Showing papers on "Serotonin published in 1975"
TL;DR: It was possible to conclude that, in the tissue slice system, an experimentally observed release was real, whereas a releasing action evoked an apparent inhibition of uptake equal in magnitude to the releasing action.
473 citations
TL;DR: It would appear that SPA has a neural substrate at least partly independent of that underlying baseline pain responsiveness, and the existence of a common pain-inhibitory system in the brain activated by morphine and by focal electrical stimulation is suggested.
336 citations
TL;DR: Observations suggest that precursor availability may influence brain ACh synthesis, just as brain tryptophan and tyrosine levels have previously been shown to control the synthesis of brain serotonin and catecholamines.
332 citations
TL;DR: Pretreatment of the animals with desipramine efficiently counteracts the long-term effects of 5,7DHT on NA neurons while the neurotoxic effects on the serotonin neurons are unimpaired.
Abstract: IN A SERIES of morphological and biochemical investigations (BAUMGARTEN & LACHENMAYER, 1972; BAUMGARTEN et al., 1973a; BJORKLUND et al., 1973a; BAUMGARTEN et al., 1973b; JACOBY et al., 1974) 5,7-dihydroxytryptamine (5,7-DHT) has been shown to induce extensive axonal degeneration of central serotonin neurons after intraventricular or intracerebral injections in the rat. A major drawback of 5,7-DHT as a tool for chemical lesioning of serotonin meurons is, however, its poor discrimination between 5-HT and NA neurons, and thus both 5-HT and NA axons in the CNS are lesioned by the drug (BAUMGARTEN et al., 1973a; BJORKLUND et al., 1973a; JACOBY et al., 1974). In fact, in lower doses (less than 75 p g intraventriculary) the depletion of brain NA is asgreat as that of serotonin (BAUMGARTEN et al., 1973a). As the action of the neurotoxic indolamines is due to its intraneuronal accumulation by the membrane uptake mechanisms of the monoamine neurons (for discussion, see BJORKLUND eta!., 1974) one possibility to improve the selectivity of 5,7-DHT for serotonin neurons would be to block the uptake of the drug into NA neurons without affecting the uptake into the serotonin neurons. Desipramine has been reported to be more efficient in blocking the membrane pump of NA than of serotonin neurons (FUXE & UNGERSTEDT, 1968; CARLSSON et al., 1969). In the present study we report that pretreatment of the animals with desipramine efficiently counteracts the long-term effects of 5,7DHT on NA neurons while the neurotoxic effects on the serotonin neurons are unimpaired.
297 citations
TL;DR: The β-adrenergic receptors of a variety of non-neural tissues have been characterised indirectly by measurement of altered adenylate cyclase activity or of intracellular cyclic AMP in response to β- adrenergic agonists and antagonists.
Abstract: MODULATION of cellular function by the autonomic nervous system is accomplished, at least in part, by the stimulation of β-adrenergic receptors by catecholamines at neuroeffector junctions1. Activation of these receptors results in stimulation of adenylate cyclase with increased intracellular levels of cyclic AMP. The β-adrenergic receptors of a variety of non-neural tissues have been characterised indirectly by measurement of altered adenylate cyclase activity or of intracellular cyclic AMP in response to β-adrenergic agonists and antagonists. Direct characterisation of the β-adrenergic receptors in avian2,3 and amphibian4 erythrocytes and in canine heart5 has been accomplished by binding assays using radioactive β-adrenergic antagonists.
240 citations
TL;DR: Rat hippocampal pyramidal cells were studied for their response to serotonin applied iontophoretically and to stimulation of the midbrain raphe nuclei and these data satisfy several of the criteria required to identify serotonin as the inhibitory neurotransmitter for the raphe-hippocampal pathway.
214 citations
TL;DR: The metabolites of serotonin, dopamine, and norepinephrine, 5-hydroxyindoleacetic acid, homovanillic acid, and HVA were studied in cerebrospinal fluid of patients with acute schizophrenia and the suggestion that altered dopamine metabolism may reflect a biological change predisposing to acute schizophrenia is suggested.
Abstract: The metabolites of serotonin, dopamine, and norepinephrine, 5-hydroxyindoleacetic acid (5HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxy-phenylethylene glycol (MHPG), respectively, were studied in cerebrospinal fluid of patients with acute schizophrenia. Base line levels of these metabolites were not significantly different from those in normal, neurological, and affectively ill controls. Accumulations of 5HIAA and HVA following probenecid administration, which provide a measure of serotonin and dopamine turnover, were also not significantly different in patients with acute schizophrenia and affective illness. After patients had recovered from their acute schizophrenic illness, HVA accumulations were significantly reduced. We discuss results in relation to amine hypotheses of schizophrenia and the suggestion that altered dopamine metabolism may reflect a biological change predisposing to acute schizophrenia.
195 citations
TL;DR: 5,7-DHT treatment was found to enhance the depressant effects of 5-hydroxytryptophan on a fixed-ratio barpress response, suggesting that 5,7,DHT treated rats are supersensitive to serotonin in the central nervous system.
167 citations
TL;DR: The observations suggest that serotonin- and catecholamine-containing brain neurons are normally under specific dietary control.
166 citations
TL;DR: The evidence suggests that D-[3H]LSD binds to post-synaptic serotonin receptors, the only putative neurotransmitter with affinity for the LSD binding site, and psychotropically active alkylindoleamines are also potent displacing agents.
164 citations
TL;DR: The results indicate that methergoline can selectively block at least some postsynaptic 5- HT receptors in the CNS and can be an important tool in the functional and biochemical analysis of central 5-HT neurones.
Journal Article•
TL;DR: Results parallel findings in the conflict test which indicate that the depressant action of oxazepam rapidly undergoes tolerance, whereas the anxiety-reducing action is maintained over repeated doses, suggesting that the drugs actually act indirectly to reduce serotonin activity.
Abstract: If the rat conflict test were a valid animal model of anxiety neurosis, evidence which implicates serotonin systems in the anxiety-reducing actions of benzodiazepine tranquilizers could be summarized as follows: (1) The punishment-lessening effects of benzodiazepines in the conflict test are mimicked by serotonin antagonists (methysergide, cinanserin, bromolysergic acid), serotonin synthesis inhibition (PCPA), and serotonin nerve terminal damage (5,6-dihydroxytryptamine). (2) Punishment effects may be intensified by the serotonin precursor, 5-hydroxytryptophan (in combination with a monoamine oxidase inhibitor), serotonin agonists (alpha-methyltryptamine), or intraventricular injections of serotonin itself. Intraventricularly administered serotonin also antagonizes the punishment-lessening effects of benzodiazepines. (3) Stimulation of the serotonergic cell bodies in the dorsal raphe nucleus by local application of crystalline carbachol causes intense suppression of behavior. The suppressive effects of raphe stimulation are antagonized by systemic administration of benzodiazepines. (4) In biochemical experiments, the decrease in norepinephrine turnover induced by oxazepam rapidly undergoes tolerance, whereas the decrease induced in serotonin turnover is maintained over repeated doses. These results parallel findings in the conflict test which indicate that the depressant action of oxazepam rapidly undergoes tolerance, whereas the anxiety-reducing action is maintained over repeated doses. Although central serotonin neurons are thus implicated in the therapeutic actions of benzodiazepine tranquilizers, it is quite possible that the drugs actually act indirectly to reduce serotonin activity. The concept that benzodiazepines may exert a primary action on GABA-containing neurons, which in turn regulate serotonergic transmission, was supported by preliminary psychopharmacological evidence. The GABA-antagonist picrotoxin, at doses that do not disrupt unpunished behavior, fully antagonizes the punishment-lessening effects of benzodiazepines in the conflict test.
TL;DR: Rats fed tryptophan-poor corn diets have reduced levels of brain serotonin and show increased responsiveness to electric shock, and this diet-induced hyperalgesia can be reversed by feeding the animals diets with adequate amounts of tryptophile, or by systemic injections of the amino acid.
Abstract: Rats fed tryptophan-poor corn diets have reduced levels of brain serotonin and show increased responsiveness to electric shock. This diet-induced hyperalgesia can be reversed by feeding the animals diets with adequate amounts of tryptophan, or by systemic injections of the amino acid.
Journal Article•
TL;DR: It is indicated that ouabain or K+ blocks the effect of norepinephrine on N-acetyltransferase activity; it appears that the blockade is at some point in the sequence of events leading to the increase in enzyme activity which follows the generation of cAMP.
Abstract: Rat pineal glands were cultured for 48 hr and then treated with 10 µM norepinephrine. This resulted in the predictable 50-100-fold increase in acetyl-CoA:serotonin N-acetyltransferase) (EC 2.3.1.5) activity at 6 hr. This increase failed to occur in glands simultaneously treated with 1 µM ouabain or 80 mM K+. Prior treatment of pineal glands with ouabain or K+ did not, however, depress the 100-200-fold norepinephrine-stimulated increase in the pineal content of adenosine cylic 39,59-monophosphate (cAMP) observed at 15-20 min; neither was there any alteration in the rate of disappearance of cAMP after this time. Ouabain or K+ alone failed to depress the conversion of L-[3H]tryptophan to either [3H]5-hydroxytryptophol or [3H]5-hydroxyindoleacetic acid. The conversion of L-[3H]tryptophan to [3H]serotonin was increased in the presence of 80 mM K+ but was not affected by the presence of 1 µM ouabain. This suggests that ouabain or K+ does not depress either the activity of the process responsible for the uptake and hydroxylation of L-[3H]tryptophan or the general indole metabolism in the pineal gland. Treatment with N6, O29-dibutyryladenosine cyclic 39,59-monophosphate (DBcAMP) or theophylline, compounds which are known to mimic the effects of norepinephrine on pineal N-acetyltransferase activity, did not stimulate N-acetyltransferase activity in the presence of 80 mM K+ or 1 µM ouabain. Ouabain given in vivo also reduced by 55-80% the effect of an injection of 20 mg/kg of isoproterenol on pineal N-acetyltransferase activity. Intracellular microelectrode recordings from acutely explanted pineal glands indicated that both 40 mM and 80 mM K+ caused a modest depolarization of the pineal cell membrane. In contrast, treatment with 1 µM ouabain for several minutes did not significantly change the resting membrane potential. However, both 80 mM K+ and 1 µM ouabain attenuated or reversed the hyperpolarization associated with exposure to norepinephrine. A small but significant hyperpolarizing effect was also elicited by treating the pineal gland with cAMP or DBcAMP. These findings indicate that ouabain or K+ blocks the effect of norepinephrine on N-acetyltransferase activity; it appears that the blockade is at some point in the sequence of events leading to the increase in enzyme activity which follows the generation of cAMP.
01 Jan 1975
TL;DR: These studies suggest that aging processes may significantly affect monoamine mechanisms and be a predisposing factor to the development of clinical diseases in man such as depression, parkinsonism and other disorders of central nervous system homeostasis.
Abstract: A series of studies of monoamines and their metabolism in a variety of human tissues indicate that there are aging effects that may alter neurotransmitter substances. Monoamine oxidase (MAO) activity has a significant positive correlation with age in plasma and blood platelets of normal subjects and patients suffering from depressive disorders. Monoamine oxidase and age correlate positively in hindbrain and in eight separate areas of human brains from patients who died from a variety of causes. Hindbrain norepinephrine concentration progressively decreases with advancing age (r = −0.44, P < 0.01) while no changes were noted for serotonin (5-HT) and 5-hydroxy.indoleacetic acid (5-HIAA). Hindbrain norepinephrine concentration has a significant negative correlation with MAO (r = −0.41, P < 0.025) and hindbrain 5-HIAA has a significant positive correlation with MAO (r = +0.66, P = <0.05). These studies suggest that aging processes may significantly affect monoamine mechanisms and be a predisposing factor to the development of clinical diseases in man such as depression, parkinsonism and other disorders of central nervous system homeostasis.—Rorinson, D. S. Changes in monoamine oxidase and monoamines with human development and aging. Federation Proc. 34: 103–107, 1975.
TL;DR: The present study suggests that only serotonergic drugs produce similar effects on release of prolactin and TSH, whereas drugs that alter CA and pilocarpine depress prolact in release but have little or no effect of TSH.
Abstract: The effects of a single injection of drugs on serum prolactin and TSH were determinedin male and in estrogen-primed ovariectomized rats. The precursor of serotonin, 5-hydroxytryptophan (5-HTP), produced a significant rise in serum prolactin and TSH, whereas para chloroamphetamine,a depletor of serotonin, elicited a fall in serum prolactin and TSH. α-methylmetatyrosine (α-MMT) and reserpine, both depressors of brain catecholamine (CA) and serotonin levels, evoked significant increases in serum prolactin and reductions in serum TSH. Injection of α-MMT or reserpine together with 5-HTP further elevated serum prolactin but prevented any significant change in serum TSH. This suggests that the ability of α-MMT and reserpine to inhibit TSH release is mediated through a reduction in brain serotonin and not via a decrease in CA. α-methylparatyrosine, which inhibits CA synthesis without altering serotonin, evoked a marked increase in serum prolactin but had no effect on serum TSH. L-dopa administration significantly...
TL;DR: A rapid and sensitive method for separation and concurrent assay of 14 compounds at the picomole level in individual rat brain parts is described, using a radioenzymatic method and modified microadaptations of previously reported methods.
TL;DR: The present studies show that aspiration of the anterodorsal hippocampus of adult male rats prior to median raphe lesions or PCPA administration abolished the ability of both of these treatments to produce locomotor hyperactivity in animals chronically housed in tilt cages, indicating that serotonin depletion-inducedhyperactivity in the rat is mediated by the hippocampus.
TL;DR: The dihydroxylated tryptamines 5,6-D HT and 5,7-DHT, have been utilized as pharmacological tools to produce selective degeneration of serotonin (5-HT)-containing neurons in the CNS but have so far limited their use in functional studies of indoleamine neurons.
TL;DR: Tryptophan hydroxylase in brain is only neuronal and cytoplasmic, exists in multiple forms, and is associated with microtubules, suggesting it may be transported from sites of synthesis in cell body into axons.
Abstract: Tryptophan hydroxylase [EC 1.14.16.4; L-tryptophan, tetrahydropteridine:oxygen oxidoreductase (5-hydroxylating)], the enzyme catalyzing the rate-limiting step in the biosynthesis of serotonin, was purified 79-fold from the region of the raphe nucleus of rat midbrain by sequential column chromatography and disc-gel electrophoresis. In electrophoresis three bands were distinguished, A, B, and C, which, when separated and submitted individually to electrophoresis, reproduced the same three bands. Bands A and C were enzymatically active and inhibited by para-chlorohenylalanine. Antibodies produced to each of the three bands crossreacted by immuno double diffusion and electrophoresis with each other and homogenates of raphe nuclei; they completely inhibited enzyme activity only of tryptophan hydroxylase. Tryptophan hydroxylase was localized by light and electron immunohistochemistry to serotonin neutrons of the raphe. Ultrastructurally, in cell bodies, the enzyme was distributed in cytoplasm and in association with endoplasmic reticulum and Golgi apparatus. In dendrites and axons, it was associated with microtubules. Tryptophan hydroxylase in brain is only neuronal and cytoplasmic, exists in multiple forms, and is associated with microtubules, suggesting it may be transported from sites of synthesis in cell body into axons.
TL;DR: Findings indicate that the depletion of brain serotonin by 4-chloroamphetamine is initially reversible but that there is a gradual transition into an irreversible effect between 24 and 48 hr after 4- chloroamphetamine injection.
TL;DR: Cell-free preparations from superior and inferior colliculi of very young rats contained adenylate cyclase systems which were highly responsive to serotonin, which are consisent with the existence of multiple receptors in rat brain which are capable of interacting with indoleamines.
TL;DR: Biochemical human post-mortem studies on depressed patients indicate an unspecific deficiency of neurotransmitters in several brain areas and a circadian disrhythm in depressed patients resulting in lowered VMA- and HVA-levels in urines during the morning and a remission to normal values in the evening.
Abstract: Biochemical human post-mortem studies on depressed patients indicate an unspecific deficiency of neurotransmitters in several brain areas. The loss of drive of these patients could be correlated with a decrease of striatal dopamine concentration. Noradrenaline was significantly diminished in red nucleus, a fact which points to the characteristic posture of depressed patients. Serotonin was diminished in all brain areas. During remission all values trended to be normal.
Journal Article•
TL;DR: The data suggest that 110140 is a specific drug for inhibiting uptake into serotoninergic neurons in the brain in rats, and suggests that reserpine does not require the membrane pump for entry into the neuron.
Abstract: 3-(p-Trifluoromethylphenoxy)-N-methyl-3-phenylpropylamine (Lilly 110140), when injected into rats at i.p. doses of 1 to 10 mg/kg, prevented the lowering of brain serotonin by 4-chloroamphetamine. The duration of 110140 action was very long, significant antagonism of 4-chloroamphetamine action being apparent still at 48 hours after a single dose of 10 mg/kg of 110140. The N,N-dimethyl tertiary amine derivative was as effective as 110140 itself in antagonizing serotonin depletion by 4-chloroamphetamine, but other structurally related compounds has less activity or were inactive. Likewise, six tricyclic antidepressant drugs injected at 10 mg/kg i.p. did not antagonize the action of 4-chloroamphetamine. When injected into rats whose brain serotonin levels had already been depleted by 3-hour pretreatment with 4-chloroamphetamine, 110140 terminated the action of 4-chloroamphetamine and permitted serotonin levels to return to normal. Lilly 110140 did not antagonize the depletion of brain serotonin or norepinephrine by reserpine, which implies that reserpine does not require the membrane pump for entry into the neuron. The depletion of brain serotonin, but not norepinephrine, by alpha-ethyl-3-hydroxy-4-methylphenethylamine (H75/12) was blocked by 110140. In contrast to chlorimipramine, 110140 did not antagonize the depletion of norepinephrine levels in heart and spleen by 6-hydroxydopamine. The data suggest that 110140 is a specific drug for inhibiting uptake into serotoninergic neurons in the brain.
Journal Article•
TL;DR: The data suggest that the area of the nucleus tractus solitarii is a site of action of hypotensive drugs which may act by noradrenergic receptor stimulation in the brain as indicated by the association of elevated blood pressure and brainstem serotonin depletion during treatment with para-chorophenylalanine of normotensive and genetic hypertensive rats.
Abstract: Noradrenaline and alpha-methylnoradrenaline applied to the area of the nucleus tractus solitarii of the medulla oblongata decreased arterial blood pressure and heart rate of anesthetized normotensive rats. Alpha-Methylnoradrenaline was more effective than noradrenaline. Prior administration of the alpha-adrenergic blocking agent phentolamine at the same site prevented the central inhibitory action of the two catecholamines and even reversed the effect on blood pressure. The hypotensive responses evoked by electrical stimulation or alpha-methylnoradrenaline application were found to have a common distribution of the most effective site, comprising the middle-caudal part of the nucleus tractus solitarii at the obex level. Bilateral electrolytic lesions of this area caused an immediate and severe hypertension. The data suggest that the area of the nucleus tractus solitarii is a site of action of hypotensive drugs which may act by noradrenergic receptor stimulation in the brain. In addition brain serotonin may also play an inhibitory role as indicated by the association of elevated blood pressure and brainstem serotonin depletion during treatment with para-chorophenylalanine of normotensive and genetic hypertensive rats.
TL;DR: Intracellular stores of dopamine and serotonin were found to be synthesized in the proper neuron and transported down the axon to the terminal varicosities and taken up by both kinds of nerve cells and by some other tissues.
Abstract: Monoamine localization was accomplished in Mytilus edulis by the use of histofluorescence. Intracellular stores of dopamine and serotonin were found to be synthesized in the proper neuron and transported down the axon to the terminal varicosities.Most of the cells in the cortex of the cerebral and visceral ganglia were non-fluorescent. Of the fluorescent cells, serotonin predominated in the cerebral ganglion and dopamine predominated in the visceral ganglion. There was a net flow of serotonin in the cerebro-visceral connective from the cerebral to the visceral ganglion and a net flow of dopamine in the opposite direction.Serotonin fluorescence was localized in intracellular granules in neurons and blood cells. Dopamine fluorescence was distributed homogenously in neurons and in the supporting rod of the gill. The visceral ganglion supplies the gill with nerve fibers of both types.Exogenously supplied serotonin and dopamine were taken up by both kinds of nerve cells and by some other tissues. Endogenous st...
TL;DR: It appears that serotonin may be significant modulating neurotransmitter for the control of growth hormone secretion, limiting sleep-related release, and enhancing insulin-induced release.
Abstract: Methysergide, a clinically-used blocker of serotonin receptors, was administered to 10 normal young men at a dose of 2 mg every 6 h for 48 h. After drug treatment, serum levels of growth hormone during sleep were 41.9% higher than placebo values (less than 0.001). In contrast, drug treatment was associated with a 36.4% decrease in stimulated growth hormone secretion during insulin tolerance testing (P less than 0.01). These opposite effects of methysergide suggest that different mechanisms are responsible for sleep-related and insulin-induced growth hormone secretion. Accordingly, data obtained with pharmacologic stimuli may lead to erroneous inferences regarding physiologic growth hormone control mechanisms. Administration of methysergide profoundly suppressed sleep-related prolactin secretion; overall nocturnal mean prolactin fell by 70.3% from 4.30+/-0.19 to 1.28+/-0.06 ng/ml (P less than 0.0001). It appears that serotonin may be significant modulating neurotransmitter for the control of growth hormone secretion, limiting sleep-related release, and enhancing insulin-induced release. It seems likely from these data that the role of serotonin in the control of prolactin secretion is relatively more important, since serotonin receptor blockade dramatically reduced sleep-related prolactin secretion.
01 Aug 1975
TL;DR: A review of a variety of behavioral effects of 5-HT depletion including an enhanced response to lysergic acid diethylamide and amphetamine suggests that the ascending serotonergic system may have a general role in the inhibition of arousal, rather than a specific role with respect to various categories of behavior.
Abstract: Depletion of telencephalic serotonin (5-HT) content by medial forebrain bundle lesions, which interrupt the ascending serotonergic pathways or by dl-p-chlorophenylalanine produces an increased sensitivity to pain as measured by the flinch-jump, stabilimetric, or hot-plate methods. Examination of the effects of a number of other lesions and drugs indicated that dopamine, norepinephrine and acetylcholine are not involved in pain sensitivity. Dosages of 75 mg/kg dl-5-hydroxytryptophan(5-HTP), 37.5 mg/kg l-5-HTP or 50 mg/kg Ro 4-4602 (N 1-(dl-seryl)-N 2-(2,3,4-trihydroxybenzyl)hydrazine) plus 37.5 mg/kg l-5-HTP administered to medial forebrain bundle lesioned rats returned both the telencephalic content of 5-HT and the pain threshold to normal values. Injection of 37.5 mg/kg of d-5-HTP or an equimolar dose of l-dopa had no effect on pain threshold. Normal animals display increased sensitivity to pain and decreased 5-HT contents in frontal pole, hippocampus, and amygdala during dark as compared to light hours. All three of these telencephalic areas are innervated by the ascending serotonergic pathways, and cells in these areas show inhibition of firing following the iontophoretic application of 5-HT. Taken together, these data suggest that the serotonergic system normally acts to inhibit the effects of painful stimuli. A review of a variety of behavioral effects of 5-HT depletion including an enhanced response to lysergic acid diethylamide and amphetamine suggests that the ascending serotonergic system may have a general role in the inhibition of arousal, rather than a specific role with respect to various categories of behavior.—Harvey, J. A., A.J. Schlosberg and L. M. Yunger. Behavioral correlates of serotonin depletion. Federation Proc. 34: 1796-1801, 1975.
TL;DR: The ability of methysergide to release prolactin in rats with serotonin receptors presumably blocked, suggests that the serotonin receptor-blocking and the prolactIn-releasing actions of MES are not related.
Abstract: The effect of methysergide (MES, 2.5 mg/100 g body wt), a serotonin antagonist, on prolactin release has been studied in lactating and ovariectomized rats. MES caused significant increases in prolactin release in both animals. Studies in ovariectomized, hypophysectomized rats indicate that this effect is not due to a decrease in the peripheral metabolism of prolactin. In vitro incubations of anterior pituitary fragments with MES failed to demonstrate any increase in prolactin release, suggesting that MES does not act directly on the anterior pituitary. Parachlorophenylalanine (PCPA; 32 mg/100 g body vvt) decreased brain serotonin levels in ovariectomized rats 5, 24, and 70 h after its administration, yet did not alter plasma prolactin levels. L-tryptophan (6.3 mg/100 g body wt) given 1 and l½ h prior to sacrifice increased brain serotonin levels, yet did not affect plasma prolactin levels. Neither PCPA nor L-tryptophan altered MESinduced prolactin release. In lactating rats, suckling caused marked increas...