Showing papers on "Serotonin published in 1977"

Serotonin-containing neurons: their possible role in pain and analgesia.

Abstract: Experimental evidence is reviewed showing that brain and spinal cord serotonergic neurons are involved in nociceptive responses, as well as in the analgesic effects of opiate narcotics. This evidence, based on studies employing pharmacological, surgical, electrophysiological and dietary manipulations of central nervous system serotonergic neurotransmission, suggests that increases in the activity of brain and spinal cord serotonin neurons are associated with analgesia and enhanced antinociceptive drug potency, whereas decreases in the activities of these neurons correlate with hyperalgesia and diminished analgesic drug potency.

Is there a role for serotonin (5-hydroxytryptamine) in feeding?

Abstract: A review of evidence indicates that experimentally induced changes in the activity of serotonin (5-hydroxytryptamine) systems are associated with pronounced changes in feeding behaviour. In general, treatments and procedures believed to lead to an increased availability of 5-HT in the synaptic cleft or which directly activate 5-HT receptors reduce food consumption, while procedures which either directly or indirectly decrease 5-HT receptor activation bring about the opposite effect. Interpretation of findings is hindered by methodological difficulties involved in the experimental manipulation of serotonin metabolism, by the lack of precise behavioural measures of feeding, and by the presence of large stores of serotonin outside the brain. However, available data favour the idea that serotonin systems play an inhibitory role in feeding, possibly in the mediation of satiety. This proposal has implications for further experimental investigations of the control of food intake, and for the aetiology and treatment of obesity.

Evidence for Depressed Catecholamine and Enhanced Serotonin Metabolism in Aging Male Rats: Possible Relation to Gondotropin Secretion2

Abstract: The steady state concentration of dopamine (DA), norepinephrine (NE), and serotonin (5HT) was determined and turnover estimated in several brain regions of young (3–4 months) and old (21 months) male Wistar rats. An estimate of DA and NE turnover was obtained by determining their depletion rates after treatment with α-methylpara- tyrosine, a tyrosine hydroxylase inhibitor. Serotonin turnover was estimated by determining its rate of increase after monoamine oxidase inhibition with pargyline. In old males, medial basal hypothalamic (MBH) DA concentration and depletion rate were significantly lower than in young males. DA concentration of the remaining hypothalamus also was lower in old than in young males, but depletion rates were not different. DA concentration and depletion rate in the olfactory tubercle were the same in both age groups. The steady state concentration of NE in the MBH and remaining hypothalamus, and the hypothalamic NE depletion rate, were significantly lower in old than in young animals....

Cocaine: Discussion on the Role of Dopamine in the Biochemical Mechanism of Action

Abstract: The central stimulant effect of cocaine is generally considered related to its potentiating effect on biogenic amines. However, the individual role and significance of the amines involved in various stimulant effects of cocaine are still a controversial topic. Cocaine is a potent inhibitor of noradrenaline uptake (Hertting, Axelrod, and Whitby, 1961; Ross and Renyi, 1967; Langer and Enero, 1974; Azzaro, Ziance, and Rutledge, 1974), dopamine uptake (Fuxe, Hamberger, and Malmfors, 1967; Ross and Renyi, 1967; Harris and Baldessarini, 1973; Heikkila, Orlansky, Mytilineou, and Cohen, 1975), and serotonin uptake (Ross and Renyi, 1969; Friedman, Gershon, and Rotrosen, 1975). High affinity uptake of tryptophan into synaptosomes is also inhibited (Knapp and Mandell, 1972). In vivo studies have shown that cocaine induces a short-lasting uptake inhibition into brain tissues of noradrenaline (Schanberg and Cook, 1972), dopamine (Fuxe, Ham-berger, and Malmfors, 1967), and serotonin (Ross and Renyi, 1969).

Inhibition of serotonin reuptake.

Abstract: An uptake system on the serotonin neuronal membrane apparently functions to inactivate serotonin that has been released into the synaptic cleft Various inhibitors of this active transport system on serotonin neurons are known, and some are specific in the sense that they do not inhibit the active uptake system on norepinephrine neurons The most widely studied specific inhibitor of the serotonin neuron pump is fluoxetine, 3-(p-trifluoromethylphenoxy-N-methyl-3-phenyl propylamine (Lilly 110140) When fluoxetine or other effective but less specific serotonin uptake inhibitors are given, a rapid decrease in serotonin turnover occurs and the rate of firing of single neural units in the serotonin rich raphe area of brain is reduced This decrease in serotonin turnover and release may be a compensatroy mechanism in response to an enhanced action of serotonin on synaptic receptors Through the use of fluoxetine and other serotonin uptake inhibitors, the role of serotonin neurons in various brain functions--behavior, sleep, regulation of pituitary hormone release, thermoregulation, pain responsiveness, and so on--can be studied

Further evidence that serotonin is a neurotransmitter involved in the control of prolactin secretion.

Abstract: Administration of a new specific serotonin uptake inhibitor, fluoxetine, depressed the firing rate of raphe neurons A highly significant increase in serum prolactin levels was observed after ip injection of 30 mg/kg of 5-hydroxytryptophan (5-HTP) in male or female rats pretreated with 10 mg/kg (ip) of fluoxetine Neither 5-HTP nor fluoxetine given separately had any effect on serum prolactin levels In animals pretreated with methysergide the combination of fluoxetine and 5-HTP did not increase significantly serum levels of prolactin In addition, the serotonin agonist quipazine elevated significantly serum prolactin levels in male and female rats The results of this study strengthen the idea that 5-HTP is acting via serotonin-containing neurons that influence anterior pituitary prolactin release, and that serotonin receptor activation leads to prolactin release

Evidence for dopamine deamination by both type A and type B monoamine oxidase in rat brain in vivo and for the degree of inhibition of enzyme necessary for increased functional activity of dopamine and 5-hydroxytryptamine.

Abstract: 1 Tranylcypromine (20 mg/kg) administration to rats totally inhibited brain monoamine oxidase (MAO) oxidation of 5-hydroxytryptamine (5-HT), phenylethylamine and dopamine as measured in vitro. When l-3,4-dihydroxyphenylalanine (l-DOPA) (50 mg/kg) was given 30 min after the tranylcypromine, brain dopamine and noradrenaline concentrations rose markedly and the rats displayed characteristic behavioural changes and locomotor activity. 2 Clorgyline (5 mg/kg) administration inhibited 5-HT oxidation by almost 100% but phenylethylamine by only 29% while (-)-deprenil (5 mg/kg) injection almost totally inhibited phenylethylamine oxidation and inhibited 5-HT metabolism by only 31%. Administration of l-DOPA after pretreatment with either drug did not alter brain dopamine or noradrenaline concentrations and the animals did not display any behavioural changes. 3 Administration of clorgyline plus (-)-deprenil (5 mg/kg of each) almost totally inhibited oxidation of both phenylethylamine and 5-HT; there was a large rise of brain dopamine and noradrenaline concentrations and the animals displayed the behavioural changes observed when tranylcypromine and l-DOPA had been given. 4 The effects of tranylcypromine (20 mg/kg) on brain 5-HT, dopamine and noradrenaline concentrations up to 48 h after injection were recorded. Brain 5-HT concentrations were considerably elevated for 18 h after injection and then fell steadily. In contrast, brain dopamine concentrations rose slightly and remained at this level for 48 h while noradrenaline levels doubled and also remained at this level for 48 hours. 5 When l-tryptophan (50 mg/kg) was given at various times after tranylcypromine the characteristic hyperactivity syndrome appeared at 12 h but not 18 h after tranylcypromine and a further rise in brain 5-HT was only observed at 12 hours. When l-DOPA (50 mg/kg) was given at various times after tranylcypromine a further large rise in brain dopamine and noradrenaline occurred at 12 h but not at 18 h and all the behavioural changes were observed only at 12 hours. 6 Measurement of MAO activity at the above times after tranylcypromine showed that the half-life of recovery of the enzyme activity with 5-HT and dopamine as substrates was 4.5 days and 8.5 days with phenylethylamine as substrate. Inhibition of MAO oxidation of dopamine and 5-HT was approximately 85%, 18 h after tranylcypromine injection. 7 It is concluded from both the studies with clorgyline and deprenil and the recovery of MAO activity after tranylcypromine, that dopamine is metabolized by both Type A and Type B MAO in vivo and that it is only when both forms are almost totally inhibited that there is an increase in dopamine and 5-HT functional activity, as judged by the appearance of the hyperactivity syndromes.

Effects of the diet on brain neurotransmitters

Abstract: The synthesis of neurotransmitters in mammalian brain responds rapidly to changes in precursor availability. Serotonin synthesis depends largely on the brain concentrations of L-tryptophan, its precursor amino aicd. This relationship appears to be physiologic: when brain tryptophan levels vary because of insulin secretion or meal ingestion, corresponding alterations occur in the rate of serotonin formation. The ability of any food to modify brain tryptophan (and serotonin) depends on how its ingestion changes the serum concentration of not only tryptophan, but also several other large neutral amino acids that compete with tryptophan for uptake into the brain. Such precursor-induced changes in brain serotonin appear to be functionally important: animals having a reduced level of brain serotonin (caused by the chronic ingestion of a naturally tryptophan-poor diet, such as corn) demonstrate a heightened sensitivity to painful stimuli; this pain sensitivity can be acutely restored to normal values by a single injection of L-tryptophan, which rapidly elevates brain serotonin. The synthesis of catecholamines (e.g., dopamine, norepinephrine) in the brain also varies with the availability of the precursor amino acid L-tyrosine. Single injections of this amino acid increase brain tyrosine levels and accelerate brain catechol synthesis, while injections of a competing neutral amino acid (e.g., leucine, tryptophan) reduce brain tyrosine and its rate of conversion to dopa. The rate of catecholamine synthesis, however, appears to be influenced less by precursor levels than is serotonin formation: tyrosine hydroxylase, whcih catalyzes the rate-limiting step in catecholamine synthesis, responds strongly to end-product inhibition and to other controls that reflect variations in neuronal activity. The synthesis of acetylcholine in brain responds to substrate (choline) availability much like serotonin synthesis. Short-term alterations in brain choline levels are mirrored by similar changes in brain acetylcholine concentration. Variations in the daily dietary intake of choline also modify brain choline and acetylcholine. The relationship between choline availability and acetylchyoline synthesis has already foudn a cletween choline availability and acetylchyoline synthesis has already found a clinical application: choline has been used successfully in the treatment of tardive dyskinesia, a disorder of the central nervous system thought to reflect a deficiency in cholinergic transmission. These relationships between precursor availability from the periphery and brain neurotransmitter synthesis may ultimately provide the brain with information about peripheral metabolic state.

Long-Term Therapy of Myoclonus and Other Neurologic Disorders with L-5-Hydroxytryptophan and Carbidopa

Abstract: We evaluated the therapeutic effect of L-5-hydroxytryptophan (L-5HTP), the precursor of serotonin (5-hydroxytryptamine), combined with carbidopa, a peripheral decarboxylase inhibitor, in patients with intention myoclonus and examined the serotonin metabolites in spinal fluid, blood and urine before and during therapy. In 18 patients with intention myoclonus due to anoxia or other brain damage, 11 derived more than 50% overall improvement during treatment with L-5HTP and carbidopa. Spinal-fluid 5-hydroxyindoleacetic acid was 35% lower in patients with intention myoclonus than in controls (P less than 0.05). Therapy with L-5HTP and carbidopa increased the concentration of serotonin metabolites in urine and spinal fluid. We postulate that a deficiency of brain serotonin is causally related to intention myoclonus and that the therapeutic effect of L-5HTP and carbidopa may be due to the repletion of serotonin in regions of the brain where serotoninergic neurons have degenerated.

Effects of mianserin, a new antidepressant, on the in vitro and in vivo uptake of monoamines.

Abstract: 1 The effects of mianserin and of selected tricyclic antidepressants were compared in a number of monoamine uptake models. 2 The ability of mianserin to block the noradrenergic neurone membrane amine pump of rabbit brain stem slices was comparable to that of imipramine and amitriptyline and less than that of desipramine and nortriptyline. Both mianserin and desipramine were competitive inhibitors of noradrenaline uptake in vitro. The effect of mianserin on noradrenaline uptake in vivo was studied both peripherally and centrally. The ability of 6-hydroxydopamine to lower rat heart noradrenaline levels was found to be very sensitive to inhibition by tricyclic antidepressants. Mianserin was active in this model. However, its ability to block the 6-hydroxydopamine-induced fall in rat heart noradrenaline concentration was appreciably less than that of the tricyclics studied. 3 Mianserin, like tricyclic antidepressants, was essentially devoid of effect on dopamine uptake both in vitro and in vivo. 4 The ability of mianserin to inhibit [3H]-5-hydroxytryptamine uptake by rat hypothalamic synaptosomes was appreciably less than that of the tricyclic antidepressants studied. Mianserin was essentially devoid of effect on rat brain 5-hydroxytryptamine uptake in vivo. 5 It is concluded that in certain situations large doses of mianserin may block noradrenaline uptake in vivo. However, in no way does mianserin rival tricyclic antidepressants in blocking monoamine uptake in vivo. The clinical efficacy of mianserin cannot be attributed to inhibition of monoamine uptake.

Antinociceptive Effect of Intrathecally Administered Serotonin

Abstract: It has been suggested that serotonin neurons and their pathways may mediate sensitivity to nociceptive stimuli by activating the descending inhibitory mechanisms at the spinal cord. This antinociceptive effect may be induced by direct administration of serotonin into the cerebrospinal fluid pathways. The experiment is designed to demonstrate the changes in the tail-flick response latency after the intrathecal injection of serotonin. Serotonin, 100 or 200 microgram, administered into the lumbar intrathecal space, produced an analgesic effect for as long as 40 minutes. Behavioral and morphologic observations after serotonin injections showed no adverse reaction. It is assumed that serotonin molecules penetrate the spinal cord tissue and activate the antinociceptive serotonergic pathyways.

Neurochemical effects of cocaine following acute and repeated injection.

Abstract: Following repeated injection in the rat, cocaine decreased the concentration of serotonin in the septum-caudate and increased the metabolism of hypothalamic norepinephrine and also striatal dopamine to a lesser extent. Furthermore, cocaine significantly decreased the activity of the rate-limiting enzyme, tryptophan hydroxylase. In a comparative study d-amphetamine and methylphenidate were found to exert an effect opposite to cocaine in the activation of tryptophan hydroxylase. These findings indicate that cocaine may lower central serotonin function by decreasing its availability for neural transmission. This could account for the stimulation of locomotor activity observed after cocaine administration.

Depression of serotonin clearance by rat lungs during oxygen exposure.

Abstract: The effect of oxygen (O2) exposure on the ability of the isolated, perfused rat lung to clear serotonin (5-hydroxytryptamine, 5-HT) from the perfusate was evaluated in normal or vitamin E-deficient...

Monoamine metabolites in cerebrospinal fluid and serotonin uptake inhibition during treatment with chlorimipramine.

Abstract: The effects of chlorimipramine on the concentrations of the main metabolites of serotonin (5-HT) norepinephrine (NE), and dopamine, i.e. 5-hydroxyindoleacetic acid (5-HIAA), 4-hydroxy-3-methoxyphenyl glycol (HMPG) and homovanillic acid (HVA), respectively, were studied in cerebrospinal fluid from 14 depressed patients, and related to the serotonin- and NE uptake inhibiting activity in vitro of plasma drawn from the patients. Chlorimipramine inhibited the uptake of both transmitter amines in all patients. During treatment, the levels of 5-HIAA and HMPG in cerebrospinal fluid (CSF) were significantly reduced. HVA levels were reduced in 6 patients and increased in 8 patients; there was no mean change. The decrease in 5-HIAA level in CSF was correlated to the uptake inhibition of 5-HT but there was no corresponding relationship between NE uptake and HMPG levels. The changes in HVA levels were also correlated to the uptake of 5-HT despite the absence of a unidirectional change of this metabolite.

Distribution of serotonin and synthesizing enzymes in discrete areas of the brain.

Abstract: With the use of sensitive radio-enzymatic microtechniques, serotonin and its synthesizing enzymes, tryptophan hydroxylase and L-amino acid decarboxylase, can be quantitatively detected in discrete regions of the rat brain. A microdissecting technique allows us to study their localization in specific brain areas and nuclei. Serotonin and its related enzymes are concentrated in the raphe nuclei. Relatively high serotonin concentrations are also present in areas and nuclei of the hypothalamus, limbic system, and brain stem, as well as in the circumventricular organs and the pituitary gland. The localization of its synthesizing enzymes in the same regions suggests that the formation of serotonin actually takes place in these areas. Catecholamines are also present in the raphe nuclei of the rat. Changes in catecholamine metabolism result in changes in serotonin levels in specific brain areas. These results suggest that serotonin may be involved in the regulation of a number of autonomic functions, and in neuroendocrine control mechanisms. The neuroanatomical and biochemical relations between the catecholaminergic and serotonergic system in the brain support the hypothesis of a physiological interaction of these two systems in specific, localized brain structures.

Serotonergic neurons in the peripheral nervous system: identification in gut by immunohistochemical localization of tryptophan hydroxylase

Abstract: A specific antibody to tryptophan hydroxylase [L-tryptophan, tetrahydropteridine:oxygen oxidoreductase (5-hydroxylating), EC 1.14.16.4] has been used to localize the enzyme immunohistochemically in neurons of the mammalian gut. The enzyme was found in perikarya of intestinal neurons of mice, rats, and guinea pigs. Neurons containing the enzyme survived for up to 3 weeks in organotypic tissue culture and were intrinsic to the gut. These neurons are probably serotonergic and are the first such neurons to be found in the peripheral nervous system.

Effect of serotonin treatment on intestinal transport in the rabbit.

Abstract: The hormone serotonin (5-hydroxytryptamine) has been implicated as the cause of the diarrhea seen in many patients with the carcinoid syndrome. To determine whether serotonin is an intestinal secretagogue, the effect of serotonin on intestinal water and electrolyte transport was evaluated in the rabbit. Two weeks of daily subcutaneous injection of serotonin suspended in oil resulted in a blood serotonin level elevated to twice that of controls. Intestinal transport was studied in vivo by a perfusion technique. Serotonin treatment resulted in ileal secretion and decreased mid-jejunal absorption of water and electrolytes but did not effect water absorption in the proximal jejunum or colon. Intestinal absorption of D-glucose and the amino acid L-tryptophan and glucose-dependent water and electrolyte absorption were normal in serotonin-treated animals. Serotonin-induced ileal secretion was reversed by methysergide, a peripheral antagonist of serotonin action. No alterations in intestinal histology or permeability occurred in serotonin-treated animals. Serotonin-induced intestinal secretion was not associated with alterations in the activities of intestinal mucosal adenylate cyclase, cyclic nucleotide phosphodiesterase, or Na-K-ATPase.

Initial clinical trial based on biochemical methodology of zimelidine (a serotonin uptake inhibitor) in depressed patients.

Abstract: The bicyclic compound Z-1-(4-bromophenyl)-1-(3-pyridyl)-3-dimethylaminopropen (zimelidine) has a pronounced inhibitory effect on neuronal 5-hydroxytryptamine (5-HT) uptake in animals. Zimelidine was given to 6 depressed patients in doses ranging between 25 and 150 mg twice daily for about 3 wk. To get an objective assessment of its pharmacologic effects, the following variables were monitored: (1) plasma levels of parent compound and its desmethylated metabolite; (2) the 5-HT and norepinephrine (NE) uptake inhibiting activity in vitro of plasma drawn from the patients; and (3) the concentrations of the main metabolites of serotonin (5-HT), tryptamine, NE, and dopamine in cerebrospinal fluid (CSF), i.e., 5-hydroxyindoleacetic acid (5-HIAA), indoleacetic acid (IAA), 4-hydroxy-3-methoxyphenylglycol (HMPG), and homovanillic acid (HVA), respectively. Plasma from the patients markedly inhibited 5-HT uptake compared to NE uptake. The inhibitory effect of 5-HT uptake and the plasma concentration of the desmethylated metabolite correlated significantly. The 5-HIAA levels in CSF decreased markedly in 4 patients while the IAA levels increased. The levels of HMPG also decreased significantly, but less so than the 5-HIAA levels. The effects on HVA were inconsistent. Zimelidine appears to be a selective inhibitor of 5-HT uptake in central monoamine neurons and is therefore an interesting pharmacologic tool in future central nervous system (CNS) research.

The effect of intracerebroventricularly administered GABA on brain monoamine metabolism

Abstract: Intracerebroventricular injection of γ-aminobutyric acid (GABA) was performed in male rats and the brain monoamines, 5-hydroxyindoleacetic acid (5-HIAA), tyrosine and tryptophan levels were measured. GABA induced within 30 min a marked dose-dependent increase in the brain contents of dopamine (DA), serotonin (5-HT), tyrosine and tryptophan, while noradrenaline (NA) was lowered. Large doses of GABA, i.e. 1.5–3 mg/rat, were required for these effects. Aminooxyacetic acid (AOAA), an inhibitor of GABA-transaminase, when given alone in a dose of 25 mg/kg i.p. caused a significant rise of DA, 5-HT and tryptophan. The combination of GABA and AOAA raised these levels more than either agent alone. Picrotoxin (4 mg/kg, i.p.) a claimed GABA receptor antagonist partially counteracted the GABA-induced DA rise. Monoamine synthesis was studied in different parts of the brain by measuring the accumulated dopa and 5-hydroxytryptophan (5-HTP), 30 min after NSD 1015 (3-hydroxybenzylhydrazine HCl, 100 mg/kg) an inhibitor of aromatic L-aminoacid decarboxylase, given i.p. 5 min after GABA. GABA caused a marked rise in dopa formation both in DA-and NA-predominated brain regions. Also 5-HTP formation was enhanced. The effects on both dopa and 5-HTP formation showed marked regional differences. The data suggest that GABA, by activating specific receptors, causes inhibition of firing of dopaminergic neurones and the opposite effect on the noradrenergic neurones. The nature of the effect on 5-HT metabolism needs further investigation.

Cadmium alters behaviour and the biosynthetic capacity for catecholamines and serotonin in neonatal rat brain.

Abstract: — Daily exposure to cadmium (10 μg/100g) for 30 days since birth significantly increased spontaneous locomotor activity as well as striatal tyrosine hydroxylase and mid-brain tryptophan hydroxylase. The endogenous levels of norepinephrine, dopamine and serotonin failed to change in various brain regions of cadmium-treated rats. In contrast, the concentration of 5-hydroxyindoleacetic acid tended to rise but was significantly different from controls only in the mid-brain region. The data suggest that cadmium treatment in early life increased the synthesis and physiological utilization of these putative transmitters which in turn probably altered locomotor performance. Increasing the dose of cadmium to 100 μg/100 g for 30 days decreased body weight (by 19%) and produced slight increases in the turnover of brain amines. However, the rise was not dose-dependent. Furthermore, the locomotor activity remained the same as that seen in rats treated with the low dose of cadmium. The levels of dopamine in hypothalamus and that of norepinephrine in several brain regions examined were enhanced. This could in part, be attributed to decreased (12%) activity of catechol-O-methyl transferase enzyme. Administration of the high dose of cadmium produced significant increases in 5-hydroxyindoleacetic acid level. Data suggest that cadmium acts at some step in the sequence of intracellular events that leads to increased synthesis and presumably turnover of brain catecholamines and serotonin. Since high dosage of this heavy metal failed to produce a dose-dependent change in locomotor activity, it is not possible to impute any casual role for these amines in the production of hyperactivity seen in cadmium-treated rats.