Showing papers on "Serotonin published in 1983"
TL;DR: 3H-PAT seems to be a useful ligand for studying the biochemical and pharmacological characteristics of presynaptic autoreceptors in selected regions of rat brain.
Abstract: Binding studies with appropriate labelled ligands have revealed the existence of two types of serotonin (5-HT) receptor, 5-HT1 and 5-HT2, in the central nervous system of mammals1. The 5-HT1 type is characterized by a higher affinity for agonists than for antagonists, whereas the 5-HT2 type binds preferentially to antagonists. However, neither of these receptor types apparently corresponds to the presynaptic autoreceptor controlling 5-HT release2. In an attempt to identify the presynaptic autoreceptor directly, we synthesized the tritiated derivative of 8-hydroxy-2-(di-n-propylamino) tetralin (PAT), a new tetralin derivative with potent 5-HT agonist properties3 and carried out binding studies with rat brain membranes. As we report here, in the hippocampus, the properties of 3H-PAT binding sites correspond closely to those of 5-HT1 sites. In contrast, in the striatum, 3H-PAT binding sites exhibit a subcellular distribution and pharmacological characteristics usually associated with presynaptic autoreceptors. Furthermore, a marked loss of 3H-PAT binding sites occurs in the striatum (but not in the hippocampus) after the selective degeneration of serotoninergic fibres in 5,7-hydroxytryptamine (5,7-HT)-treated rats. Conversely, the sprouting of additional 5-HT terminals in the brain stem of adult rats treated at birth with 5,7-HT is associated with an increased density of 3H-PAT binding sites in this region. 3H-PAT thus seems to be a useful ligand for studying the biochemical and pharmacological characteristics of presynaptic autoreceptors in selected regions of rat brain.
762 citations
TL;DR: In patients who had discontinued L-DOPA at least 4 days before death (group I), the levels of dopamine and its metabolites were reduced in these cortical areas, although to a lesser extent than in the caudate nucleus.
724 citations
TL;DR: The combined findings of both studies support the decreased use of serotonin in suicide victims and may also throw light on the mechanism of action of antidepressant drugs.
500 citations
TL;DR: Markers of serotonin synapses in entire temporal lobe and frontal and temporal neocortex were examined for changes in Alzheimer's disease by use of both neurosurgical and autopsy samples, indicating that serotonin nerve terminals are affected.
Abstract: Markers of serotonin synapses in entire temporal lobe and frontal and temporal neocortex were examined for changes in Alzheimer's disease by use of both neurosurgical and autopsy samples. Uptake of [3H]sero-tonin, binding of [3H]imipramine, and content of indola-mines were all significantly reduced, indicating that serotonin nerve terminals are affected. Binding of [3H]serotonin was also reduced, whereas that of [3H]qui-nuclidinyl benzilate, [3H]muscimol, and [3H]dihydroal-prenolol were unaltered. When the Alzheimer's samples were subdivided according to age, the reduction in [3H]serotonin binding was a feature of only autopsy samples from younger patients. In contrast, presynaptic cholinergic activity was reduced in all groups of Alzheimer's samples, including neurosurgical specimens. Five markers, thought to reflect cerebral atrophy, cytoplasm, nerve cell membrane, and neuronal perikarya were measured in the entire temporal lobe. In Alzheimer's disease the reductions (mean 25%, range 20–35%) were thought to be too large to be due only to loss of structures associated with the presumed cholinergic perikarya in the basal forebrain and monoamine neurones in the brain stem.
441 citations
Journal Article•
TL;DR: It is proposed that selective blockade of serotonin reuptake can induce activation of norepinephrine neurons and subsequent down-regulation of norpinephrine receptors and that sertraline, a highly selective inhibitor of serotonin uptake, may be an efficacious antidepressant without anticholinergic or cardiovascular side-effects.
Abstract: Sertraline [1S,4S-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthylamine] was found to be a highly selective and potent competitive inhibitor of synaptosomal serotonin uptake. Sertraline also selectively reduced ex vivo uptake of serotonin and strongly antagonized the serotonin-depleting action of p-chloroamphetamine, indicating potent blockade of serotonin uptake in vivo. Acute and repeated dosing of sertraline decreased serotonin content of whole blood. Sertraline only weakly inhibited rat heart uptake of i.v. [3H]norepinephrine. In substantiation of selective blockade of serotonin uptake, sertraline potentiated various symptoms of 5-hydroxytryptophan but did not reverse reserpine-induced hypothermia. Sertraline was a very weak inhibitor of [3H]quinuclidinyl benzilate binding to rat brain membranes in vitro and did not produce anticholinergic effects in mice in vivo. Sertraline was well tolerated in mice, rats and dogs, with no locomotor stimulant effects in rats or untoward cardiovascular effects in dogs. The major metabolite, N-demethylsertraline, was also a selective serotonin uptake blocker. Sertraline strongly reduced immobility of mice in the Porsolt swim test for antidepressants. After repeated dosing in rats, sertraline diminished the cyclic AMP response of limbic forebrain adenylate cyclase to norepinephrine, as well as the binding of [3H]dihydroalprenolol to cortical membranes. It is proposed that selective blockade of serotonin reuptake can induce activation of norepinephrine neurons and subsequent down-regulation of norepinephrine receptors and that sertraline, a highly selective inhibitor of serotonin uptake, may be an efficacious antidepressant without anticholinergic or cardiovascular side-effects.
239 citations
TL;DR: It is suggested that there are two different aromatic amino acid decarboxylases in Drosophila brains, one that decar boxylates L-dopa and 5-hydroxytryptophan and another that decARboxylates tyrosine.
Abstract: The biogenic monoamine neurotransmitters octopamine, dopamine and serotonin have been detected in nervous tissue from many insects1. We report here that intact Drosophila melanogaster brains, when incubated with the radioactive amino acids tyrosine and tryptophan, synthesized and accumulated labelled monoamines. In two mutant strains monoamine synthesis was abnormal. The pero mutation abolishes the normal circadian rhythm2–4. Brains from pero flies, when incubated in tritiated tyrosine, accumulated one-third as much labelled octopamine as did brains from wild-type flies, but had normal dopamine and serotonin synthesis. In contrast, dopa decarboxylase (Ddc) mutations5,6 decreased dopamine and serotonin synthesis but did not affect octopamine synthesis. These results suggest that there are two different aromatic amino acid decarboxylases in Drosophila brains, one that decarboxylates L-dopa and 5-hydroxytryptophan and another that decarboxylates tyrosine. Direct measurement of L-dopa, 5-hydroxytryptophan and tyrosine decarboxylase activities in the different strains confirmed this suggestion.
216 citations
TL;DR: A specific and sensitive double immunocytochemical staining for the visualization of glutamate decarboxylase (GAD) and serotonin (5-HT) on the same brain section is developed and cell bodies containing both antigens are observed in each raphe nuclei.
208 citations
TL;DR: The data suggest that increased secretion of ACTH induced by fluoxetine is mediated, at least in part, by an increase in the hypothalamic secretion of both CRF and AVP.
202 citations
TL;DR: Neurons containing the enzyme aromatic-L-amino-acid decarboxylase (AADC) but lacking either tyrosine hydroxylase or serotonin were found in the spinal cord of neonatal and adult rats by light and electron microscopic immunocytochemistry.
Abstract: Neurons containing the enzyme aromatic-L-amino-acid decarboxylase (AADC) but lacking either tyrosine hydroxylase or serotonin were found in the spinal cord of neonatal and adult rats by light and electron microscopic immunocytochemistry. The majority of these neurons localized to area X of Rexed contact ependyma. Thus, spinal AADC neurons have the enzymatic capacity to catalyze directly the conversion of the amino acids tyrosine, tryptophan, or phenylalanine to their respective amines tyramine, tryptamine, or phenylethylamine. These amines normally present in the central nervous system may be of potential clinical significance as endogenous psychotomimetics.
171 citations
TL;DR: The present findings with fluoxetine are consistent with the virtual absence of anticholinergic or other side effects often observed with tricyclic antidepressant drugs in animal models or during the treatment of depressed patients.
165 citations
TL;DR: Evidence is given that neuropeptide receptors and glutamate receptors can in vitro rapidly modulate the characteristics of different types of DA and 5-HT receptors by way of receptor--receptor interactions at the comodulate level or at the local circuit level.
Abstract: Substance P (SP) (10−8 M) can rapidly reduce the affinity and increase the density of 3H-5-HT binding sites in spinal cord membranes.
TL;DR: It is concluded that NE is an excitatory hypothalamic monoamine for ACTH release in stress and that hypothalamic 5-HT activity is reduced after stress.
Abstract: Despite evidence that ACTH release after stress is under excitatory hypothalamic control, a stimulatory role for any of the monoamine neurotransmitters is yet to be clearly demonstrated. In the present investigation computerized gas chromatography/mass spectrometry was used to assess the neuronal activities of hypothalamic dopamine, norepinephrine (NE), and serotonin (5-HT) in rats after stress-induced ACTH release. Medial basal hypothalamic NE neuronal activity as assessed by the ratio of 3,4-dihydroxyphenylethyleneglycol (DHPG) to NE. (DHPG/NE) was elevated (P < 0.0005) within 2 min after a 3-min cold water swim stress. Ether stress also caused a marked elevation in NE activity (P < 0.0025). A highly significant positive correlation between the ratio of hypothalamic DHPG/NE and serum corticosterone was found over a large population of normal and stressed rats. Consistent with this relationship between hypothalamic NE neuronal activity and ACTH release being a causal one were the findings that 1) adrenal...
TL;DR: It is concluded that peripheral hormones modulate binding by serotonin 1 receptors, and the status of the serotonin receptor system may affect the reproductive capacity of an organism and may be related to sex-linked emotional disturbances in humans.
Abstract: Male and female rats exhibit sex differences in binding by serotonin 1 receptors in discrete areas of the brain, some of which have been implicated in the control of ovulation and of gonadotropin release. The sex-specific changes in binding, which occur in response to the same hormonal (estrogenic) stimulus, are due to changes in the number of binding sites. Castration alone also affects the number of binding sites in certain areas. The results lead to the conclusion that peripheral hormones modulate binding by serotonin 1 receptors. The status of the serotonin receptor system may affect the reproductive capacity of an organism and may be related to sex-linked emotional disturbances in humans.
TL;DR: The ability of methysergide and BOL to readily antagonize the effects of intrathecal 5-HT versus the relative inactivity of spiroperidol and ketanserin, used to characterize the5-HT2 binding site, suggests the likely role of 5- HT1 receptors in mediating the spinnal effects of 4-HT in the tail flick, but not the hot plate test of nociception.
TL;DR: In human brain, [3H]ketanserin was found to bind on serotonin (5-HT) S2-receptors; only 5-HT antagonists competed with the labelled ligand at nanomolar concentrations; other drugs were much less active or inactive.
TL;DR: The authors suggest that the pharmacodynamics of platelet serotonin may be different in chronic schizophrenia than in bipolar major depressive disorder.
Abstract: The authors found that platelet serotonin concentrations were significantly elevated in patients with chronic schizophrenia and in patients with bipolar major depressive disorder. High-affinity serotonin uptake was significantly reduced only in patients with bipolar major depressive disorder. Thrombin-induced release of serotonin from platelets in any patient group was not different from that of normal control subjects. Platelet serotonin storage in chronic schizophrenic patients was also not different from that in normal control subjects. These platelet findings could not be explained by age, sex, or medication variables. The authors suggest that the pharmacodynamics of platelet serotonin may be different in chronic schizophrenia than in bipolar major depressive disorder.
TL;DR: A nonpeptidic constituent of rat brain capable of displacing [3H]imipramine from its high-affinity binding site and of inhibiting the serotonin uptake in a dose-related manner has been extracted and its partial purification is described.
Abstract: Imipramine inhibits the serotonin uptake by binding with high affinity to regulatory sites of this uptake located on axons that release serotonin. The number of imipramine recognition sites located on crude synaptic membrane preparations is reduced by two daily injections of imipramine or desmethylimipramine for 3 weeks. When the binding sites for [3H]imipramine are down-regulated the Vmax of the neuronal uptake of serotonin is increased. Moreover, in minces prepared from the brain hippocampus of rats receiving imipramine in a dose regimen that reduces the number of [3H]imipramine recognition sites, the efficiency of imipramine as a blocker of the serotonin uptake is diminished. Hence the high-affinity binding sites for [3H]imipramine may have a physiological role in modulation of serotonin reuptake. Probably this is mediated by an endogenous effector of these regulatory sites. A nonpeptidic constituent of rat brain capable of displacing [3H]imipramine from its high-affinity binding site and of inhibiting the serotonin uptake in a dose-related manner has been extracted and its partial purification is described.
TL;DR: The results are interpreted as suggesting that [3H]imipramine binds to a site associated with the serotonin uptake system but different from either the substrate recognition site for serotonin or the site of action of the nontricyclic inhibitors of neuronal uptake of serotonin.
Abstract: Tricyclic antidepressant drugs inhibit [3H]imipramine binding to the rat brain cortex in a competitive manner, giving linear Hofstee plots and Hill coefficients of approximately 1.0. Serotonin, the only neurotransmitter to inhibit [3H]imipramine binding, does so in a complex manner, exhibiting a Hill coefficient of 0.40-0.50. Nontricyclic inhibitors of serotonin uptake such as fluoxetine, paroxetine, norzimelidine, and citalopram inhibit [3H]imiprarnine binding in the same complex manner as serotonin. These results are interpreted as suggesting that [3H]imipramine binds to a site associated with the serotonin uptake system but different from either the substrate recognition site for serotonin or the site of action of the nontricyclic inhibitors of neuronal uptake of serotonin.
TL;DR: A hypothesis is presented for explaining the possible role of the enterochromaffin cells in the pathophysiology of cholera secretion, where a diminished 5-HT content was associated with a decreased rate of fluid absorption or an increased rate of secretion.
Abstract: The effect of cholera toxin on the content of 5-hydroxytryptamine (5-HT) in the enterochromaffin cells of the cat small intestine was estimated by cytofluorimetry of individual enterochromaffin cells at varying times after exposing the intestinal mucosa to the toxin. The observed changes in 5-HT levels in the enterochromaffin cells were correlated with the simultaneously measured rate of net fluid transport across the intestinal epithelium. Intestinal segments exposed to cholera toxin showed a statistically significant decrease in 5-HT levels of enterochromaffin cells compared with segments exposed to heat-inactivated cholera toxin. A good correlation (r = 0.73) was found between relative 5-HT fluorescence in enterochromaffin cells and net fluid transport across the intestinal epithelium. Thus, a diminished 5-HT content was associated with a decreased rate of fluid absorption or an increased rate of secretion. A hypothesis is presented for explaining the possible role of the enterochromaffin cells in the pathophysiology of cholera secretion.
TL;DR: Although serotonin and octopamine modulate the excitability of the escape response, neither monoamine appears to significantly alter the rate at which this response habituates.
Abstract: Serotonin and octopamine have opposite effects on a simple behavioral response, the crayfish's lateral giant escape reaction. Specifically, serotonin depresses the lateral giants' responsiveness, whereas octopamine enhances it. Both effects are largely confined to the disynaptic pathway from the sensory afferents to the lateral giants, although, occasionally, small effects are also seen in the monosynaptic pathway to the lateral giants. One specific locus of the octopaminergic effect is the synapse between the afferents and the largest of the sensory interneurons in the disynaptic pathway, interneuron A. Serotonin, however, does not have a consistent effect at this synapse. Although serotonin and octopamine modulate the excitability of the escape response, neither monoamine appears to significantly alter the rate at which this response habituates.
Journal Article•
TL;DR: It can be concluded that the alpha-2 adrenoceptors which regulate, respectively, norepinephrine and serotonin release in the cerebral cortex are located on presynaptic nerve terminals and represent two stereochemically different subtypes of alpha-1 adrenoceptor antagonists.
Abstract: The effects of norepinephrine and of various alpha adrenoceptor antagonists on the depolarization-evoked release of norepinephrine and 5-hydroxytryptamine were studied in nerve terminals isolated from rat cerebral cortex, preincubated with the radioactive amines and exposed during superfusion to 15 mM KCI. Exogenous norepinephrine inhibited in a concentration-dependent way both the release of norepinephrine and that of serotonin. The inhibitory effect of norepinephrine was antagonized by yohimbine and mianserin, but not by prazosin, indicating the involvement of alpha-2 adrenoceptors. The two enantiomers of mianserin were examined as alpha-2 adrenoceptor antagonists in the two release systems. Only (+)-mianserin was an effective antagonist at the alpha-2 autoreceptors mediating regulation of norepinephrine release; (-)-mianserin was inactive. In contrast, both enantiomers antagonized exogenous norepinephrine at the alpha-2 adrenoceptors regulating 5-hydroxytryptamine release. It can be concluded that the alpha-2 adrenoceptors which regulate, respectively, norepinephrine and serotonin release in the cerebral cortex are located on presynaptic nerve terminals and represent two stereochemically different subtypes of alpha-2 adrenoceptors.
Journal Article•
TL;DR: The lack of effectiveness of LY53857 to lower blood pressure in the SHR indicates that blockade of both central and vascular serotonin receptors is not a sufficient mechanism to lowerBlood pressure in this model of hypertension.
Abstract: LY53857 was a potent antagonist of vascular contraction to serotonin, which is mediated by serotonergic (5-HT2) receptors, with a dissociation constant in vitro of 5.4 X 10(-11) M. Unlike several other serotonin antagonists, LY53857 showed minimal affinity for vascular alpha adrenergic receptors (dissociation constant of 1.4 X 10(-5) M). Thus, LY53857 was a highly potent and selective antagonist at 5-HT2 receptors. In vivo activity paralleled the in vitro observations. In pithed spontaneously hypertensive rats (SHR), LY53857 at 0.1 and 3.0 mg/kg i.p. produced a 22-and 480-fold shift, respectively, in the pressor response to serotonin whereas LY53857 at 10 mg/kg did not alter the pressor response to the alpha receptor agonist, methoxamine. Furthermore, LY53857 administered peripherally also inhibited central serotonin receptors, as evidenced by blockade of the serum corticosterone increase produced by the central actions of the serotonin agonist, quipazine, and by antagonism of tryptamine-induced convulsions in rats. LY53857 in doses that blocked the pressor response to serotonin and that blocked central serotonin receptors did not lower mean arterial blood pressure in the SHR. Thus, the lack of effectiveness of LY53857 to lower blood pressure in the SHR indicates that blockade of both central and vascular serotonin receptors is not a sufficient mechanism to lower blood pressure in this model of hypertension.
TL;DR: Ketanserin is the prototype of a new series of serotonin antagonists which competitively and selectively block the 5-HT 2 (or S 2 ) receptor and was found to be effective and well tolerated in the treatment of several acute and chronic disorders of cardiovascular origin.
TL;DR: It appears that rat brain mRNA encodes the translation of serotonin receptors into the oocyte membrane, and the combination of serotonin with these receptors leads to the opening of membrane channels.
Abstract: When poly(A)+-mRNA, extracted from rat brain, was injected into Xenopus laevis oocytes, it induced the appearance of serotonin receptors in the oocyte membrane. Application of serotonin to injected oocytes elicited, after a long delay, oscillations in membrane current. The equilibrium potential of this current corresponded with the chloride equilibrium potential. It appears that rat brain mRNA encodes the translation of serotonin receptors into the oocyte membrane. The combination of serotonin with these receptors leads to the opening of membrane channels.
01 Feb 1983
TL;DR: Influences of antidepressants on 5-HT2 receptors may provide a useful predictive test for antidepressant drug action.
Abstract: Identification of multiple receptors for neurotransmitters has had important theoretical and practical therapeutic relevance. With the advent of receptor-binding techniques, the ability to detect heterogeneity of receptors has been greatly enhanced. There appear to be multiple serotonin (5-HT) receptors in the central nervous system. At least two distinct 5-HT receptors can be differentiated by binding techniques. 5-HT1 sites are labeled preferentially by [3H]5-HT, whereas [3H]spiroperidol selectively labels 5-HT2 receptors. 5-HT and other agonists display 50-1000 times greater affinity for 5-HT1 than 5-HT2 sites, whereas most known 5-HT antagonists have 100-1000 times greater affinity for 5-HT2 than 5-HT1 receptors. Ergot-related drugs, such as LSD and lisuride, have similar affinities for 5-HT1 and 5-HT2 receptors. Drug potencies in blocking 5-HT behavioral effects in rodents and in antagonizing vascular effects of 5-HT in several blood vessel systems correlate best with influences on 5-HT2 receptors. In some adenylate cyclase systems drug effects on the 5-HT response of adenylate cyclase correlate with 5-HT1 receptor affinity. Chronic treatment with antidepressants lowers the numbers of 5-HT2 but not 5-HT1 receptors. With most antidepressants the reduction of 5-HT2 receptor site number is greater than the reduction in beta-adrenergic receptors. Thus, influences of antidepressants on 5-HT2 receptors may provide a useful predictive test for antidepressant drug action.
TL;DR: It is concluded that corticosterone triggers a serotonin response and that the specificity of the cortic testosterone action suggests involvement of the steroid receptor system located postsynaptically to the raphe-hippocampal serotonin projection.
TL;DR: The Limax system shows agonist responses similar to the vertebrate D1 receptors, but its antagonist-binding properties appear to have requirements quite different from vertebrate receptors.
Abstract: A neural system within the cerebral and buccal ganglia of the terrestrial mollusc Limax maximus responds to lip chemostimulation by emitting a feeding motor program (FMP) in vivo and in vitro. We have analyzed chemically the cerebral and buccal ganglia of Limax for neurotransmitters involved in controlling expression of FMP. Dopamine was found in clusters of cells in and the neuropil of the cerebral ganglia at a concentration of 62 pmol/ganglion; a large proportion of such dopamine-containing cells projected to the lips. The buccal ganglia contained several small dopaminergic cells and large amounts of dopamine in the neuropil; the measured concentration was 10 pmol/ganglion. Exogenous dopamine applied to the cerebral and buccal ganglia in vitro between 10(-7) M and 3 X 10(-6) M excited an autoactive salivary duct motor neuron (FB) and inhibited an autoactive secretomotor neuron (BSN). Concentrations of dopamine between 3 X 10(- 6) M and 3 X 10(-5) M triggered FMP output, with an increased probability of triggering at higher concentrations of dopamine. ADTN and SKF none of the neuroleptics tested was effective. Thus, the Limax system shows agonist responses similar to the vertebrate D1 receptors, but its antagonist-binding properties appear to have requirements quite different from vertebrate receptors. The effects of exogenous serotonin differed from dopamine's effects; serotonin excited BSN and several buccal motor neurons, could not elicit synchronized motor program cycling, and was not efficiently blocked by ergonovine. These data suggest that dopamine is a good candidate as an endogenous triggering and sustaining transmitter for the Limax feeding motor program.
Journal Article•
TL;DR: It is suggested that the serotonin present in the adrenaline-storing cells is derived from circulating serotonin and/or 5-hydroxytryptophan, and taken up directly from the circulation or formed by decarboxylation from 5-Hydroxytiptophan is subsequently incorporated in the chromaffin granules.
TL;DR: Observations are consistent with the hypothesis that circadian changes in the N-acetylation of 5-HT by indoleamine N- acetyltransferase is the major factor controlling circadianChanges in the amounts of5-HT, and 5- HT oxidation and N- Acetylation products in the rat pineal gland.
Abstract: Pineal tryptophan, serotonin [5-hydroxytrypt-amine (5-HT)], N-acetylserotonin, melatonin, 5-hydroxyin-doleacetic acid, 5-hydroxytryptophol, 5-methoxytryptophol, and 5-methoxyindoleacetic acid were measured by high pressure liquid chromatography with electrochemical detection. A complete analysis required less than the equivalent of two rat pineal glands. Samples were obtained at eight time points. A reciprocal physiological relationship was found between oxidation and N-acetylation products of 5-HT. 5-HT and the oxidation products 5-hydroxyindoleacetic acid, 5-hydroxytryptophol, 5-methoxy-tryptophol, and 5-methoxyindoleacetic acid decreased at night, when the N-acetylation products N-acetylserotonin and mela-tonin increased. These observations are consistent with the hypothesis that circadian changes in the N-acetylation of 5-HT by indoleamine N-acetyltransferase is the major factor controlling circadian changes in the amounts of 5-HT, and 5-HT oxidation and N-acetylation products in the rat pineal gland....