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PubMed1978

Release of endogenous serotonin from two identified serotonin-containing neurones and the physiological role of serotonin re-uptake.

1. The amounts of endogenous serotonin (5-HT) released into the medium by the cerebro-buccal ganglionic ring of Aplysia californica incubated in artificial sea water (ASW) were measured. The rate of spontaneous 5-HT release varied between 0.4 and 1.2 p-mole per hour, which is less than 1% of the total 5-HT present in this preparation.2. Direct stimulation of the ordinarily silent 5-HT-containing giant cerebral neurones resulted in a 80-100% increase of the 5-HT released, but only when the 5-HT uptake was blocked by chlorimipramine (1-10 muM).3. High K(+) media (50 mM) also caused a significant increase in the amount of 5-HT released from the preparation provided that chlorimipramine (1-10 muM) was present in the incubation fluid.4. Co(2+) ions (10-30 mM) added to the incubating medium blocked the spontaneous leak of endogenous 5-HT as well as the release, in the presence of chlorimipramine, evoked either by stimulation of the 5-HT-giant cerebral neurones or high K(+)-media.5. In the presence of chlorimipramine or desmethylimipramine, the duration and/or the amplitude of the excitatory or the inhibitory synaptic potentials evoked in the buccal neurones by the stimulation of the 5-HT giant cerebral neurones were markedly enhanced.6. These results strongly support the idea that 5-HT is the synaptic transmitter released at the excitatory and inhibitory junctions established by the 5-HT giant cerebral neurones in the ipsilateral buccal ganglia. In addition, they underline the role of amine re-uptake in the physiological inactivation of 5-HT as a transmitter.

Action Potentials↗
PubMed1987

Serotonin receptors in the human brain--III. Autoradiographic mapping of serotonin-1 receptors.

The anatomical distribution of serotonin-1 receptors in human postmortem brain tissue was studied by quantitative light microscopic autoradiography. [3H]Serotonin was used to label all the subtypes of serotonin-1 sites (serotonin-1A, serotonin-1B, serotonin-1C). Serotonin-1A receptors were specifically labelled with [3H]8-hydroxy-2-[N,N-di-N-propyl-amino]tetralin, while [3H]mesulergine was used to identify serotonin-1C receptors. Receptor densities were quantified by means of a computer-assisted microdensitometric system. Confirming previous findings, serotonin-1A and serotonin-1C receptors were found in the human brain, while sites with the pharmacological characteristics of serotonin-1B binding sites could not be identified in this tissue. In addition, serotonin-1C receptors appeared to present differences in terms of pharmacology, depending on the brain area analysed. The distribution of both serotonin-1A and serotonin-1C receptor subtypes throughout the human brain was heterogeneous. High or very high densities of serotonin-1A receptors were found over the Ca1 field of the hippocampus, raphé nuclei, layers I and II of the cortex and some nuclei of the thalamus and amygdala. The claustrum, posterior hypothalamus, mesencephalic and pontine central grey matter and substantia gelatinosa of the cervical spinal cord, among others, presented intermediate concentrations of serotonin-1A receptors. In contrast, high densities of serotonin-1C receptors were present in the choroid plexus, substantia nigra, globus pallidus and ventromedial hypothalamus, while low or very low amounts of this receptor subtype were found in many other human brain areas. The anatomical distribution of serotonin-1A and serotonin-1C receptors is discussed taking into account the distribution of serotonergic neurons and fibres, the central functions in which serotonin appears to be involved and the characteristics of the neurological and psychiatric disorders where changes in brain serotonin-1 receptors have been reported.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed2001

[(3)H]-serotonin release from bovine iris-ciliary body: pharmacology of prejunctional serotonin (5-HT(7)) autoreceptors.

In the present study, we investigated the pharmacological characteristics of electrically stimulated [(3)H]-serotonin release from mammalian iris-ciliary bodies. Isolated bovine and human iris-ciliary bodies were loaded with [(3)H]-serotonin, superfused with Krebs buffer solution and then stimulated with trains of 300 direct current (d.c.) pulses to initiate the release of the transmitter. The modification of this [(3)H]-serotonin release process by various serotonergic agonists and antagonists was studied in order to define the pharmacology of serotonin receptor(s) present in the iris-ciliary body. In bovine iris-ciliary body, electrically-evoked [(3)H]-serotonin release was calcium-dependent, tetrodotoxin-sensitive and was enhanced by serotonin (EC(50) = 200 n M) and 5-carboxmidotryptamine (EC(50) = 4 n M). The rank order of potency of agonists in enhancing field-stimulated [(3)H]-serotonin release was: 5-carboamidotryptamine > m-chlorophenylbiguanide > 2-methyl-5-hydroxytryptamine = 5-methoxy-dimethyltryptamine > serotonin > 5-methoxy-tryptamine > L-694,247 = alpha-methyl-5-hydroxytryptamine > CGS 12066A = 8-hydroxy-2-(di- n -propylamino)tetraline. Serotonin and m-chlorophenylbiguanide also enhanced electrically-evoked [(3)H]-serotonin release from human iris-ciliary bodies with EC(50)s of 3 microM and 30 n M, respectively. The pharmacological profile displayed by serotonin receptor agonists was supported by the potent antagonism of the serotonin-induced enhancement of [(3)H]-serotonin release by 5HT(7)receptor antagonists SB-258718 (IC(50) = 18.6 +/- 1.2 nM; n = 4) and mesulergine (IC(50) = 0.26 +/- 0.05 nM; n = 4). However, antagonists at 5HT(6)and 5HT(3)receptors exhibited a relatively weak blockade of serotonin induced enhancement of field-stimulated [(3)H]-serotonin release. These studies have shown the presence of functionally active prejunctional 5HT(7)autoreceptors regulating the release of [(3)H]-serotonin from bovine iris-ciliary bodies. Excitatory prejunctional 5-HT autoreceptors also exist in human iris-ciliary bodies. It is possible that these serotonin autoreceptors may have relevance to the regulation of aqueous humor dynamics in the anterior uvea.

Adult↗
PubMed2001

Plasticity in serotonin uptake in primary neuronal cultures of serotonin transporter knockout mice.

The cross talk between dopaminergic and serotonergic systems in the brain has multiple neurophysiological and behavioral implications. Primary neuronal cultures of embryonic wild type (+/+) and serotonin transporter knockout (-/-) mice were used as a model to elucidate the possibility of plasticity at the level of serotonin uptake. Serotonergic neurons were identified in midbrain-hindbrain cultures of both wild type and knockout mice, using polyclonal anti-serotonin antibodies. Adding serotonin (10 microM) to wild type midbrain-hindbrain cultures increased the intensity of serotonin immunostaining, but did not change the number of serotonergic neurons. This increased intensity of serotonin staining was blocked by the serotonin transporter inhibitors fluoxetine and imipramine, but not with the dopamine transporter inhibitor nomifensine. In serotonin transporter knockout cultures, however, serotonin increased both the intensity of serotonin immunostaining and the number of serotonin positive neurons, and nomifensine decreased the number of serotonin-labeled neurons. Uptake of [3H]serotonin to wild type midbrain-hindbrain cultures was completely blocked by 1 microM fluoxetine, whereas nomifensine had a very small effect. In contrast, [3H]serotonin uptake to serotonin transporter knockout cultures, although very weak, was better inhibited by nomifensine than fluoxetine. The results imply that midbrain-hindbrain neuronal cultures of knockout mice, that do not express serotonin transporters, acquire the capacity to take up serotonin, apparently via dopamine transporters.

Adrenergic Uptake Inhibitors↗
PubMed1996

The effects of clozapine and haloperidol on serotonin-1A, -2A and -2C receptor gene expression and serotonin metabolism in the rat forebrain.

The therapeutic and side-effect profiles of clozapine differ from those of typical antipsychotic drugs such as haloperidol. Effects on the serotonin system, especially serotonin-2 receptors, may contribute to clozapine's atypicality. We injected rats for 14 days with clozapine (25 mg/kg/day) or haloperidol (2 mg/kg/day), and measured three aspects of the serotonin system in forebrain regions: abundance of serotonin-2A, -2C and -1A receptor messenger RNAs by in situ hybridization histochemistry; serotonin-2A and -1A binding sites using receptor autoradiography, and levels of serotonin and 5-hydroxyindoleacetic acid with high-performance liquid chromatography. Clozapine administration decreased serotonin-2A receptor messenger RNA and the density of [3H]ketanserin binding in cingulate and frontal cortex, but not in piriform cortex. Serotonin-1A receptor expression and serotonin-2C receptor messenger RNA were unchanged in all areas. The treatment markedly decreased serotonin and 5-hydroxyindoleacetic acid concentrations in striatum with similar trends in cortex and hippocampus. Haloperidol administration did not affect the expression of the three serotonin receptors, but was associated with a modest reduction of striatal and hippocampal 5-hydroxyindoleacetic acid. The selective reduction of serotonin-2A receptors confirms earlier findings and supports the view that this receptor may have relevance for the actions of clozapine. The fact that the encoding messenger RNA is decreased shows that the the effect is mediated at the level of gene expression. In contrast, the unchanged serotonin-2C receptor messenger RNA level indicates that the reported loss of serotonin-2C receptors after clozapine treatment is due to translational or post-translational events. The relationship between the reduction in serotonin-2A receptor expression and the altered serotonin metabolism remains unclear.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1995

Serotonin metabolism following platinum-based chemotherapy combined with the serotonin type-3 antagonist tropisetron.

The administration of platinum-based chemotherapy induces serotonin release from the enterochromaffin cells, causing nausea and vomiting. This study was conducted to evaluate parameters of serotonin metabolism following platinum-based chemotherapy given in combination with the serotonin type-3 antagonist tropisetron as an antiemetic agent. In nine chemotherapy-naive patients with disseminated germ-cell tumors, parameters of serotonin metabolism in both blood and urine were evaluated during two consecutive courses of platinum-based chemotherapy. Serotonin concentrations in platelet-rich plasma and platelet-poor plasma as well as urinary 5-hydroxyindoleacetic acid (5-HIAA) and serotonin levels were measured during the full length of the courses. By means of comparison with the antiemetic agent chlorpromazine, used on day 1 of the first course only, the effect of the serotonin type-3 antagonist tropisetron, the antiemetic agent used during the rest of the courses, on these parameters was studied. Clinical effects were also recorded. No change in the parameters of serotonin metabolism could be demonstrated during either course by the serotonin type-3 antagonist tropisetron. Also in vitro, no effect of tropisetron on the active serotonin uptake by platelets was found. Serotonin levels in platelets showed no correlation with emetic response. However, the platelet serotonin content decreased significantly between the first and the second course (P < 0.01). The significant reduction in platelet serotonin content observed between the first and the second course indicates a depletion of total body serotonin. The role of a serotonin type-3 antagonist might be affected by the altered serotonin equilibrium during later courses of chemotherapy.

Adult↗
PubMed1993

The presence of a serotonin uptake inhibitor alters pharmacological manipulations of serotonin release.

The present study investigated the effects of the presence of the serotonin uptake inhibitor citalopram in the perfusion medium on pharmacological manipulations which increased and decreased striatal serotonin release using in vivo microdialysis. A high performance liquid chromatography detection system equipped with a microbore column was used which reduced the detection limit to 0.5 fmol serotonin/5 microliters sample and enabled basal striatal serotonin release to be measured without the addition of a serotonin uptake inhibitor to the perfusion medium. Although serotonin uptake inhibitors have frequently been used to enhance the serotonin content of dialysate samples, the effects of the presence of serotonin uptake inhibitors on pharmacological manipulations which increased and decreased the release of serotonin have not yet been characterized. Serotonin release was reduced by the systemic administration of the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). Although 5-HT release was reduced by 8-OH-DPAT after the addition of citalopram, the 5-HT1A receptor agonist did not reduce absolute levels of extracellular serotonin below basal values of serotonin measured in the absence of citalopram. In addition, citalopram dramatically prevented the four-fold increase in the release of serotonin produced by the systemic administration of the serotonin-releasing agent fenfluramine. The blockade of fenfluramine's effects by citalopram supports the hypothesis that transport of fenfluramine into serotonergic neurons is necessary to increase serotonin release. This study demonstrates that the use of an HPLC detection system equipped with a microbore column can reliably measure basal serotonin release using in vivo microdialysis.(ABSTRACT TRUNCATED AT 250 WORDS)

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1998

A role for serotonin in the circadian system revealed by the distribution of serotonin transporter and light-induced Fos immunoreactivity in the suprachiasmatic nucleus and intergeniculate leaflet.

Components of the circadian system, the suprachiasmatic nucleus and the intergeniculate leaflet receive serotonin input from the raphe nuclei. Manipulations of serotonin neurotransmission disrupt cellular, electrophysiological, and behavioural responses of the circadian system to light, suggesting that serotonin plays a modulatory role in photic regulation of circadian rhythms. To study the relation between serotonin afferents and light-activated cells in the suprachiasmatic nucleus and intergeniculate leaflet, we used immunostaining for the serotonin transporter and for the transcription factor, Fos. Serotonin transporter, a plasma membrane protein located on serotonin neurons, regulates the amount of serotonin available for neurotransmission by re-accumulating released serotonin into presynaptic neurons; expression of Fos in the suprachiasmatic nucleus identifies light-activated cells involved in photic resetting of circadian clock phase. In the suprachiasmatic nucleus, immunostaining for serotonin transporter revealed a dense plexus of fibres concentrated primarily in the ventrolateral region. In the intergeniculate leaflet, serotonin transporter immunostaining identified vertically-oriented columns of fibres. Serotonin transporter immunostaining was abolished by pretreatment with the serotonin neurotoxin, 5,7-dihydroxytryptamine. Exposure to light for 30 min during the dark phase of the light cycle induced Fos expression in the ventrolateral suprachiasmatic nucleus and intergeniculate leaflet regions. In both structures the Fos-expressing cells were encircled by serotonin transporter-immunoreactive fibres often in close apposition to these cells. These results support the idea that serotonin activity plays a modulatory role in processing of photic information within the circadian system.

Animals↗
PubMed1981

Radioenzymatic assay of platelet serotonin, dopamine and norepinephrine in subjects with normal and increased serotonin production.

Platelet serotonin, dopamine and norepinephrine concentrations were determined with sensitive and specific radioenzymatic methods in normal volunteers and in sick subjects with both normal and increased serotonin production. In the assays, a 3H-labeled methyl group is transferred from [3H]S-adenosyl methionine to the monoamine under investigation by a semi-purified enzyme. The platelet serotonin concentration (expressed as pmol serotonin/mg platelet protein) was significantly higher in the patients with increased serotonin production from carcinoid tumors (5400 +/-0 500) than in the normal volunteers (900 +/- 100) or the sick subjects with normal serotonin production (900 +/- 100). Although eight of the subjects with increased serotonin production had symptoms of the carcinoid syndrome such as flushing and diarrhea, two of the subjects with increased serotonin production did not have these symptoms. The radioenzymatic method of platelet serotonin measurement was as effective as a conventional fluorometric technique for serum serotonin in detecting patients with serotonin overproduction from carcinoid tumors, and had the advantages of being more sensitive and specific. The great sensitivity and specificity of the radioenzymatic techniques suggest that it might be useful in evaluating disease states in which platelet serotonin is decreased. Using these techniques we found that dopamine and norepinephrine were also present in platelets, although in much lower amounts than serotonin. Despite the markedly increased serotonin concentration in the platelets of subjects with serotonin overproduction from carcinoid tumors, there was no alteration in the dopamine or norepinephrine concentration of their platelets.

Adult↗
PubMed1990

The role of serotonin release and autoreceptors in the dorsalis raphe nucleus in the control of serotonin release in the cat caudate nucleus.

Using a push-pull cannula technique and an isotopic method for estimating [3H]serotonin continuously synthesized from [3H]tryptophan, the effects of changes in the release of serotonin in the dorsalis raphe nucleus on in vivo release of [3H]serotonin in the cat caudate nucleus were investigated. The increase in the release of serotonin in the dorsalis raphe nucleus caused by local application of parachlorophenylethylamine (10(-6) M) reduced striatal [3H]serotonin release. This inhibition in serotonin release in the striatum was blocked by the prior and continuous local superfusion of the dorsal raphe with methiothepin (10(-6) M), a serotonin autoreceptor antagonist. GABA (5 x 10(-5) M) applied to the dorsalis raphe reduced both local and striatal release of [3H]serotonin. However, picrotoxin (10(-5) M), a GABA A receptor antagonist applied locally in the dorsalis raphe nucleus increased [3H]serotonin release while decreasing striatal [3H]serotonin release. This decrease in serotonin release in the striatum was again blocked by continuous superfusion of the raphe with methiothepin. Furthermore, superfusion of serotonergic cell bodies of the dorsalis raphe nucleus with methiothepin alone never altered local release or striatal release of [3H]serotonin. These data strongly suggest that the release of serotonin from the cell body in the dorsalis raphe nucleus phasically controls release of the amine at the axonal nerve ending through serotonergic autoreceptors located on serotonergic nerve cell bodies in the dorsalis raphe nucleus. The origin of the serotonin released in the dorsalis raphe nucleus and the possibility that this type of regulation could be related to changes in nerve impulse conduction of the serotonergic raphe-striatal system are discussed.

Animals↗
PubMedDate not supplied

Synaptic circuitry of serotonin-synthesizing and serotonin-accumulating amacrine cells in the retina of the cane toad, Bufo marinus.

The synaptic connections of amacrine cells synthesizing or accumulating serotonin in the retina of the cane toad, Bufo marinus, were studied by using preembedding double-labeling electron-microscopic immunocytochemistry. The binding sites of an anti-serotonin antibody were revealed by the diaminobenzidine reaction, whilst a colloidal gold-conjugated secondary antibody was used to detect an antibody to phenylalanine hydroxylase. Since the latter antibody recognizes tryptophan 5-hydroxylase, one of the synthesizing enzymes for serotonin, as well as tyrosine hydroxylase, the rate-limiting enzyme for catecholamine synthesis, the double labeling of the present study enabled us to identify three groups of labeled profiles at the ultrastructural level. The profiles of serotonin-synthesizing amacrine cells contained both diaminobenzidine reaction product and colloidal gold particles, whilst those of serotonin-accumulating and dopaminergic amacrine cells contained only diaminobenzidine reaction product or colloidal gold particles, respectively. The synapses of serotonin-synthesizing or serotonin-accumulating amacrine cells were distributed all through the inner plexiform layer of the retina. The profiles of serotonin-synthesizing amacrine cells predominantly received synapses from, and made synapses onto, unlabeled amacrine cell dendrites. They also received synapses from, and made synapses onto, bipolar cell terminals. They also made synapses onto presumed ganglion cell dendrites. However, the profiles of serotonin-accumulating cells made synapses only with unlabeled amacrine cell processes. There were close contacts between the profiles of serotonin-synthesizing and serotonin-accumulating amacrine cells. No synaptic relationships were observed between dopaminergic and serotonin-synthesizing or serotonin-accumulating amacrine cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2000

Synthesis and characterization of photolabile derivatives of serotonin for chemical kinetic investigations of the serotonin 5-HT(3) receptor.

A series of photolabile o-nitrobenzyl derivatives of serotonin (caged serotonin) were synthesized: the amine-linked serotonin derivatives N-(2-nitrobenzyl) serotonin (Bz-5HT) and N-(alpha-carboxy-2-nitrobenzyl) serotonin (N-CNB-5HT), and O-alpha-carboxy-2-nitrobenzyl) serotonin (O-CNB-5HT), which has the caging group attached to the phenolic OH group. All the derivatives released free serotonin when excited by 308-nm or 337-nm laser pulses. The time constant of serotonin release from N-CNB-5HT was 1. 2 ms, with a quantum yield of 0.08. This is too slow for rapid chemical kinetic measurements. O-CNB-5HT is suitable for transient kinetic investigations of the serotonin 5-HT(3) receptor. It released serotonin with a time constant of 16 micros and a quantum yield of 0.03. The biological properties of O-CNB-5HT were evaluated, and the applicability of the compound for kinetic studies of the 5-HT(3) receptor was demonstrated. O-CNB-5HT does not activate the 5-HT(3) receptor by itself, nor does it modulate the response of a cell when co-applied with serotonin. When irradiated with a 337-nm laser pulse, O-CNB-5HT released free serotonin that evoked 5-HT(3) receptor-mediated whole-cell currents in NIE-115 mouse neuroblastoma cells.

Animals↗
PubMed1980

Monoamine oxidase inhibitors and serotonin uptake inhibitors: differential effects on [3H]serotonin binding sites in rat brain.

Rats were administered either monoamine oxidase inhibitors or serotonin uptake inhibitors for either 1, 4 or 16 days. The binding of [3H]serotonin to brain homogenates and the concentration of serotonin in brain was measured at these times. Treatment with inhibitors of serotonin uptake did not change the specific binding of [3H]serotonin in either cerebral cortex or hippocampus, nor did it produce any consistent alterations in the concentration of serotonin in the cerebral cortex. In contrast, monoamine oxidase inhibitors capable of inhibiting A-type monoamine oxidase significantly decreased [3H]serotonin binding after both 4 and 16 days of treatment; serotonin concentrations were significantly elevated at all time intervals. Inhibitors of B-type monoamine oxidase had no effect on either [3H]serotonin binding or serotonin concentrations in cerebral cortex. The reduction in labeled serotonin binding caused by monoamine oxidase inhibitors is due to a decrease in the maximum number of specific binding sites with no change in the affinity of the binding sites for labeled serotonin.

Amitriptyline↗
PubMed2003

The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity.

BACKGROUND: There are difficulties with the diagnosis of serotonin toxicity, particularly with the use of Sternbach's criteria. AIM: To improve the criteria for diagnosing clinically significant serotonin toxicity. DESIGN: Retrospective analysis of prospectively collected data METHODS: We studied all patients admitted to the Hunter Area Toxicology Service (HATS) following an overdose of a serotonergic drug from January 1987 to November 2002 (n = 2222). Main outcomes were: diagnosis of serotonin toxicity by a clinical toxicologist, fulfillment of Sternbach's criteria and treatment with a serotonin receptor (5-HT(2A)) antagonist. A learning dataset of 473 selective serotonin reuptake inhibitor (SSRI)-alone overdoses was used to determine individual clinical features predictive of serotonin toxicity by univariate analysis. Decision rules using CART analysis were developed, and tested on the dataset of all serotonergic overdose admissions. RESULTS: Numerous clinical features were associated with serotonin toxicity, but only clonus (inducible, spontaneous or ocular), agitation, diaphoresis, tremor and hyperreflexia were needed for accurate prediction of serotonin toxicity as diagnosed by a clinical toxicologist. Although the learning dataset did not include patients with life-threatening serotonin toxicity, hypertonicity and maximum temperature > 38 degrees C were universal in such patients; these features were therefore added. Using these seven clinical features, decision rules (the Hunter Serotonin Toxicity Criteria) were developed. These new criteria were simpler, more sensitive (84% vs. 75%) and more specific (97% vs. 96%) than Sternbach's criteria. DISCUSSION: These redefined criteria for serotonin toxicity should be more sensitive to serotonin toxicity and less likely to yield false positives.

Analysis of Variance↗
PubMed1998

Excitatory amino acids and serotonin uptake blockers reveal two physiologically distinct serotonin systems in the retina of the skate, Raja erinacea.

The retina of the skate (Raja erinacea) contains at least 2 types of cell (amacrines and bipolars) that can be visualized with an antiserum against serotonin. We have employed serotonin immunocytochemistry in combination with pharmacological manipulation of retinal tissue to analyze physiological properties of serotonergic amacrine cells and serotonin-accumulating bipolar cells. Excitatory amino acids (NMDA, aspartate) had no detectable effects on serotonin-immunoreactivity in bipolar cells but decreased staining in amacrine cells. High K+ Ringer increased staining in bipolar cell somata, however, it depleted the inner plexiform layer of the retina of serotonin. Zimelidine, a serotonin uptake inhibitor, completely blocked serotonin accumulation by bipolar cells but had no effect on amacrine cells, whereas incubation of the retinas in fluoxetine (Prozac), a different inhibitor of serotonin uptake, did not block serotonin accumulation into bipolar cells which was actually enhanced in some cases. We conclude that amacrine and bipolar cells of the skate retina employ two different serotonin uptake carrier systems, thus generating two distinct pharmacological components that are capable of interacting with each other as they compete for extracellular serotonin. Similar mechanisms may exist in the vertebrate CNS and further examination of the interaction of these systems could provide important insights into the action and possible side effects of serotonin-related drugs.

Animals↗
PubMed1998

Increase in serotonin-1A autoreceptors in the midbrain of suicide victims with major depression-postmortem evidence for decreased serotonin activity.

It has been hypothesized that a deficit in serotonin may be a crucial determinant in the pathophysiology of major depression. Serotonin-1A receptors are located on serotonin cell bodies in the midbrain dorsal raphe (DR) nucleus, and the activation of these receptors inhibits the firing of serotonin neurons and diminishes the release of this neurotransmitter in the prefrontal cortex. Repeated treatment with some antidepressant medications desensitizes serotonin-1A receptors in the rat midbrain. The present study determined whether the binding of [3H]8-hydroxy-2-(di-n-propyl)aminotetralin (8-OH-DPAT), an agonist at serotonin-1A receptors, is altered in the midbrain of suicide victims with major depression. Radiolabeling of the serotonin-1A receptor in the DR varied significantly along the rostral-to-caudal extent of the human midbrain. The binding of [3H]8-OH-DPAT to serotonin-1A receptors was increased significantly in the midbrain DR of suicide victims with major depression as compared with psychiatrically normal control subjects. In suicide victims with major depression, the increase in the binding of [3H]8-OH-DPAT to serotonin-1A receptors was detected in the entire DR and specifically localized to the dorsal and ventrolateral subnuclei. Enhanced radioligand binding of an agonist to inhibitory serotonin-1A autoreceptors in the human DR provides pharmacological evidence to support the hypothesis of diminished activity of serotonin neurons in suicide victims with major depression.

8-Hydroxy-2-(di-n-propylamino)tetralin↗