Showing papers on "Serotonin published in 1980"
TL;DR: The decrease in the number of receptor sites is most marked for [3H]spiroperidol-labeled serotonin receptors and is characteristic for antidepressants of several classes.
Abstract: Antidepressants compete at several neurotransmitter receptor binding site, but drug affinities do not correlate with clinical efficacy. Long-term, but not short-term, antidepressant treatment decreases the numbers of both serotonin and beta-adrenergic receptors. The decrease in the number of receptor sites is most marked for [3H]spiroperidol-labeled serotonin receptors and is characteristic for antidepressants of several classes.
832 citations
Journal Article•
TL;DR: This relationship allows precursor administration to produce selective physiologic effects by enhancing neurotransmitter release from some but not all of the neurons potentially capable of utilizing the precursor for this purpose, and allows the investigator to predict when administering the precursor might be useful for amplifying a physiologic process, or for treating a pathologic state.
Abstract: Studies performed during the past decade have shown that the rates at which certain neurons produce and release their neurotransmitters can be affected by precursor availability, and thus by the changes in plasma composition that occur after ingestion of the precursors in purified form or as constituents of foods. Thus, tryptophan administration or a plasma ratio of tryptophan to other large neutral amino acids, thereby raising brain tryptophan levels, increasing the substrate saturation of tryptophan hydroxylase, and accelerating the synthesis and release of serotonin. Tyrosine administration or a high-protein meal similarly elevates brain tyrosine and can accelerate catecholamine synthesis in the CNS and sympathoadrenal cells, while the consumption of lecithin or choline increases brain choline levels and neuronal acetylcholine synthesis. The physiologic and biochemical mechanisms that must exist in order for nutrient consumption to affect neurotransmitte synthesis have been characterized and include: 1) the lack of significant feedback control of plasma levels of the precursor; 2) the lack of a real "bloodbrain barrier" for the precursor, i.e. the ability of the plasma level of the precursor to control its influx into, or efflux from, the CNS; 3) the existence of a low-affinity (and thus unsaturated) transport system mediating the flux of the precursor between blood and brain; 4) low-affinity kinetics for the enzyme that initiates the conversion of the precursor to the transmitter; and, 5) the lack of end-product inhibition of the enzyme, in vivo, by its ultimate product, the neurotransmitter. The extent to which neurotransmitter synthesis in any particular aminergic neuron happens to be affected by changes in the availability of its precursor probably varies directly with the neuron's firing frequency. This relationship allows precursor administration to produce selective physiologic effects by enhancing neurotransmitter release from some but not all of the neurons potentially capable of utilizing the precursor for this purpose. It also allows the investigator to predict when administering the precursor might be useful for amplifying a physiologic process, or for treating a pathologic state. (for example, tyrosine administration raises blood pressure in hypotensive rats, lowers it in hypertensive animals, and has little effect on blood pressure in normotensive animals; the elevation in blood pressure probably reflects enhanced catecholamine release from sympathoadrenal cells, while the reduction in hypertensive animals probably results from increased catecholamine release within the brain-stem.) Such predictions are now being tested clinically in many institution. Available evidence suggests that lecithin or cholie administration can diminish the frequency of abnormal movements in patients with tardive dyskinesia...
644 citations
TL;DR: The authors examined the potencies of 22 neuroleptic drugs competing for binding sites associated with dopamine, serotonin, alpha-adrenergic, and histamine receptors in brain membranes and found that although many neuroleptics are quite potent in competing at several receptor sites, the average antipsychotic clinical potency correlates closely only with the drug affinity for dopamine receptors labeled by 3H-spiroperidol.
Abstract: The authors examined the potencies of 22 neuroleptic drugs competing for binding sites associated with dopamine, serotonin, alpha-adrenergic, and histamine receptors in brain membranes. They found that although many neuroleptics are quite potent in competing at several of these receptor sites, the average antipsychotic clinical potency correlates closely only with the drug affinity for dopamine receptors labeled by 3H-spiroperidol At clinically effective doses, however, substantial occupancy of serotonin, alpha-adrenergic, and histamine receptors often occurs and may account for some of the auxiliary actions of neuroleptics.
517 citations
TL;DR: It was found here that various brain regions differ markedly in their membrane lipid viscosity, which may have important implications for physiological processes in the central nervous system, which are associated with modulation of membrane lipids, such as aging.
Abstract: The binding of [3H]serotonin to mouse brain crude membrane and synaptosomal membrane preparations was investigated as a function of membrane fluidity changes by lipids. The microviscosity (eta) of the synaptic membranes was increased by in vitro incubation with either cholesteryl hemisuccinate or stearic acid, resulting in an up to 5-fold increase in the specific binding of [3H]serotonin. Serotonin binding increased progressively until it reached a maximum at 1.75 relative eta units; then it declined. Fluidization of membrane lipids, by treatment with lecithin or linoleic acid, caused a small but significant decrease in serotonin binding. These observations are compatible with the concept of vertical displacement of membrane proteins, indicating that in the untreated brain tissue the accessibility (Bmax) of serotonin receptor binding sites constitutes only a fraction (about 20%) of the potential binding capacity stored in the membrane. Scatchard plots of [3H]serotonin binding, at different eta values, indicate a continuous change in the binding affinity (Kd) of serotonin to its receptor, concomitant with changes in its accessibility. These results may have important implications for physiological processes in the central nervous system, which are associated with modulation of membrane lipids, such as aging. In addition, the regional heterogeneity and plasticity of receptors may be accounted for by differences in membrane lipid fluidity. It was found here that various brain regions differ markedly in their membrane lipid viscosity.
423 citations
TL;DR: The results suggest that high-affinity [3H]imipramine binding might be associated with the mechanism of serotonin uptake in the brain.
Abstract: Inhibition of the binding of [3H]imipramine and inhibition of the uptake of [3H]serotonin and [3H]norepinephrine by a series of antidepressants and other drugs were studied in the rat hypothalamus. No correlation was found between the potencies of these drugs for the inhibition of [3H]imipramine binding and the inhibition of [3H]norepinephrine uptake. There was, however, a highly significant correlation between the potencies of these drugs for the inhibition of [3H]serotonin uptake. These results suggest that high-affinity [3H]imipramine binding might be associated with the mechanism of serotonin uptake in the brain.
354 citations
TL;DR: Excessively high doses of tryptophan may actually decrease the production of cerebral serotonin and 5-hydroxyindoleacetic acid.
Abstract: One pathway by which tryptophan is metabolized in the brain as well as in the periphery is through cleavage of the indole ring to formylkynurenine and then kynurenine. Indoleamine-2,3-dioxygenase, the enzyme that catalyzes this cleavage, and kynurenine are distributed all across the different anatomic regions of brain. Approximately 40% of the kynurenine in brain is synthesized there, the remainder having come from plasma. Tryptophan loading, which has been used both experimentally and therapeutically as a means of increasing tryptophan conversion to serotonin, also increases kynurenine formation in the brain and in the periphery. Because of the formation of kynurenine, which competes for cerebral transport and cellular uptake of L-tryptophan, and because of substrate inhibition on tryptophan hydroxylase, excessively high doses of tryptophan may actually decrease the production of cerebral serotonin and 5-hydroxyindoleacetic acid.
283 citations
TL;DR: The mechanisms underlying this complex response may be mediated by descending 5-HT systems that result in motor excitation at the spinal cord level, in contrast to rostral projections to forebrain that may mediate many behaviorally inhibitory responses.
264 citations
TL;DR: The reduction in sympathetic outflow produced by increasing brain serotonin levels in dogs protects the heart against ventricular fibrillation and may, therefore, constitute a reasonable adjunct in the management of high-risk, cardiac-arrest patients.
Abstract: Alterations in the dynamics of brain serotonin biosynthesis can lead to changes in cardiovascular function. It appears that the activation of cerebral serotonin receptors produces a pressor effect in normotensive rats but produces a depressor effect in normotensive cats or dogs. On the other hand, reductions in the levels of serotonin can prevent the onset of hypertension in some experimental hypertensive models and lower the blood pressure of organisms with established hypertension. The ability of brain serotonin to modulate arterial blood pressure may be mediated by the influences of the serotonergic neuronal systems on efferent sympathetic activity. Finally, the reduction in sympathetic outflow produced by increasing brain serotonin levels in dogs protects the heart against ventricular fibrillation and may, therefore, constitute a reasonable adjunct in the management of high-risk, cardiac-arrest patients.
253 citations
TL;DR: The reversal of learned helplessness by cortical desipramine restored a deficit in septal release of serotonin and could be prevented by administration of bicuculline into the hippocampus but not the lateral geniculate body, consistent with two types of desipamine-sensitive cells, one regulating a GABA-modulatedrelease of serotonin in the septum, and the other regulating a inhibitory release of norepinephrine in the hippocampus.
250 citations
TL;DR: Investigating the membrane mechanisms underlying the modulatory effects of serotonin by obtaining intracellular recordings from rat facial motoneurones during extracellular microiontophoretic application of serotonin, methysergide (a serotonin antagonist) and noradrenaline found that these actions of serotonin are selective and receptor mediated.
Abstract: The application of serotonin to certain myenteric plexus neurones in the guinea pig small intestine causes a slow depolarization of membrane potential, accompanied by increased neuronal excitability and input resistance1. On the other hand, microiontophoretic application of large amounts of serotonin onto mammalian spinal motoneurones is reported to cause membrane hyperpolarization and decreased excitability2. However, on the basis of recording spinal reflex activity, serotonin has been reported to enhance net motoneurone activity3. Moreover, studies using extracellular single-cell recording techniques indicate that serotonin in small amounts facilitates synaptically or glutamate-induced excitation of mammalian motoneurones in the facial nucleus4 and spinal cord5. It was suggested that these facilitatory actions were modulatory in nature, as serotonin did not induce motoneurone spiking in the absence of extrinsic excitatory input. The study reported here investigated the membrane mechanisms underlying these modulatory effects by obtaining intracellular recordings from rat facial motoneurones during extracellular microiontophoretic application of serotonin, methysergide (a serotonin antagonist) and noradrenaline. Serotonin caused a slow depolarization of membrane potential of about 5 mV which remained subthreshold, accompanied by an increase in electrical excitability of the neurone, and an increase in input resistance. Noradrenaline caused the same changes. Methysergide antagonized the effects of serotonin, but not noradrenaline, indicating that these actions of serotonin are selective and receptor mediated.
233 citations
TL;DR: It is concluded that the long-lasting increase of respiratory activity following stimulation of carotid body afferents is due to activation of an endogenous central serotoninergic mechanism which facilitates respiration.
TL;DR: It is reported that four substances, thought to function as neurohormones in Crustacea, all produce long-term changes in the physiological properties of lobster opener muscle preparations, including serotonin and octopamine, and the peptide, proctolin.
Abstract: In this communication we report that four substances, thought to function as neurohormones in Crustacea, all produce long-term changes in the physiological properties of lobster opener muscle preparations. The substances are the amines, octopamine, serotonin and dopamine, and the peptide, proctolin. The actions of these substances are superimposed on the normal synaptic apparatus that utilizes the amino acids GABA and glutamate (probably) as the inhibitory and excitatory neurotransmitter compounds. Serotonin acts on excitatory and inhibitory nerve endings to facilitate transmitter release and directly on muscle fibres to produce a contracture and to induce the appearance of Ca2+ action potentials. The latter two actions of serotonin are shared by proctolin and octopamine as well. Dopamine, on the other hand, relaxes muscle baseline tension. The mechanism of action of these substances at their target site (or sites) has been explored with electrophysiological and biochemical techniques and the results will be presented. In addition preliminary behavioural experiments have been carried out with serotonin and octopamine. These substances produce opposite postures when injected into lobsters. The amines act on central ganglia to produce these effects where they cause a programmed readout of firing of neurones that will produce either a flexed posture (serotonin) or an extended posture (octopamine).
TL;DR: In vitro experiments indicated that antidepressants are relatively weak alpha 2-receptor blocking agents, but some are potent on the alpha 1-recept system indicating that the norepinephrine releasing potency of some antidepressants may not be mediated by blockade of presynaptic autoreceptors.
TL;DR: Purified preparations of microvessels from bovine cerebral cortex contain substantial levels of alpha-adrenergic, beta-adRenergic, and histamine 1 receptor binding sites but only negligible serotonin, muscarinic cholinergic, opiate, and benzodiazepine receptor binding.
Abstract: Purified preparations of microvessels from bovine cerebral cortex contain substantial levels of alpha-adrenergic, beta-adrenergic, and histamine 1 receptor binding sites but only negligible serotonin, muscarinic cholinergic, opiate, and benzodiazepine receptor binding. Norepinephrine and histamine may be endogenous regulators of the cerebral microcirculation at the observed receptors.
TL;DR: This survey, the third in a series, presents extensive tabulations of literature on thermoregulatory effects of adrenergic and serotonergic agonists and their antagonists including ergot alkaloids, amphetamines, tryptamines, monoamine oxidase inhibitors, tricyclic and other antidepressants.
TL;DR: The results suggest that lithium administration causes selective changes in brain neurotransmitter receptor systems and that the net result of these changes may be a decrease in GABAergic and serotoninergic activity.
Abstract: Chronic, but not acute, consumption of lithium leads to a significant decrease in serotonin and GABA receptor binding in selected regions of the rat brain, with no changes noted in P-adrenergic or cholinergic muscarinic receptor binding. In addition, the concentration of β-methoxytyramine, a dopamine metabolite, in the corpus striatum was increased in the animals treated chronically with lithium, suggesting a possible enhancement in dopamine release, or inhibition of uptake, in this brain area. In contrast, chronic consumption of rubidium had no effect on any of the parameters studied. The results suggest that lithium administration causes selective changes in brain neurotransmitter receptor systems and that the net result of these changes may be a decrease in GABAergic and serotoninergic activity. The fact that these alterktions are noted only after chronic administration suggests that they may be related to the therapeutic action of lithium in the prophylactic treatment of recurrent manic- depressive psychosis.
TL;DR: Serotonin infused into the lateral ventricle in rats produced a dose-dependent depression of the acoustic startle reflex, and when infused onto the spinal cord, serotonin produced adose-dependent increase in startle.
Abstract: Serotonin infused into the lateral ventricle in rats produced a dose-dependent depression of the acoustic startle reflex. When infused onto the spinal cord, serotonin produced a dose-dependent increase in startle. Thus the same neurotransmitter can modulate the same behavior in opposite ways, depending on which part of the central nervous system is involved.
TL;DR: It is demonstrated that although selective depletion of NA does not alter the drug-induced serotonin- and dopamine-mediated responses, it abolishes the ECS-induced enhancement of these behaviours.
Abstract: When rats are given a series of electroconvulsive shocks (ECSs) over several days, they display enhanced behavioural responses to both serotonin- and dopamine-receptor agonists 1–3. Because these changes are seen when the ECS is given in ways closely mimicking the clinical administration of electroconvulsive therapy (ECT), it has been suggested that the changes in post-synaptic monoamine function may be involved in the antide-pressant mechanisms of ECT4,5. Ligand-binding studies have excluded the possibility that ECS alters the characteristics of either the serotonin or dopamine receptor6–8; ECS may therefore be acting on neuronal systems which modulate monoamine neurotransmission. As repeated ECS has recently been reported to decrease both noradrenaline (NA)-sensitive adenylate cyclase9 and β-adrenoreceptor binding8,10,11, we have examined here whether changes in NA function are related to the effects of ECS on the serotonin- and dopamine-mediated behaviours. We demonstrate that although selective depletion of NA does not alter the drug-induced serotonin- and dopamine-mediated responses, it abolishes the ECS-induced enhancement of these behaviours.
TL;DR: It is demonstrated that the serotonin-induced hyperpolarization of neuron R15 is mediated by cyclic AMP, similar to the serotonin receptor that was shown to be coupled to adenylate cyclase.
Abstract: Addition of serotonin to the medium bathing an Aplysia abdominal ganglion causes a change in the endogenous bursting activity of the identified neuron R15. At serotonin concentrations in the micromolar range, the predominant effect is an increase in depth and duration of the interburst hyperpolarization and consequent decrease in burst rate. At higher concentrations (10 microM) serototin can inhibit bursting completely. We have shown previously that these changes can be mimicked by bath application or intracellular injection of several cyclic AMP analogs substituted at the 8 position. Voltage clamp analysis indicates that serotonin and cyclic AMP analogs both cause an increase in membrane slope conductance in R15, with reversal potentials for the responses between -75 and -80 mV, close to the K+ equilibrium potential. When the K+ concentration in the bathing medium is changed, the reversal potentials change in a manner suggesting that serotonin and cyclic AMP analogs on K+ conductance are not additive. Furthermore, the effects of low concentrations of serotonin can be potentiated by the phosphodiesterase inhibitor Ro 20-1724. A pharmacological analysis indicates that the serotonin receptor that mediates hyperpolarization in R15 is similar to the serotonin receptor that we have shown to be coupled to adenylate cyclase. The present electrophysiological and pharmacological observations, together with our previous biochemical and pharmacological results, demonstrate that the serotonin-induced hyperpolarization of neuron R15 is mediated by cyclic AMP.
TL;DR: Biochemical analysis indicated that whereas medial raphe lesions significantly reduced serotonin in the septohippocampal complex, dorsal raphe patients had no such effect, and the differing roles of the mesolimbic and mesostriatal serotonergic systems in learning to ignore irrelevant stimuli were discussed.
Abstract: Rats received either 0 or 30 preexposures to a tone which was later used as a conditioned stimulus (CS) in a two-way avoidance task. Tone preexposure resulted in retarded conditioning in normal animals and animals with dorsal raphe lesions. This latent inhibition effect, however, was not present in animals with medial raphe lesions. The failure of CS preexposure to retard conditioning in animals with medial raphe lesions was not due to differences in auditory sensitivity or shock reactivity. Biochemical analysis indicated that whereas medial raphe lesions significantly reduced serotonin in the septohippocampal complex, dorsal raphe lesions had no such effect. The results are discussed in terms of the differing roles of the mesolimbic and mesostriatal serotonergic systems in learning to ignore irrelevant stimuli.
TL;DR: It is suggested that supersensitivity to noradrenaline and serotonin induced by SAH may be involved in the production of chronic cerebral vasospasm.
Abstract: This study analyzes the time course of the changes induced by subarachnoid hemorrhage (SAH) in the sensitivity of cat cerebral arteries to noradrenaline and serotonin. Cerebral arteries to noradrenaline and serotonin. Cerebral arteries displayed a supersensitivity to these amines, which was most marked 3 days after the experiment and then gradually disappeared. The supersensitivity to serotonin was greater and longer than the response to noradrenaline. The increase in the vascular contractile response induced by SAH was similar to that seen after superior cervical ganglionectomy or intracisternal injections of 6-hydroxydopamine. It is suggested that supersensitivity to noradrenaline and serotonin induced by SAH may be involved in the production of chronic cerebral vasospasm.
TL;DR: Treatment of rats with daily intraperitoneal injections of several clinically effective tricyclics for 14–20 days was found to enhance responses to norepinephrine and serotonin, and to an intravenously administered 5-HT agonist, 5-MeODMT.
TL;DR: Patients had various specific disorders of the nervous system, though patients with movement disorders and biochemical defects known to affect the neurotransmitter systems examined in this study were specifically avoided.
Abstract: Homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) were measured in lumbar cerebrospinal fluid from a group of patients ranging in age from 1 week to 45 years. Quantitation of these biogenic amine metabolites was achieved using a gas chromatographic/mass spectrometric technique. The subjects had various specific disorders of the nervous system, though patients with movement disorders and biochemical defects known to affect the neurotransmitter systems examined in this study were specifically avoided.
The results indicated a strong inverse correlation in children between CSF HVA and 5-HIAA concentrations and age. The decline in these metabolites with age appeared to be exponential. No significant age effect was observed for MHPG. The results indicate the importance of comparing CSF metabolite levels in children with values in age-matched controls.
TL;DR: The data suggest that the brain tryptophan content is an important factor in the control of both 5-hydroxytryptamine and tryptamine synthesis and brain 5-Hydrosytryptamines metabolism exhibits a U-shaped relationship with age.
Abstract: Tryptophan, 5-hydroxyindoleacetic acid and indoleacetic acid were measured in cerebrospinal fluid, taken during pneumoencephalography, from a large series of patients, the majority of whom were epileptics, most of them receiving anticonvulsants. CSF indoleacetic acid reflects CNS tyrptamine metabolism in the same way that CSF 5-hydroxyindoleacetic acid reflects CNS 5-hydroxytryptamine metabolism. Our data suggest that (i) the brain tryptophan content is an important factor in the control of both 5-hydroxytryptamine and tryptamine synthesis (ii) brain 5-hydroxytryptamine metabolism exhibits a U-shaped relationship with age (iii) the mean brain tryptophan content and rate of 5-hydroxytryptamine metabolism are greater for women than men (iv) indoleamine metabolism is unaffected in untreated epileptics compared with non-epileptics, but anticonvulsant drugs decrease the rate of 5-hydrosytryptamine metabolism.
Journal Article•
TL;DR: The hypothesis that some types of human depression may be primarily due to an excess of free 5-HT acting at postsynaptic receptors is supported.
Abstract: Rats working on a food-reinforced operant schedule and exhibiting behavioral depression following administration of D,L-5-hydroxytryptophan (5-HTP) were pretreated with one of three drugs: methysergide, fluoxetine, or amitriptyline. The former two drugs were used to establish a basis for distinguishing between pre- and postsynaptic events. We found that methysergide, a known postsynaptic blocker of serotonin, almost completely abolished the depressive effect of 5-HTP, whereas fluoxetine, a known specific uptake blocker of serotonin, potentiated the depressive effect of the 5-hydroxytryptamine (5-HT) precursor. Amitriptyline, one of the commonly prescribed antidepressive drugs, reduced the behavioral depression following 5-HTP by approximately 50%. These data indicate that amitriptyline can act as an antagonist of 5-HT at the postsynaptic receptor. The results of this study, as well as those recently reported from CNS membrane binding studies, suggest that the therapeutic effects of some antidepressive drugs may be explained by their postsynaptic rather than presynaptic properties at central serotonergic receptors. Thus, these studies support the hypothesis that some types of human depression may be primarily due to an excess of free 5-HT acting at postsynaptic receptors.
TL;DR: It is concluded that 5-HT denervation induces neither pre- nor postsynaptic types of supersensitivity in hippocampal pyramidal cells, contrasting with the previously shown supersensitivity of ventral lateral geniculate and amygdaloid neurons following 5- HT denervation.
TL;DR: Earlier evidence that brain serotonin neurons have a stimulatory influence on pituitary-adrenocortical function in rats is strengthened, as evidence that the increase in serum corticosterone concentration was mediated by serotonin release is strengthened.
Abstract: (± )pChloroamphetamine hydrochloride, at doses of 1–8 mg/kg i.p. in rats, caused a dose-related increase in serum corticosterone concentration. The increase occurred rapidly, within 30 min, and was ov
TL;DR: The effects of 'peripheral' serotonin (5-HT) antagonists on the facilitation of facial motoneuron excitation by 5-HT were investigated in the present study and appear to directly block the latter component.
TL;DR: The data suggest that 3H-d-LSD bound to more than one serotonin site in the calf frontal cortex and that3H-spiperone bound to a separate serotonergic site, which supports previous suggestions that supersensitivity develops specifically in serotonin receptors following afferent denervation.