Showing papers on "Serotonin published in 1988"

(+/-)3,4-Methylenedioxymethamphetamine selectively damages central serotonergic neurons in nonhuman primates.

Abstract: ( ± )3,4-Methylenedioxymethamphetamine (MDMA) is a popular recreational drug that has been proposed to be useful as an adjunct to psychotherapy. This study assessed the neurotoxic potential of MDMA in nonhuman primates. Monkeys were repeatedly administered doses (2.50, 3.75, and 5.00 mg/kg) of MDMA subcutaneously and analyzed for regional brain content of serotonin and 5-hydroxyindoleacetic acid two weeks later. In all regions of the monkey brain examined, MDMA produced a selective dose-related depletion of serotonin and 5-hydroxyindoleacetic acid. These neurochemical deficits were associated with evidence of structural damage to serotonergic nerve fibers. In addition, MDMA produced pathological changes in nerve cell bodies in the dorsal, but not median, raphe nucleus. These results indicate that MDMA is a selective serotonergic neurotoxin in nonhuman primates and that humans using this drug may be at risk for incurring central serotonergic neuronal damage. ( JAMA 1988;260:51-55)

Histamine H3 receptor-mediated inhibition of serotonin release in the rat brain cortex.

Abstract: Rat brain cortex slices preincubated with 3H-serotonin were superfused with physiological salt solution (containing citalopram, an inhibitor of serotonin uptake) and the effect of histamine on the electrically (3 Hz) evoked 3H overflow was studied. Histamine decreased the evoked overflow in a concentration-dependent manner. The inhibitory effect of histamine was antagonized by impromidine and burimamide, but was not affected by pheniramine, ranitidine, metitepine and phentolamine. Given alone, impromidine facilitated the evoked overflow, whereas burimamide, pheniramine and ranitidine had no effect. The results suggest that histamine inhibits serotonin release in the rat brain cortex via histamine H3 receptors, which may be located presynaptically.

Serotonin function in obsessive-compulsive disorder. A comparison of the effects of tryptophan and m-chlorophenylpiperazine in patients and healthy subjects.

Abstract: To evaluate the role of serotonin (5-HT) function in obsessive-compulsive disorder (OCD), behavioral and biochemical responses to the 5-HT receptor agonist m-chlorophenylpiperazine (MCPP) and the 5-HT precursor tryptophan were examined in healthy subjects and patients with OCD. Baseline prolactin levels and the prolactin rise following MCPP were significantly reduced in female patients compared with female healthy subjects. In contrast, the increase in prolactin level following tryptophan administration was not significantly different between male or female patients with OCD and the respective sex-matched healthy subjects. The prolactin responses to MCPP and tryptophan were both significantly higher in female patients and healthy subjects than in their male counterparts. The cortisol and growth hormone responses to MCPP and tryptophan were similar in the patients and healthy subjects and were not related to gender. The behavioral responses to MCPP or tryptophan were not consistently different between patients and healthy subjects, and neither MCPP nor tryptophan had effects on obsessive or compulsive symptoms. These results lend only partial support to the hypothesis that 5-HT dysfunction may be linked to the pathophysiology of OCD and point to the need for the evaluation of other neurotransmitter systems in future investigations of OCD.

Chronic Stress Increases Serotonin and Noradrenaline in Rat Brain and Sensitizes Their Responses to a Further Acute Stress

Abstract: The effects of 1 h/day restraint in plastic tubes for 24 days on the levels of serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), tryptophan (TP), and noradrenaline (NA) in six regions of rat brain 20 h after the last restraint period were investigated. The levels of 5-HT, 5-HIAA, and NA but not TP increased in several regions. The effects of 1 h of immobilization on both control and chronically restrained rats were also studied. Immobilization per se did not alter brain 5-HT, 5-HIAA, and TP levels, but decreased NA in the pons plus medulla oblongata and hypothalamus. However, immobilization after chronic restraint decreased 5-HT, increased 5-HIAA, and decreased NA in most brain regions in comparison with values for the chronically restrained rats. We suggest that chronic restraint leads to compensatory increases of brain 5-HT and NA synthesis and sensitizes both monoaminergic systems to an additional acute stress. These changes may affect coping with stress demands.

Alterations of central serotonin and dopamine turnover in rats treated with ipsapirone and other 5-hydroxytryptamine1A agonists with potential anxiolytic properties.

Abstract: Measurements of tissue levels of monoamines and their metabolites, and of the rates of 5-hydroxytryptophan and dihydroxy-phenylalanine accumulation after blockade of aromatic amino acid decarboxylase by benserazid indicated that ipsapirone (1-10 mg/kg i.p.) decreased 5-hydroxytryptamine (5-HT) turnover and accelerated dopamine (DA) turnover in various brain regions. The reduced 5-HT turnover probably resulted from the stimulation of 5-HT1A autoreceptors within the anterior raphe nuclei as in vitro tests [( 3H]-8-hydroxy-2-[di-n-propylamino]tetralin binding and adenylate cyclase assays) demonstrated that ipsapirone was a 5-HT1A agonist almost as potent as 8-OH-DPAT, and the same decrease in 5-hydroxytryptophan accumulation could be induced by the i.p. (5 mg/kg) or intraraphe (1 microgram) injection of ipsapirone. Ipsapirone-induced acceleration of DA turnover persisted after the selective degeneration of serotoninergic neurons by intraraphe 5,7-dihydroxytryptamine infusion, and could be reproduced by i.p. administration of other 5-HT1A agonists like buspirone and gepirone, but not 8-OH-DPAT. These results demonstrate that ipsapirone-induced acceleration of DA turnover did not result from the stimulation of 5-HT1A (auto)receptors, but involved additional target(s) of the drug. The possible participation of dopaminergic systems in the "anxiolytic" properties of ipsapirone should deserve further investigations.

Dopamine and serotonin inhibition of neurite elongation of different identified neurons

Abstract: This study demonstrates that a second classical neurotransmitter, dopamine, can act to suppress regenerative neurite outgrowth. Single identified neurons were dissected from two central ganglia of the snail Helisoma, and growth cone motility was studied as neurites regenerated in cell culture. Both dopamine and serotonin inhibited growth cone motility and elongation of neurites. Outgrowth inhibition ranged from sustained arrest to a similar but transient response. The effects of dopamine and serotonin are neuron-selective. Specific neurons affected by dopamine and serotonin represent distinct sets. One neuron was found that responds to both agents. The implications of neurotransmitter regulation of the dynamics of neuronal morphology are discussed.

Interleukin-1 induces changes in norepinephrine metabolism in the rat brain

Abstract: Interleukin-1 (IL-1) is a hormone that, apart from playing a key role in immune and inflammatory processes, can also affect mechanisms under brain control. To gain a better understanding of the action of this cytokine on the CNS, its effects on the contents of norepinephrine (NE), dopamine (DA) and serotonin (5-HT), and their main metabolites and precursors, were evaluated in different regions of the forebrain, brain stem, and spinal cord. Following administration of human recombinant IL-1 (beta form) to rats, a modest decrease in the content of NE was observed in the hypothalamus as well as in the dorsal posterior brain stem. However, the most relevant finding was that 3-methoxy-4-hydroxyphenylethylene glycol (MHPG), the main NE metabolite, and the relation MHPG/NE were increased in all the regions studied, revealing a stimulatory effect of IL-1 on NE metabolism in the CNS. This effect seems to be specific for NE since no comparable changes in the brain content of DA, 5-HT, or its metabolite, 5-hydroxyindole acetic acid, were detected after administration of the cytokine. However, tryptophan was significantly increased in all brain regions and in the cervical spinal cord. The capacity of IL-1 to affect the metabolism of NE, a neurotransmitter involved in the control of a variety of brain functions, provides further proof for the relevance of this cytokine in brain-immune interactions.

Converting enzyme activity and angiotensin metabolism in the dog brainstem.

Abstract: The concentrations of angiotensin converting enzyme (ACE) activity, norepinephrine, and serotonin were measured in microdissected regions of the dog's brainstem and spinal cord. In addition, we determined the in vitro metabolism of 125I-angiotensin I (Ang I) in homogenates of the same brain punch regions. High ACE-specific activity was found in the monoamine-containing regions of the brainstem and in the intermediolateral column of the spinal cord. In brainstem homogenates 125I-Ang I was metabolized to angiotensin II (Ang-[1-8]) and the N-terminal heptapeptide Ang-(1-7). In the presence of MK 422 (50 microM), Ang-(1-7) was still generated, while the production of Ang-(1-8) was inhibited. This study revealed the presence of high ACE activity in monoamine regions of dog brainstem and spinal cord, and showed that the metabolite Ang-(1-7) is the major product generated from Ang I in the presence and absence of ACE inhibition.

A regional study of sex differences in rat brain serotonin

Abstract: 1. Male and female rats were compared with respect to serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), tryptophan, dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 3-methoxytyramine (3-MT) levels in five brain regions (brainstem, hypothalamus/preoptic area, corpora striata, limbic forebrain and cortex). Brain 5-HT synthesis rate was also studied in the two sexes. 2. There were no consistent gender differences in the dopaminergic system. 3. In contrast, the serotonergic system was more expressed in females: 5-HT levels were significantly higher in females than in males in the brainstem and limbic forebrain and tended to be so in the cortex. 5-HIAA levels were significantly higher in females in all five brain regions. The 5-HIAA/5-HT ratios were significantly higher in females in the hypothalamus/preoptic area and limbic forebrain and tended to be so in the striatum and cortex. Tryptophan concentrations were significantly higher in females in the brainstem, striatum and cortex. In no brain region were 5-HT, 5-HIAA or tryptophan levels higher in males. Following L-amino acid decarboxylase inhibition 5-hydroxytryptophan (5-HTP) accumulation was more pronounced in the female rat brain. 4. Taken together these results suggest that the brain 5-HT system has a higher potential in female than in male rats. This sex difference is not restricted to a specific region but seems to exist generally in the brain.

Lysergic acid diethylamide and 2,5-dimethoxy-4-methylamphetamine are partial agonists at serotonin receptors linked to phosphoinositide hydrolysis.

Abstract: Based on electrophysiological, radioligand binding, and behavioral studies in laboratory animals, it is generally believed that the psychotomimetic effects of the phenethylamine and indolealkylamine hallucinogens are mediated by central serotonin (5-HT) receptors, in particular the 5-HT-2 subtype. Agonist-stimulated phosphoinositide hydrolysis was utilized to determine the potency and efficacy of racemic 1-(2,5)-dimethoxy-4-methyl-phenyl)-2-aminopropane (DOM), and d-lysergic acid diethylamide (LSD) at the 5-HT-2 receptor in rat cerebral cortex and the 5-HT-1c receptor in rat choroid plexus. Both DOM and LSD stimulated phosphoinositide hydrolysis in cerebral cortex. These effects were blocked by the 5-HT-2 antagonists, ketanserin and spiperone, but not by antagonists of muscarinic, alpha-1 adrenergic or histaminergic receptors. The maximum responses of DOM and LSD, respectively, were 76% and 25% of the maximum response to 5-HT. However, LSD was 500 times more potent than was racemic DOM. Consistent with a partial agonist effect, LSD partially blocked the effect of 5-HT, with a maximal inhibition equivalent to the intrinsic activity of LSD alone. In choroid plexus, DOM and LSD stimulated phosphoinositide hydrolysis and both responses were blocked by mianserin and less effectively by spiperone. The maximum effect of DOM was 67% of that of 5-HT, whereas the maximum effect of LSD was only 34% of the maximum response of 5-HT. LSD was 50 times more potent than was racemic DOM. LSD partially antagonized the effect of 5-HT in the choroid plexus, consistent with a partial agonist effect at the 5-HT-1c receptor in this tissue.(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanisms of effects of d-fenfluramine on brain serotonin metabolism in rats: uptake inhibition versus release.

Abstract: d-Fenfluramine is an anorectic drug believed to act by enhancement on serotonergic function in the brain. d-Fenfluramine (or the racemate) releases serotonin through a carrier-dependent mechanism, and serotonin release is the mechanism usually thought to produce its serotonergic effects. However, d-fenfluramine also inhibits serotonin uptake in vitro, and serotonin uptake inhibition is sometimes suggested to contribute to its mechanism of anorectic activity. Neurochemical experiments were done to examine serotonin release and serotonin uptake inhibition as mechanisms of action of d-fenfluramine in rats and to compare d-fenfluramine to fluoxetine, a serotonin uptake inhibitor. d-Fenfluramine decreased serotonin concentration in rat brain as early as 1 hr; at 1 hr 5-hydroxyindoleacetic acid (5HIAA) concentration was slightly increased, but at later times 5HIAA was also decreased. Fluoxetine, in contrast, did not change serotonin concentration in whole brain but decreased 5HIAA concentration at all time points. At all time intervals studied, the 5HIAA/serotonin ratio was increased by d-fenfluramine (and by Ro 4-1284, a nonspecific serotonin releaser) but was decreased by fluoxetine, a serotonin uptake inhibitor. No decrease in 5HIAA concentration or in the 5HIAA/serotonin ratio was apparent at any time or after any dose of d-fenfluramine studied. The possibility that doses of d-fenfluramine below those needed for serotonin release might inhibit serotonin uptake was tested by determining whether d-fenfluramine could block the acute depletion of brain serotonin by p-chloroamphetamine, or the long-term neurotoxic effect of p-chloroamphetamine on brain serotonin neurons.(ABSTRACT TRUNCATED AT 250 WORDS)

Serotonin and Melatonin Synthesis in Peripheral Blood Mononuclear Cells: Stimulation by Interferon-7 as Part of an Immunomodulatory Pathway

Abstract: Serotonin and melatonin inhibit phytohemagglutinin- (PHA) induced interferon-γ (IFN-γ) production by lymphocytes. In this paper, it is shown that IFN-γ-increased tryptophan uptake by lymphocytes an...

Pharmacological profile of ritanserin: A very specific central serotonin S2-antagonist

Abstract: Ritanserin, a novel methylenepiperidine derivative, was studied in a wide range of common pharmacological tests mainly in rats. The lowest ED50, 0.0070 mg/kg, was obtained against tryptamine-induced cyanosis. At 0.037 mg/kg, tryptamine-induced bilateral clonic seizures were inhibited. Slightly higher doses, up to 0.11 mg/kg, inhibited mescaline and 5-hydroxytryptophan (5-HTP)-induced head twitches and antagonized tryptamine-induced coarse body tremors. Ritanserin did not generalize with LSD but was a weak antagonist of the LSD-discriminative stimulus. Potent serotonin S2-antagonism was confirmed by the inhibition of reactions mediated by endogenous serotonin, such as reversal of mast cell serotonin (5-HT) cyanosis (0.012 mg/kg) and inhibition of gastric lesions (0.028 mg/kg). The lowest dose reducing the intensity of serotonin-induced skin reactions was 0.04 mg/kg. Reduction of histamine-induced skin reactions required a dose of at least 10 mg/kg. Time-course studies in several tests indicated a relatively long duration of serotonin S2-antagonism. Ritanserin doses up to 40 mg/kg were devoid of central dopamine antagonism and did not interfere with the neurotransmitters norepinephrine and acetylcholine. In an additional series of interactions and functional tests, ritanserin was virtually devoid of effect. In the wide range of tests, peripheral histamine antagonism was the first activity component unrelated to serotonin and it was observed at 270 times the dose for central S2-antagonism. It is concluded that ritanserin is a very effective central serotonin S2-antagonist which is at the same time relatively long acting and very specific.

Gabapentin augments whole blood serotonin in healthy young men.

Abstract: It has been previously demonstrated that gabapentin, a gamma-amino butyric acid analogue, inhibits monoaminergic neurotransmitter release from rabbit caudate nucleus slices and from rat cortex. In humans this drug has been shown to have anti-epileptogenic activity. Serotonin may act as an inhibitory neurotransmitter and its interaction with blood platelets is thought to reflect its central actions. We investigated sleep stages, whole blood serotonin levels, and serum melatonin in healthy men after the administration of gabapentin. With increasing serum gabapentin levels six healthy subjects showed an increase in sleep stages 3 and 4 and in whole blood serotonin (P less than 0.05) Serum melatonin levels were not influenced. On account of these results we speculate that gabapentin modulates the release of serotonin from blood platelets. The increase in peripheral serotonin points paradigmatically to an increase in the bioavailability of serotonin which may account for the increase in sleep stages 3 and 4.

Sympathetic stimulation and hypertension in the pyridoxine-deficient adult rat.

Abstract: Pyridoxal phosphate is the coenzyme of various decarboxylases involved in the formation of monoamine neurotransmitters such as gamma-aminobutyric acid, serotonin, dopamine, and norepinephrine. Adult male Sprague-Dawley rats placed on a pyridoxine-deficient diet for 8 weeks showed significant hypertension compared with pyridoxine-supplemented controls. Hypothalamic contents of pyridoxal phosphate, gamma-aminobutyric acid, and serotonin in the pyridoxine-deficient rats were significantly lower than those in pyridoxine-supplemented controls. Hypertension was associated with sympathetic stimulation. Treatment of pyridoxine-deficient rats with a single dose of pyridoxine (10 mg/kg body weight) reversed the blood pressure to normal levels within 24 hours, with concomitant restorations of hypothalamic serotonin and gamma-aminobutyric acid as well as the return of plasma norepinephrine and epinephrine to normal levels. Also, pyridoxine treatment reversed the hypothalamic hypothyroidism observed in pyridoxine-deficient rats. These results indicate an association between pyridoxine deficiency and sympathetic stimulation leading to hypertension.

Detection and characterization of the serotonin 5-HT 1D receptor in rat and human brain.

Abstract: In the presence of 1 microM ( +/- )-pindolol [to block 5-hydroxytryptamine (5-HT, serotonin) 5-HT 1A and 5-HT 1B receptors] and 100 nM mesulergine (to block 5-HT 1C receptors), 20 nM [3H]5-HT binding to rat cortical homogenates is specific, saturable, and reversible Scatchard analysis of [3H]5-HT binding, in the presence of 1 microM ( +/- )-pindolol and 100 nM mesulergine, produced a KD of 32 nM and Bmax of 43 fmol/mg protein Distribution studies show this site to be present in most rat brain regions This site is also detectable in human caudate The pharmacological profile of this site is distinct from the previously identified 5-HT receptor subtypes Compounds with high affinity for 5-HT 1A (8-hydroxydipropylaminotetralin), 5-HT 1B (trifluoromethylphenylpiperazine), 5-HT 1C (mesulergine), 5-HT 2 (4-bromo-2,5-dimethoxyphenylisopropylamine), and 5-HT3 (ICS 205-930) receptors have low affinity for this site These data suggest the presence of an additional, previously unidentified, 5-HT binding site in rat and human brain tissue This putative novel 5-HT receptor has a similar pharmacology to the "5-HT 1D" site detected in bovine brain by Heuring and Peroutka

Neurochemical profile of tianeptine, a new antidepressant drug.

Abstract: Tianeptine is a new effective antidepressant drug. However, its neurochemical profile in animals differs from that of tricyclic or atypical antidepressants. In the present study, we compared the ex vivo effects of tianeptine on platelet serotonin uptake to those of clomipramine. Ex vivo, after subchronic (15 days, washout 24 h) treatment (10 mg/kg/day i.p.) in rats, tianeptine induced an increase (30%) in [14C]serotonin uptake at a [14C]serotonin concentration of 500 nM while clomipramine induced a decrease (40%) in [14C]serotonin uptake. Stimulation of uptake affected mainly Vmax but not Km. Tianeptine did not inhibit monoamine oxidase (MAO), MAOA or MAOB activity. In vitro, there was no binding of tianeptine to any of the various receptors examined: alpha- and beta-adrenergic, dopamine, serotonin, imipramine, GABA, glutamate, benzodiazepine, muscarinic, histamine, Ca2+ channels. After chronic administration (10 mg/kg/day for 15 days) tianeptine did not alter the concentration (Bmax) or the affinity (Kd) of alpha-2, beta-1, serotonin-1, serotonin-2, imipramine, benzodiazepine, or GABAB receptors. The major effect of tianeptine in rat platelets and synaptosomes is a small increase in 5-HT uptake after subchronic administration.

Serotonin and its place in the pathogenesis of depression.

Abstract: The authors review the literature in an attempt to evaluate the relationship between serotonin and depression. Animal studies show that the administration of tryptophan (the precursor of serotonin) increased serotonin synthesis and influenced behavior. Low plasma tryptophan levels have been found in patients with endogeneous depression. Postmortem studies have shown an association between lowered hindbrain serotonin levels and suicide among depressed persons. The decreased serotonin levels in blood platelets during depression mirrored the neuronal changes. Tricyclic antidepressants inhibited platelet serotonin uptake and reduced imipramine binding sites on the platelets. A positive correlation between depression rating scores and platelet aggregatory response has been reported. Serotonin stimulated release of prolactin and growth hormone, although the prolactin response was less marked in depression. A marker for depressive illness is still sought, but it is likely to be related in some way to serotonin.