydroxy-indoleacetic acid (5-HIAA) are significantly higher at the ages at which 5-HTP induces FSH release than at other ages suggesting that hypothalamic turnover of these substances is related is related to the releasing effect of 5-HTP on FSH.
5-Hydroxytryptophan↗
Effect of cocaine and desmethylimipramine on the uptake, retention and metabolism of 3H-5-hydroxytryptamine in rat brain slices.
Uptake and metabolism of 3H-5-dydroxytryptamine (3H-5-HT) in slices of hypothalamus, brain stem caudate nucleus and parietal cortex were examined in vitro. The results indicate that 3H-5-HT taken up by neurons is firmly retained and that there are regional differences in the uptake and retention of 3H-5-HT. For example, the caudate had a significantly greater maximum rate of uptake and binding (Vmax) than the other brain areas tested, particularly the cortex. In contrast the caudate appeared to have the lowest apparent for 3H-5-HT uptake (Km). Uptake and retention of 3H-5-HT by four brain areas were markedly inhibited by cocaine and desmethylimipramine (DMI) in vitro. The inhibitory effect of both drugs was noncompetitive in nature, with exception of thct that cocaine and DMI failed to reduce the formation of 3H-5-hydroxy-indoleacetic acid despite ther potent blocking action of 3H-5-HT uptake suggests that a significant amount of 3H-5-HT is oxidatively deaminated at extraneouronal sites. This extraneuronal metabolism of 5-hydroxytryptamine may play an play an important role in regulating the action of this neurotransmitter.
Animals↗
Lateralized effect of cerebral infarction on spinal fluid monoamine metabolite concentrations in rats.
Using a rat model of stroke, we studied the effect of unilateral middle cerebral artery ligation on cerebrospinal fluid monoamine metabolites at different intervals over a 40-day postoperative period. Male Sprague-Dawley rats were divided into four groups: an unoperated control group (n = 9), a sham-operated group (n = 9), a right middle cerebral artery ligation group (n = 10), and a left middle cerebral artery ligation group (n = 10). One hundred microliters of cerebrospinal fluid were collected percutaneously from the cerebellomedullary cistern just before and 5, 20, and 40 days after the surgical procedure. Monoamine metabolites--3-methoxy-4-hydroxyphenylglycol (MHPG), 5-hydroxy-indoleacetic acid (5-HIAA), and homovanillic acid (HVA)--were measured using high-performance liquid chromatography. MHPG concentration in the right lesion group was significantly depleted from control levels 5, 20, and 40 days after surgery. No such depletion was observed in the left lesion rats. Concentration of 5-HIAA was relatively lower at Days 5 and 20 in the right lesion group than in the left lesion group. HVA concentration did not differ among the groups at any time. Our study has demonstrated a differential effect of unilateral ischemia on cerebrospinal fluid neurochemistry in rats dependent on the cerebral hemisphere involved.
Analysis of Variance↗
Endocrine aspects of argentaffinoma, with special reference to the use of urinary 5-hydroxyindoleacetic acid estimations in diagnosis.
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Carcinoid Tumor↗
The clinical pharmacokinetics of zolmitriptan.
Zolmitriptan (Zomig, formerly 311C90) is a novel, oral, acute treatment for migraine. In healthy volunteers it is rapidly and extensively absorbed and has favorable oral bioavailability (approximately 40%) which is not affected by concomitant food intake. On average, 75% of its eventual Cmax is achieved within 1 h of dosing. Plasma concentrations are sustained for 4 to 6 h after dosing with single or multiple peaks in the plasma concentration-time profile, reflecting continued absorption down the gastrointestinal tract. The pharmacokinetics of zolmitriptan indicate dose proportionality over the dose range of 2.5 to 50 mg and there are no significant changes on multiple dosing. Zolmitriptan is cleared by metabolism followed by urinary excretion of the metabolites. There are three major metabolites, one of which, the N-desmethyl metabolite, is active as a 5HT1D agonist and has mean plasma concentrations approximately two thirds those of the parent compound. The other two metabolites, the N-oxide and indoleacetic acid, are inactive. The elimination half lives of zolmitriptan and its metabolites are similar, approximately 3 h. Zolmitriptan and its active metabolite are minimally protein bound in the plasma (approximately 25%). In migraine patients, plasma concentrations of zolmitriptan and its metabolites are lower during a migraine attack than outside an attack. In summary, the pharmacokinetics of zolmitriptan are simple, predictable and appropriate to an acute oral treatment for migraine.
Absorption↗
Changes in CNS levels of serotonin and its metabolite in SART-stressed (repeatedly cold-stressed) rats.
Central nervous system levels of serotonin (5-HT) and 5-hydroxy-indoleacetic acid (5-HIAA) in SART (specific alternation of rhythm in temperature)-stressed (repeatedly cold-stressed) rats were examined by HPLC-ECD. In SART-stressed rats, the levels of both 5-HT and 5-HIAA decreased in many brain areas. In the spinal cord, only the 5-HT level decreased. Therefore, the ratio of 5-HIAA to 5-HT increased only in the spinal cord. These results suggest that SART-stressed rats have some form of abnormality in the synthetic system of 5-HT.
Animals↗
Effects of exogenous materials on pollen tube growth in Lilium longiflorum pistils.
With the use of stigmatic exudate or distilled water as carriers, various antimetabolites, inhibitors, and miscellaneous materials were injected into the hollow styles of detached Lilium longiflorum pistils before, at, or after compatible or incompatible pollination. Pollen tube lengths were measured 48 hr after pollination with pollinated styles incubated at 22-23 degrees C. Substances considered inhibitors of protein synthesis in microbial systems significantly retarded both compatible and incompatible pollen tube growth while inhibitors of RNA synthesis tended to significantly inhibit compatible pollen tube growth with less or no effect on incompatible pollen tubes. Application of the inhibitors in stigmatic exudate at or after compatible pollination produced significant results at the lowest concentrations. Significant retardation of pollen tube growth also occurred after injection of 2,4-dinitrophenol, mercaptoethanol, indoleacetic acid, naphthaleneacetic acid, benzyladenine, dimethyl sulfoxide, or potassium or sodium iodide. Pollen tube growth in detached pistils of L. longiflorum may be useful as a bioassay in situ for screening biologically active materials.
Amino Acids↗
[Synthesis of 5,6-dihydroxytryptophan and (5,6-dihydroxy-3-indolyl)-acetic acid].
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5-Hydroxytryptophan↗
Exciplex-type behavior and partition of 3-substituted indole derivatives in reverse micelles made with benzylhexadecyldimethylammonium chloride, water and benzene.
The fluorescence properties of 3-methylindole (MI), 3-indoleacetic acid (IAA), 3-indoleethyltrimethylammonium bromide (IETA), L-tryptophan (Trp) and tryptamine hydrochloride (TA) were studied in reverse micelles solutions made with the cationic surfactant benzylhexadecyldimethylammonium chloride (BHDC) in benzene as a function of the molar ratio water/surfactant R (= [H2O]/[BHDC]). The fluorescence quenching of the model compound MI by benzene in cyclohexane solutions and by BHDC in benzene solutions were also studied in detail. The fluorescence of MI in benzene is characteristic of a charge-transfer exciplex. The exciplex is quenched by the presence of BHDC, due to the interactions of the surfactant ion pairs with the polar exciplex. In reverse micelle solutions at low R values, all the indoles show exciplex-type fluorescence. As R increases, the fluorescence behavior strongly depends on the nature of the indole derivative. The anionic IAA remains anchored to the cationic interface and its fluorescence is quenched upon water addition due to the increases of interface's micropolarity. For IETA, TA and Trp an initial fluorescence quenching is observed at increasing R, but a fluorescence recovery is observed at R > 5, indicating a probe partition between the micellar interface and the water pool. For the neutral MI, the fluorescence changes with R indicate the partition of the probe between the micellar interface and the bulk benzene pseudophase. A simple two-site model is proposed for the calculation of the partition constants K as a function of R. In all cases, the calculation showed that even at the highest R value, about 90% of the indole molecules remain associated at the micellar interface.
Journal Article↗
Tryptophan metabolism in liver cirrhosis: influence of oral antibiotics on neuropsychiatric symptoms.
Oral tryptophan loading tests were performed on patients with cirrhosis of the liver before and after treatment with an oral antibiotic practically unabsorbed from the gastrointestinal tract. After antibiotic therapy, neuropsychiatric manifestations evoked by the oral administration of tryptophan were reduced in duration by about 50% and in severity as well despite a slightly enhanced elevation of serum total and free tryptophan levels, compared to pre-treatment loading tests. The urinary indican output also showed a significantly greater decrease in the post-treatment test (p less than 0.05) whereas no appreciable difference was observed in urinary 5-hydroxy-indoleacetic acid excretion between the pre- and post-treatment tests. The data suggest that neuropsychiatric manifestations seen following oral administration of tryptophan may be attributed to intestinal tryptophan metabolites rather than to this aromatic amino acid itself and/or its metabolites in the brain.
Adult↗