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At least 19 recordsLinked to original sources

PubMed1993

Regulation of the human serotonin transporter. Cholera toxin-induced stimulation of serotonin uptake in human placental choriocarcinoma cells is accompanied by increased serotonin transporter mRNA levels and serotonin transporter-specific ligand binding.

Treatment of confluent cultures of JAR human placental choriocarcinoma cells with cholera toxin or forskolin for 16 h markedly stimulated (2.4-fold) serotonin transport activity in these cells. Cycloheximide, an inhibitor of protein synthesis or actinomycin D, an inhibitor of mRNA synthesis effectively blocked this stimulation. Northern blot analysis revealed that treatment with cholera toxin resulted in severalfold increase in the concentrations of the three mRNA species (6.8, 4.9 and 3.0 kilobases in size) which hybridized to the human placental serotonin transporter cDNA. Under similar conditions, the concentrations of the mRNA species which hybridized to the human placental taurine transporter cDNA or to the human beta-actin cDNA were not affected. Analysis of paroxetine-sensitive binding of the cocaine analog 2 beta-carbomethoxy-3 beta-(4- [125I]iodophenyl)tropane to the membranes prepared from control and cholera toxin-treated cells indicated that the maximal binding capacity was increased 2.5-fold by cholera toxin, with no significant change in the binding affinity. Thus, stimulation of serotonin transporter activity in the placental choriocarcinoma cells following cholera toxin treatment is likely a result of an increase in cell surface density of the serotonin transporter protein as a consequence of increased steady state serotonin transporter mRNA levels.

Binding Sites↗

PubMed1990

Serotonin uptake blockers influence serotonin autoreceptors by increasing the biophase concentration of serotonin and not through a "molecular link".

The mechanism of the attenuation, by serotonin uptake blockers, of the release-inhibiting effect of exogenous serotonin autoreceptor agonists was studied in rabbit brain cortex and rat hypothalamus slices. The slices were preincubated with 3H-serotonin and then superfused and stimulated electrically. In rabbit brain slices stimulated by trains of 4 pulses at 100 Hz, 5-carboxamidotryptamine and 5-methoxytryptamine reduced the evoked overflow of tritium, and their concentration-response curves were not changed by any of three serotonin uptake inhibitors, namely citalopram, fluvoxamine and 6-nitroquipazine. In contrast, when the slices were stimulated by trains of 10 pulses at 0.033 Hz, fluvoxamine shifted the concentration-response curve of 5-methoxytryptamine to the right. Experiments with the autoreceptor antagonist metitepine indicated that little, if any, endogenous autoinhibitory tone developed in the course of trains of 4 pulses/100 Hz, irrespective of the absence or presence of uptake inhibitors, as well as during trains of 10 pulses/0.033 Hz in the absence of uptake inhibitors, whereas marked autoinhibition developed when 10 pulses/0.033 Hz were applied in the presence of fluvoxamine. In rat hypothalamic slices stimulated by trains of 4 pulses at 100 Hz, citalopram also failed to change the concentration-response curve of 5-methoxytryptamine. These results indicate that serotonin uptake blockers attenuate the effect of exogenous autoreceptor agonists by an increase in the biophase concentration of released serotonin and, hence, in endogenous autoinhibitory tone, and not by some direct "molecular link" unrelated to the biophase concentration of released serotonin.

5-Methoxytryptamine↗

PubMed1982

Serotonin storage pools in basophil leukemia and mast cells: characterization of two types of serotonin binding protein and radioautographic analysis of the intracellular distribution of [3H]serotonin.

We studied binding of serotonin to protein(s) derived from rat basophil leukemia (RBL) cells and mast cells. We found two types of serotonin binding protein in RBL cells. These proteins differed from one another in molecular weight and eluted in separate peaks from sephadex G-200 columns. Peak I protein (KD = 1.9 X 10(-6) M) was a glycoprotein that bound to concanavalin A (Con A); Peak II protein (KD1 = 4.5 X 10(-8) M; KD2 = 3.9 X 10(-6) M) did not bind to Con A. Moreover, binding of [3H]serotonin to protein of peak I was sensitive to inhibition by reserpine, while binding of [3H]serotonin to protein of peak II resisted inhibition by that drug. Other differences between the two types of binding protein were found, the most significant of which was the far more vigorous conditions of homogenization required to extract peak I than peak II protein. Neither peak I nor peak II protein resembled the serotonin binding protein (SBP) that is found in serotonergic neurons of the brain and gut. Electron microscope radioautographic analysis of the intracellular distribution of [3H]serotonin taken up in vitro by RBL cells or in vivo by murine mast cells indicated that essentially all of the labeled amine was located in cytoplasmic granules. No evidence for a pool in the cytosol was found and all granules were capable of becoming labeled. The presence of two types of intracellular serotonin binding proteins in these cells may indicate that there are two intracellular storage compartments for the amine. Both may be intragranular, but peak I protein may be associated with the granular membrane while peak II protein may be more free within the granular core. Different storage proteins may help to explain the differential release of amines from mast cell granules.

Animals↗

PubMed1976

Cerebral arterial spasm. Part 4: in vitro effects of temperature, serotonin analogues, large nonphysiological concentrations of serotonin, and extracellular calcium and magnesium on serotonin-induced contractions of the canine basilar artery.

In vitro experiments were performed using a small volume chamber to study serotonin-induced contractions of the canine basilar artery. Temperature was found to have a profound effect on the artery's response to serotonin. Raising the temperature to 40 degrees C (104 degrees F) increased the maximum response by 20% and lowering the temperature by 10 degrees C caused a 40% reduction in the maximum contraction. Cumulative log-dose response curves for analogues of serotonin demonstrated a high degree of specificity for the serotonin receptor and large nonphysiological concentrations of serotonin caused relaxation of the contracted artery. Extracellular calcium was shown to be an absolute requirement for serotonin-induced contractions. Extracellular magnesium, in contrast, was shown to inhibit serotonin-induced contractions.

Animals↗

PubMedDate not supplied

Involvement of serotonin in depression: evidence from postmortem and imaging studies of serotonin receptors and the serotonin transporter.

Definitive conclusions on the role of serotonin receptors and transporter in suicide and depression have been elusive in studies of postmortem brain tissue. A number of methodological differences in these studies have made it difficult to reach a consensus, but crucial issues are being identified and incorporated into newer studies. This review will follow the evolution of serotonin receptor and transporter studies in postmortem tissues that initially focused on suicide and gradually incorporated depressive disorders as psychiatric assessments were increasingly performed. Studies in postmortem tissues on the serotonin-1A and serotonin-2A receptors and the serotonin transporter will be reviewed and compared with imaging studies of the same sites in depressed subjects. Critical issues to control in future studies of serotonin receptors in postmortem tissues include variables such as the cause of death (i.e. suicide), the specific psychiatric diagnoses of the subjects, whether the disorder was in remission at the time of death, long-term medication histories, psychoactive substance use disorders, the smoking history, the hemisphere from which tissues were dissected, and the specific cytoarchitectonic region to be evaluated. Carefully controlled studies in postmortem tissues will ensure a greater likelihood of reaching a consensus on the involvement of monoamine measures in the etiology of depression.

Autopsy↗

PubMed2001

Serotonin 1A receptors, serotonin transporter binding and serotonin transporter mRNA expression in the brainstem of depressed suicide victims.

Suicide and depression are associated with reduced serotonergic neurotransmission. In suicides, there is a reduction in serotonin transporter (SERT) sites and an increase in postsynaptic 5-HT(1A) receptors in localized regions of the prefrontal cortex. In depression, there is a diffuse decrease in SERT binding throughout the dorsoventral extent of the prefrontal cortex. Serotonergic innervation of the prefrontal cortex arises predominantly from neurons in the brainstem dorsal raphe nucleus (DRN). We, therefore, examined postmortem SERT binding and mRNA expression, as well as 5-HT(1A) autoreceptor binding in the DRN of 10 matched pairs of controls and depressed suicide victims. The concentration of SERT sites, SERT mRNA, and 5-HT(1A) binding was not different between controls and suicides (p >.05). In the DRN of suicides, the volume of tissue defined by 5-HT(1A) binding was 40% smaller than controls. An index of the total number of 5-HT(1A) receptors (receptor binding x volume of receptor distribution) was 43.3% lower in the DRN of suicides, compared with controls. The suicide group had 54% fewer DRN neurons expressing SERT mRNA compared with controls. In the serotonin neurons that expressed the SERT gene, expression per neuron was greater in suicides. Less total 5-HT(1A) and SERT binding is consistent with results of in vivo studies in depression. Less feedback inhibition of serotonin DRN firing via 5-HT(1A) autoreceptors and enhancement of serotonin action due to less uptake of serotonin, is consistent with compensatory changes in response to hypofunction in depressed suicides.

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

PubMed2003

Despite the general correlation of the serotonin transporter gene regulatory region polymorphism (5-HTTLPR) and platelet serotonin concentration, lower platelet serotonin concentration in migraine patients is independent of the 5-HTTLPR variants.

Platelet serotonin (5-HT) concentrations in a headache-free period during the mid-follicular phase and the serotonin transporter gene regulatory region polymorphism (5-HTTLPR) were measured in female migraine patients without aura (n = 64) and healthy controls (n = 42). High-pressure liquid chromatography (HPLC) was used to determine the platelet 5-HT concentration and genetic polymorphism was determined by polymerase chain reaction. Significantly lower platelet 5-HT concentrations were found in migraine patients compared to controls. Concerning the 5-HTTLPR polymorphism, the S/S genotype was associated with a significantly higher platelet 5-HT concentration (P = 0.027) in the whole study population. This association between the 5-HTTLPR genotypes and platelet 5-HT concentrations was independent of the diagnosis. In addition, the platelet 5-HT concentration was lower in migraineurs in all genotypes (S/S, S/L, L/L). In conclusion, 5-HTTLPR variants may have an effect on the platelet 5-HT concentrations, but the lower 5-HT concentrations in migraine patients seem to be determined by other factors.

Adult↗

PubMed2000

Serotonin, noradrenaline and cognitive function: a preliminary investigation of the acute pharmacodynamic effects of a serotonin versus a serotonin and noradrenaline reuptake inhibitor.

Comparisons of the behavioural side-effect profiles of antidepressants that inhibit either serotonin or both serotonin and noradrenaline reuptake, may reveal differences in cognitive and psychomotor functions, which may be attributed to their relative pharmacological selectivity for potentiating monoamine neurotransmission in the central nervous system. The aim of the present study was to determine the acute pharmacodynamic effects of citalopram and venlafaxine, on cognitive and psychomotor performance. Nine healthy male volunteers received a single clinical dose of citalopram, venlafaxine or amitriptyline (positive control) in a double-blind placebo-controlled design. Cognitive and psychomotor tests and a subjective measure of sedation were examined before and 1, 2 and 4 hours after drug administration. Citalopram improved psychomotor responses to sensory stimuli and sustained attention, with significant decreases in movement times of the choice reaction time test and an increase in critical flicker fusion threshold. Venlafaxine did not affect performances on any of the cognitive or psychomotor tests examined. Differences may be related to relative potencies of the compounds for monoamine reuptake inhibition.

Adult↗

PubMed2002

Changes in serotonin, serotonin transporter expression and serotonin denervation supersensitivity: involvement in chronic central pain after spinal hemisection in the rat.

Spinal cord injury (SCI) results in abnormal locomotor and pain syndromes in humans. In a rodent SCI model, T13 unilateral spinal hemisection results in bilateral mechanical allodynia and thermal hyperalgesia, partly by interruption of tonic descending serotonin (5-HT) inhibition. In the current study, we examined changes in density and distribution of 5-HT and 5-HT(T) in cervical (C8) and lumbar (L5) enlargements after T13 spinal hemisection and studied the effects of intrathecally delivered 5-HT (10, 21, and 63 microg), 5-HT antagonist methysergide (125 microg/kg), and 5-HT reuptake inhibitor fluvoxamine (75 microg/kg) on pain-related behaviors. Thirty-day-old male Sprague-Dawley rats were spinally hemisected and sacrificed at 3 (n = 20) and 28 (n = 20) days postsurgery for immunohistochemistry, Western blot, and ELISA analysis and compared against sham-operated animals (n = 10). At day 3, C8 5-HT levels were not significantly changed but at L5 there was a significant decrease in ipsilateral 5-HT in laminae I-II followed by incomplete recovery at 28 days postinjury. At both 3 and 28 days postinjury, C8 5-HT(T) levels were not significantly changed, but at L5 there was significant ipsilateral up-regulation of 5-HT(T) in laminae I-II. A second group of animals (n = 30) was hemisected and, starting at 28 days postinjury, behaviorally tested with intrathecal compounds. Increasing doses of 5-HT attenuated both fore- and hindlimb mechanical allodynia and thermal hyperalgesia, and effects of endogenous 5-HT were attenuated by methysergide and enhanced with fluvoxamine, all without locomotor alterations. Sham controls (n = 10) were unaffected. Thus, permanent changes occur in 5-HT and 5-HT(T) after SCI, denervation 5-HT supersensitivity develops, and modulation of 5-HT attenuates pain-related behaviors. Insight gained by these studies may aid in the understanding of dynamic 5-HT systems which will be useful in treating chronic central pain after SCI.

Animals↗

PubMed1998

Endogenous serotonin-2A and -2C receptors in Balb/c-3T3 cells revealed in serotonin-free medium: desensitization and down-regulation by serotonin.

We studied the endogenous expression of the serotonin-2A (5-hydroxytryptamine2A, 5-HT2A) 5-HT2C, and a splice-variant of the 5-HT2C receptor in murine Balb/c-3T3 fibroblast cells that is revealed when these cells are maintained in medium containing 5-HT-free serum. RNA editing of the 5-HT2C receptor was exclusively at a single brain-specific site. Addition of 5-HT (EC50 = 23 +/- 2.9 nM) induced an immediate release of calcium from an ionomycin-sensitive intracellular store by coupling to a pertussis toxin-insensitive pathway. The 5-HT-induced calcium mobilization displayed a 5-HT-2-like pharmacology, and ligand binding analyses indicated the presence of specific binding sites (27.5 +/- 2 fmol/mg protein) with a 5-HT2A-like pharmacology. Although the 5-HT2A receptor site was predominant, the smaller component of 5-HT2C receptors alone was sufficient to mediate a maximal calcium response. The 5-HT-induced increase in [Ca2+]i was reversibly inhibited by >75% following a 12-hr pretreatment (T1/2 = 2 hr) with 5-HT (EC50 = 400 nM). Extended treatment (24-96 hr) with 5-HT induced a complete functional desensitization that was associated with a partial (60%) reduction in 5-HT2 receptor number, implicating both receptor down-regulation and post-receptor mechanisms in 5-HT-induced desensitization. Long-term (hours to days) treatment with 5-HT did not modulate DNA synthesis, cell proliferation, or transformation in Balb/c-3T3 cells. These results demonstrate that Balb/c-3T3 cells express endogenous 5-HT2 receptors that are desensitized by the 5-HT present in normal serum, illustrating the importance of growth conditions in the identification of receptor responsiveness. The lack of proliferative response to 5-HT in Balb/c-3T3 suggests a putative role of desensitization as a "safety valve" to prevent abnormal cell growth during sustained 5-HT2 receptor activation.

3T3 Cells↗

PubMed1997

In vivo electrochemical measurements of serotonin clearance in rat striatum: effects of neonatal 6-hydroxydopamine-induced serotonin hyperinnervation and serotonin uptake inhibitors.

Diffusion and clearance of extracellular serotonin (5-HT) was examined using in vivo chronoamperometry with "delayed-pulse" recordings after pressure ejections of 1 to 60 picomoles 5-HT into rat striatum at a fixed distance from a Nafion-coated carbon fiber electrode. Signals obtained were identified based on the signal characteristics to consist of 5-HT. Clearance times of 5-HT decreased, while amplitudes and rise times increased with serotonergic hyperinnervation induced by neonatal 6-hydroxydopamine (6-OHDA) lesions of dopamine (DA) neurons. Local applications of the 5-HT uptake inhibitors zimelidine or fluoxetine, in conjunction with 5-HT ejections, produced increased clearance times in both normal and 6-OHDA-treated animals. Thus, direct in vivo evidence was obtained for the importance of high affinity nerve terminal uptake as a key mechanism for clearance of 5-HT from the extracellular space. Inhibitors of 5-HT uptake appear to prolong the extracellular presence of 5-HT by increasing its clearance time.

Animals↗

PubMed1987

Postnatal changes in serotonin receptors following prenatal alterations in serotonin levels: further evidence for functional fetal serotonin receptors.

Recent work by ourselves and others has indicated that serotonin (5-HT) acts as a regulator of neuronal growth in fetal tissue, probably through an action on the high affinity 5-HT receptors known to be present. In order for our hypothesis to be correct, these receptors must be shown to be functional in fetal tissue. Furthermore, since 5-HT has a dual role in neuronal development, these receptors must be functional both in the region of the serotonergic cell body (brainstem) and in projection areas (forebrain). We have tested the functional status of fetal 5-HT receptors by testing their ability to adapt to changes in the level of 5-HT. Pregnant rats were treated with saline, p-chlorophenylalanine (a 5-HT depletor) or 5-methoxytryptamine (a 5-HT agonist) and the characteristics of the high affinity 5-HT receptors in the rat pups determined using a binding assay with [3H]5-HT. Our results show that both forebrain and brainstem receptors respond to alterations in transmitter level in a manner similar to adult brain. Thus, fetal 5-HT receptors are functional and capable of playing a role in neuronal development.

5-Methoxytryptamine↗

PubMed1997

The serotonin 5-HT2C receptor is a prominent serotonin receptor in basal ganglia: evidence from functional studies on serotonin-mediated phosphoinositide hydrolysis.

Serotonin (5-hydroxytryptamine; 5-HT) 5-HT2A and 5-HT2C receptors belong to the class of phosphoinositide-specific phospholipase C (PLC)-linked receptors. Conditions were established for measuring 5-HT2A-linked and 5-HT2C-linked PLC activity in membranes prepared from previously frozen rat frontal cortex and caudate. In the presence of Ca2+ (300 nM) and GTPgammaS (1 microM), 5-HT increased PLC activity in caudate membranes. Pharmacological analysis using the selective 5-HT2A antagonist, spiperone, and the nonselective 5-HT(2A/2C) antagonist, mianserin, demonstrated that over half of the 5-HT-stimulated PLC activity was due to stimulation of 5-HT2C receptors as opposed to 5-HT2A receptors. Radioligand binding assays with [3H]RP 62203 and [3H]mesulergine were used to quantify 5-HT2A and 5-HT2C sites, respectively, in caudate. From these data, the Bmax for caudate 5-HT2A sites and 5-HT2C sites was 165.4 +/- 9.7 fmol/mg of protein and 49.7 +/- 3.3 fmol/mg of protein, respectively. In contrast to that in caudate, PLC activity in frontal cortex was stimulated by 5-HT in a manner that was inhibited by the 5-HT2A-selective antagonists, spiperone and ketanserin. Taken together, the results indicate that 5-HT2A- and 5-HT2C-linked PLC activity can be discerned in brain regions possessing both receptor subtypes using membranes prepared from previously frozen tissue. More importantly, significant 5-HT2C-mediated phosphoinositide hydrolysis was observed in caudate, despite the relatively low density of 5-HT2C sites. The significance of these observations with respect to the physiological function of 5-HT2C receptors is discussed.

Animals↗

PubMed1984

Effects of methiothepin and lysergic acid diethylamide on serotonin release in vitro and serotonin synthesis in vivo: possible relation to serotonin autoreceptor function.

An in vitro system characterizing the presynaptic serotonin (5-HT) autoreceptor which controls the release of 5-HT from rat brain slices is described. Using this system, methiothepin (1-10 microM) demonstrated 5-HT autoreceptor antagonist activity by enhancing 5-HT release, while several recognized postsynaptic 5-HT receptor antagonists were inactive: mianserin, cinanserin, cyproheptadine, methysergide. The activity of methiothepin was highest in hypothalamic slices and lowest in striatal slices and was inhibited by the autoreceptor agonists lysergic acid diethylamide (LSD) and 5-methoxytryptamine (5-MT). The reversal of the methiothepin-enhanced 5-HT release from hypothalamic slices by LSD was not influenced by 0.3 microM tetrodotoxin. The peripheral administration of LSD to rats has been shown to reduce 5-HT synthesis and release by a mechanism thought to involve, in part, an autoreceptor-mediated reduction in impulse flow of 5-HT neurons. In the present experiments, intraperitoneal injection of methiothepin antagonized the LSD-induced reduction in hypothalamic 5-HT synthesis (5-hydroxytryptophan accumulation) while exerting no influence by itself. Conversely, compounds which were not active as 5-HT autoreceptor antagonists in vitro (i.e., cyproheptadine, methysergide, cinanserin) did not influence the effect of LSD on 5-HT synthesis. Further, the reduction in 5-hydroxytryptophan (5-HTP) accumulation by LSD showed regional differences in inhibition by methiothepin (hypothalamus greater than cortex greater than striatum) which paralleled the autoreceptor antagonist activity of methiothepin in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

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↗