ergoline and 5-carboxamidotryptamine

1. In the present study, we investigated how alloxan-induced diabetes affects the ability of 5-hydroxytryptamine (5-HT) to modulate bradycardia induced in vivo by electrical stimulation of the vagus nerve in pithed rats. We also analysed the type and/or subtype of 5-HT receptors involved. 2. Diabetes was induced in male Wistar rats with a single injection of alloxan (150 mg/kg, s.c.). Four weeks later, rats were anaesthetized, pretreated with atenolol and pithed. Electrical stimulation (3, 6 and 9 Hz) of the vagus nerve resulted in frequency dependent decreases in heart rate (HR). 3. In diabetic rats, intravenous bolus administration of high doses of 5-HT (100 and 200 microg/kg) increased the bradycardia induced by vagal electrical stimulation. Similarly, low doses (10 microg/kg) of the 5-HT(1/7) receptor agonist 5-carboxamidotryptamine (5-CT), increased vagally induced bradycardia. However, at high doses (50, 100 and 150 microg/kg), 5-CT reduced the bradycardia. Attenuation of the vagally induced bradycardia evoked by the higher doses of 5-CT was reproduced by L-694,247 (50 microg/kg), a selective agonist for the non-rodent 5-HT(1B) and 5-HT(1D) receptors. Enhancement of the vagally induced bradycardia elicited by low doses of 5-CT was reproduced by the selective 5-HT(1A) receptor agonist 8-hydroxydipropylaminotretalin hydrobromide (8-OH-DPAT; 50 microg/kg). These stimulatory and inhibitory actions on vagal stimulation-induced bradycardia in diabetic rats were also observed after administration of exogenous acetylcholine. 4. Vagally induced bradycardia in diabetic rats was not affected by administration of the selective 5-HT(2) receptor agonist alpha-methyl-5-HT (150 microg/kg), the selective 5-HT(3) receptor agonist 1-phenylbiguanide (150 microg/kg) or the selective 5-HT(1B) receptor agonist CGS-12066B (50 microg/kg). 5. Enhancement of the electrical stimulation-induced bradycardia in diabetic rats caused by 5-CT (10 microg/kg) or 8-OH-DPAT (50 microg/kg) was abolished by the selective 5-HT(2/7) receptor antagonist mesulergine (1 mg/kg) and the selective 5-HT(1A) receptor antagonist WAY-100,635 (100 microg/kg), respectively. Similarly, pretreatment with the non-selective 5-HT(1) receptor antagonist methiothepin (0.1 mg/kg) blocked the inhibitory effect of 5-CT (50 microg/kg) on the bradycardia induced by vagal electrical stimulation in diabetic rats. BRL-15572 (2 microg/kg), a selective 5-HT(1D) receptor antagonist, inhibited the action of L-694,247 (50

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Acetylcholine; Animals; Biphenyl Compounds; Blood Glucose; Bradycardia; Cholinergic Agents; Diabetes Mellitus, Experimental; Dose-Response Relationship, Drug; Electric Stimulation; Ergolines; Heart; Heart Rate; Injections, Intravenous; Male; Methiothepin; Oxadiazoles; Piperazines; Pyridines; Rats; Rats, Wistar; Receptors, Serotonin, 5-HT1; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Tryptamines; Vagus Nerve

Previously, we demonstrated that human serotonin (5-HT) 5-HT(7) receptors display marked constitutive activity. Here, we tested if the constitutive activation of adenylyl cyclase by 5-HT(7) receptors influenced both the desensitization properties of transfected 5-HT(7) receptors and the ability of endogenous G(s)-coupled receptors to activate adenylyl cyclase. Using membranes from stably transfected HEK293 cells expressing the recombinant human 5-HT(7) receptor splice variants (5-HT(7(a)), 5-HT(7(b)) and 5-HT(7(d))), we compared the effects of 1-h or 24-h preincubation of the agonist 5-HT, partial inverse agonists mesulergine and SB269970, and full inverse agonists clozapine and methiothepin on subsequent activation of adenylyl cyclase by both 5-HT through transfected 5-HT(7) receptors and the endogenous G(s)-coupled beta-adrenoceptors and prostaglandin receptors of HEK293 cells. The data show that stable expression of 5-HT(7) receptors is sufficient to attenuate adenylyl cyclase activation by endogenous G(s)-coupled receptors. Interestingly, preincubation with inverse agonists not only failed to result in the predicted resensitization of all receptor mediated adenylyl cyclase activation, but some inverse agonists further attenuated (desensitized) beta-adrenoceptor and prostaglandin-stimulated adenylyl cyclase activation similar to long-term agonist exposure by 5-HT. These effects were not correlated with inverse agonist efficacy, were not accompanied by receptor down-regulation and appear to be mediated by a protein kinase A (PKA) independent mechanism. It is concluded that the human 5-HT(7) receptor mediates heterologous desensitization of endogenous G(s)-coupled receptors through an unknown and potentially novel mechanism.

Topics: Adenylyl Cyclases; Alternative Splicing; Binding, Competitive; Cell Line; Cell Membrane; Clozapine; Colforsin; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Enzyme Activation; Ergolines; Gene Expression; Humans; Isoproterenol; Isoquinolines; Methiothepin; Multivariate Analysis; Phenols; Protein Isoforms; Protein Kinase Inhibitors; Radioligand Assay; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Sulfonamides; Time Factors; Tritium

The aim of the present study was to identify 5-hydroxytryptamine(7) (5-HT(7)) binding sites in the mouse ileum, where the presence of mRNA for the receptor has been reported. Studies were performed using [3H]mesulergine, an antagonist with high affinity at 5-HT(7) receptors. In the presence of a combination of masking drugs to inhibit the binding of the radioligand to other receptors at which it has affinity, such as 5-HT(2A), 5-HT(2C) and dopamine D(2) receptors as well as alpha(1)/alpha(2)-adrenoceptors, [3H]mesulergine labelled two sites with pK(D) values of 9.7+/-0.7 and 7.4+/-0.4 and B(max) values of 37.2+/-21.4 and 247.8+/-62.1 fmol mg protein(-1), respectively. Displacement studies also indicated the presence of non-homogenous binding sites, which showed a significant correlation (Pearson correlation factors of 0.91 and 0. 85) with the 5-HT(2C) and 5-HT(7) receptors, respectively. Total binding to the 5-HT(2C) receptor was minimal; <30% of the total specific receptor binding. The antagonist order of affinity at the greater proportion of receptors was: risperidone (pK(i)pindolol (5. 6). This receptor also showed a high affinity for 5-carboxamidotryptamine (5-CT; 10.6) and moderate affinity for (+/-)-2-dipropyl-amino-8-hydroxy-1,2,3,4,-tetrahydronaphthalene (8-OH-DPAT; 7.2), which is typical of the 5-HT(7) receptor profile.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Binding Sites; Ergolines; Female; Ileum; Male; Mice; Receptor, Serotonin, 5-HT2C; Receptors, Serotonin; Serotonin; Serotonin Antagonists

We aimed to develop a model to study in vivo the rabbit saphenous vein pharmacology and to investigate constrictions mediated by adrenoceptor and 5-HT receptor subtypes. We used the technique of high precision ultrasonic echo-tracking for direct measurement of saphenous vein diameters in pentobarbital anesthetized rabbits. Saphenous vein constrictions induced in rabbits by the alpha(1)-adrenoceptor agonist L-phenylephrine and the 5-HT(1B) receptor agonist sumatriptan were comparable with those induced in dogs but those induced by the 5-HT(1B) and 5-HT(7) receptor agonist 5-carboxamidotryptamine failed to appear in dogs. Dose-related constrictions of rabbit veins were obtained with L-phenylephrine and the alpha(2)-adrenoceptor agonist dexmedetomidine. Frequency-related constrictions of rabbit veins induced by nerve stimulation were partially inhibited by an alpha(1)-adrenoceptor or a postsynaptic alpha(2)-adrenoceptor antagonist (prazosin and SKF 104,078) but not affected by the pre- and post-synaptic alpha(2)-adrenoceptor antagonists BRL 44408 or rauwolscine. Constrictions of rabbit veins to sumatriptan and 5-CT were inhibited by GR 127935 and those induced by quipazine, a 5-HT(2) receptor agonist were prevented by ritanserin. The initial constrictions induced by 5-CT were followed by dilatations which were inhibited by the 5-HT(7) receptor antagonist mesulergine. These data indicate that rabbit saphenous veins, in vivo and at rest, respond to activation of 5-HT(1B) and 5-HT(2) receptors, alpha(1)- and alpha(2)-adrenoceptors and nerve stimulation; the dilator effect mediated by 5-HT(7) receptor activation was also detected. The data validate a new animal model to study superficial vein reactivity and its pharmacological sensitivity.

Topics: Adrenergic Agents; Adrenergic alpha-Agonists; Adrenergic alpha-Antagonists; Anesthesia; Animals; Benzazepines; Blood Pressure; Dogs; Dose-Response Relationship, Drug; Ergolines; Imidazoles; Indoles; Injections, Intravenous; Isoindoles; Oxadiazoles; Peripheral Nervous System; Phenylephrine; Piperazines; Prazosin; Rabbits; Receptors, Adrenergic, alpha; Receptors, Serotonin; Saphenous Vein; Serotonin; Serotonin Agents; Serotonin Receptor Agonists; Sumatriptan; Tetrahydronaphthalenes; Time Factors; Ultrasonography, Doppler; Vasoconstrictor Agents

1. The primary aim of this investigation was to determine whether binding sites corresponding to the 5-HT7 receptor could be detected in smooth muscle of the rat jejunum. Binding studies in rat brain (whole brain minus cerebellum) and guinea-pig ileal longitudinal muscle were also undertaken in order to compare the binding characteristics of these tissues. Studies were performed using [3H]-mesulergine, as it has a high affinity for 5-HT7 receptors. 2. In the rat brain and guinea-pig ileum, pKD values for [3H]-mesulergine of 8.0 +/- 0.04 and 7.9 +/- 0.11 (n = 3) and Bmax values of 9.9 +/- 0.3 and 21.5 +/- 4.9 fmol mg(-1) protein were obtained respectively, but no binding was detected in the rat jejunum. [3H]-mesulergine binding in the rat brain and guinea-pig ileum was displaced with the agonists 5-carboxamidotryptamine (5-CT) > 5-hydroxytryptamine (5-HT) > or = 5-methoxytryptamine (5-MeOT) > sumatriptan and the antagonists risperidone > or = LSD > or = metergoline > ritanserin > > pindolol. 3. Despite the lack of [3H]-mesulergine binding in the rat jejunum, functional studies undertaken revealed a biphasic contractile response to 5-HT which was partly blocked by ondansetron (1 microM). The residual response was present in over 50% of tissues studied and was found to be inhibited by risperidone > LSD > metergoline > mesulergine = ritanserin > pindolol, but was unaffected by RS 102221 (3 microM), cinanserin (30 nM), yohimbine (0.1 microM) and GR 113808 (1 microM). In addition, the agonist order of potency was 5-CT > 5-HT > 5-MeOT > sumatriptan. 4. In conclusion, binding studies performed with [3H]-mesulergine were able to detect 5-HT7 sites in rat brain and guinea-pig ileum, but not in rat jejunum, where a functional 5-HT7-like receptor was present.

Topics: 5-Methoxytryptamine; Animals; Binding Sites; Binding, Competitive; Brain; Dose-Response Relationship, Drug; Ergolines; Female; Free Radical Scavengers; Guinea Pigs; Ileum; In Vitro Techniques; Jejunum; Male; Muscle Contraction; Ondansetron; Radioligand Assay; Rats; Rats, Wistar; Receptor, Serotonin, 5-HT2C; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Spiro Compounds; Sulfonamides; Sumatriptan; Tritium

It has been suggested that the late hypotensive response to serotonin (5-hydroxytryptamine; 5-HT) in vagosympathectomized rats is mediated by '5-HT1-like' receptors since this effect is mimicked by 5-carboxamidotryptamine (5-CT), is not modified by cyproheptadine, ketanserin or MDL 72222, but it is blocked by methysergide. The present study was set out to reanalyze this suggestion in terms of the classification schemes proposed in 1994 and 1996 by the NC-IUPHAR subcommittee on the classification and nomenclature of 5-HT receptors. I.v. bolus injections of 5-CT (0.01-0.3 microg x kg(-1)), 5-HT (1-30 microg x kg(-1)) and 5-methoxytryptamine (5-MeO-T; 1-30 microg x kg(-1)) produced dose-dependent hypotensive responses with a rank order of agonist potency: 5-CT >> 5-HT > 5-methoxytryptamine with sumatriptan (30-1000 microg x kg(-1)) inactive. The depressor responses to 5-HT and 5-CT were not attenuated by i.v. GR127935 (300-3000 microg x kg(-1)) or equivalent volumes of saline. In contrast, lisuride, methiothepin, mesulergine, metergoline and clozapine dose-dependently antagonized the responses to 5-HT and 5-CT; the rank order of apparent pA2 values against 5-HT and 5-CT, respectively, was: lisuride (7.7; 7.8) > methiothepin (6.8; 7.0) > or = mesulergine (6.4; 6.6) > clozapine (5.7; 5.8); metergoline displayed variable potencies (5.6; 6.4). Except for lisuride, which also affected isoprenaline-induced hypotension, the antagonism by the other drugs was selective. Based upon the above rank order of agonist potency, the blockade by a series of drugs showing high affinity for the cloned 5-ht7 receptor and the lack of blockade by GR127935, our results indicate that the 5-HT receptor mediating hypotension in vagosympathectomized rats is operationally similar to other putative 5-ht7 receptors mediating vascular and non-vascular responses (e.g. relaxation of the rabbit femoral vein, canine coronary and external carotid arteries and guinea-pig ileum as well as feline tachycardia).

Topics: 5-Methoxytryptamine; Adrenergic beta-Agonists; Animals; Blood Pressure; Clozapine; Ergolines; Heart Rate; Isoproterenol; Lisuride; Male; Metergoline; Methiothepin; Oxadiazoles; Piperazines; Rats; Rats, Wistar; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Sumatriptan; Sympathectomy

We analyzed the existence of an additional serotonin (5-HT) receptor subtype, sensitive to 5-carboxamidotryptamine, in the mammalian brain. Radioligand binding studies with [3H]5-HT were carried out in rat, guinea pig, and human brain membranes, in the presence of unlabeled drugs to mask the binding to all known 5-HT receptors, with the exception of 5-HT1E sites. Under these conditions, unlabeled 5-carboxamidotryptamine still showed a biphasic competition curve with a nanomolar affinity component. Saturation studies with 5-[3H]carboxamidotryptamine were carried out in the presence of (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin, mesulergine, and ergotamine, to mask the binding to all receptors known to be labeled by 5-carboxamidotryptamine. These studies showed the existence in cortex and hippocampus from guinea pig and human brain of a remaining binding site with high affinity (pK(D) = 7.8-8.1) and a unique pharmacological profile. 5-HT and 5-carboxamidotryptamine showed nanomolar affinity, whereas 5-methoxytryptamine recognized this binding site with intermediate affinity. Other drugs exhibited low or very low potency in inhibiting this binding. The addition of 5'-guanylylimidodiphosphate significantly reduced the number of binding sites labeled by 5-[3H]carboxamidotryptamine, in the presence of the masking drugs described above, indicating the interaction with a GTP-binding protein. Preliminary autoradiographic studies in human brain appear to indicate that this 5-HT binding site is present in areas such as the globus pallidus, neocortex, and hippocampus, among others.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Autoradiography; Binding Sites; Binding, Competitive; Brain; Cerebral Cortex; Ergolines; Ergotamine; Female; Guinea Pigs; Humans; Kinetics; Male; Mammals; Middle Aged; Organ Specificity; Radioligand Assay; Rats; Rats, Wistar; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Tritium

The influence of serotonin (5-hydroxytryptamine, 5-HT) and serotonin analogues on the direct current electroretinogram (d.c. ERG) and the standing potential of the albino rabbit eye (SP) was studied. After unilateral vitrectomy, corneal recordings were obtained during simultaneous intravitreal perfusion with a control solution alternating with 5-HT at concentrations of 25, 120 and 200 microM. The c-wave increased at 25 and 120 microM when changing from control solution to test solution (P < 0.05) but did not decrease significantly when changing back to control solution (P > 0.05). The c-wave was reversibly elevated at 200 microM (PHS-5-HT, P < 0.01; 5-HT-PHS, P < 0.05). To analyse further the influence on the c-wave, in vivo intraretinal microelectrode recordings were obtained during intravitreal perfusion with 5-HT. The transepithelial potential (TEP) increased (P < 0.01), while the slow PIII was not significantly affected (P > 0.05). The serotonin receptor agonists 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane, 5-methoxytryptamine, alpha-methyl-5-hydroxytryptamine and 2-methyl-5-hydroxytryptamine, caused a significant reversible elevation of the c-wave, whereas 5-carboxyamidotryptamine did not. Tropisetron did not block the serotonin effect and LY53857 had an effect of its own on the c-wave. The results seem to indicate that the influence of serotonin on the c-wave is mainly due to an effect on the retinal pigment epithelium (RPE) and that more than one type of serotonin receptor may be involved.

Topics: 5-Methoxytryptamine; Animals; Dose-Response Relationship, Drug; Electroretinography; Ergolines; Indoles; Membrane Potentials; Pigment Epithelium of Eye; Rabbits; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Tropisetron

5-Hydroxytryptamine elicits its physiological effects by interacting with a diverse group of receptors. Two of these receptors, the 5-HT1D beta and the 5-HT1E receptors, are approximately 60% identical in the transmembrane domains that presumably form the ligand binding site yet have very different pharmacological properties. Analysis of the pharmacological properties of a series of chimeric 5-HT1D beta/5-HT1E receptors indicates that sequences in the sixth and seventh transmembrane domains are responsible for the differential affinity of 5-carboxamidotryptamine for these two receptors. More detailed analysis shows that two amino acid differences in the sixth transmembrane domain (Ile333 and Ser334 in the 5-HT1D beta receptor, corresponding to Lys310 and Glu311 in the 5-HT1E receptor) are largely responsible for the differential affinities of some, but not all, ligands for the 5-HT1D beta and 5-HT1E receptors. It is likely that these two amino acids subtly determine the overall three-dimensional structure of the receptor rather than interact directly with individual ligands.

Topics: Amino Acid Sequence; Animals; Base Sequence; Binding Sites; Binding, Competitive; Chlorocebus aethiops; Cloning, Molecular; COS Cells; DNA Primers; Ergolines; Glutamic Acid; Humans; Isoleucine; Kinetics; Ligands; Lysine; Models, Structural; Molecular Sequence Data; Point Mutation; Polymerase Chain Reaction; Protein Structure, Secondary; Receptor, Serotonin, 5-HT1B; Receptors, Serotonin; Recombinant Fusion Proteins; Sequence Homology, Amino Acid; Serine; Serotonin; Transfection

5HT modulates the rhythmic locomotor output of most vertebrates by enhancing the duration and intensity of motor bursts in each cycle, but there is little clear evidence on the pharmacological profile of the 5HT receptor subtype(s) involved. In this study we extend our previous work on the role of 5HT in the development and modulation of locomotor behaviour in newly hatched Xenopus tadpoles by examining the 5HT receptor type responsible for enhancing the swimming activity in immobilized preparations. By applying a range of agonists and antagonists against different 5HT receptor subtypes, we conclude that serotonergic modulation of swimming activity is accomplished via the activation of just one receptor type with a pharmacological profile similar to the mammalian 5HT1a receptor. The effects of 5HT on burst duration (an increase) and on episode length (a decrease) are mimicked by the 5HT1a receptor agonists, 5-carboxamidotryptamine (5CT) and R(+)-8-OH-DPAT, and reversed by the 5HT1a receptor antagonist NAN-190. Agents acting at other 5HT1, as well as 5HT2 and 5HT3, receptor subtypes were without noticeable effect on the 5HT-enhanced swimming rhythm.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Aging; Animals; Cyproheptadine; Ergolines; Ketanserin; Metamorphosis, Biological; Methysergide; Motor Activity; Piperazines; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Swimming; Xenopus laevis

C57BL/6 mice exhibit acute transient decreases in lung conductance (GL) and dynamic compliance (Cdyn) after intravenous administration of serotonin (5-HT). To identify the specific agonist receptor subtypes responsible for this bronchoconstriction, we measured changes in pulmonary function in C57BL/6 mice in response to intravenous infusion of 5-HT receptor subtype-selective agonists and to 5-HT in the presence of antagonists selective for the 5-HT2 or 5-HT3 receptor subtypes. Agonists selective for the 5-HT1A/1B/1D or 5-HT3 receptor subtypes induced minimal or undetectable pulmonary responses, whereas infusion of alpha-methyl-5-hydroxytryptamine, a 5-HT2 receptor-selective agonist, led to dose-related decreases in Cdyn and GL. The selective 5-HT3 receptor antagonist, LY278584 maleate, (1.0 mg/kg i.v.) caused no detectable reduction in the response to 100 micrograms/kg of 5-HT. In contrast, treatment with the 5-HT2 receptor antagonist LY53857 (10 micrograms/kg i.v.) resulted in a significant diminution of the pulmonary response observed after infusion of 100 micrograms/kg of 5-HT. Dose-response relationships were established for 5-HT in experiments in which each mouse was treated with a single dose of 5-HT without antagonist or after LY53857. Compared with responses to doses of 5-HT of more than 100 micrograms/kg in the absence of antagonist, pulmonary responses to 5-HT after infusion of 10 micrograms/kg of LY53857 were significantly reduced; 100 micrograms/kg of LY53857 nearly abolished the responses to all doses of 5-HT.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Atropine; Bronchoconstriction; Ergolines; Male; Mice; Mice, Inbred C57BL; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists

Binding sites corresponding to 5-HT1E receptors were labelled in mouse, rat, and guinea-pig brains by using [3H]5-hydroxytryptamine ([3H]5-HT) in the presence of 5-carboxamidotryptamine (5-CT) (0.1 microM), and their distribution within the brain was studied by quantitative autoradiography. The results obtained with mouse brain show that 5-HT1E binding sites are particularly present in the cortex, caudate-putamen and claustrum, where they showed the highest density. Lower densities were measured in other regions. Saturation experiments showed that the affinity of [3H]5-HT for 5-HT1E binding sites (nanomolar range) was very similar in the different structures. The distribution of 5-HT1E binding sites was similar in rat and guinea-pig brains. In rat brain, selective lesioning of serotonergic fibres by intracerebroventricular injection of 5,7-dihydroxytryptamine (5,7-DHT), a specific 5-HT neurotoxin, did not affect the density of 5-HT1E binding, indicating that these receptors are mainly localized on non-serotonergic neurones.

Topics: 5,7-Dihydroxytryptamine; Animals; Autoradiography; Binding, Competitive; Brain; Brain Chemistry; Ergolines; Guinea Pigs; In Vitro Techniques; Male; Membranes; Mice; Neurons; Radioligand Assay; Rats; Rats, Wistar; Receptors, Serotonin; Serotonin; Serotonin Receptor Agonists

5-CT (5-carboxamidotryptamine)-insensitive (5-HT1E/5-HT1F) 5-HT1-like recognition sites have been mapped autoradiographically in rat and guinea pig brain using [3H]5-HT in the presence of 5-CT and mesulergine to mask 5-HT1A, 5-HT1B, 5-HT1D and 5-HT2C binding sites. Binding was more dense in the guinea pig but in both species 5-CT-insensitive 5-HT1-like sites were located in the olfactory tubercle, interpeduncular nucleus, caudate putamen, nucleus accumbens, substantia nigra, frontal cortex and hippocampus. These receptors were particularly marked in the claustrum of the guinea pig but not the rat.

Topics: Animals; Antiparkinson Agents; Autoradiography; Basal Ganglia; Brain Mapping; Ergolines; Guinea Pigs; Male; Rats; Rats, Sprague-Dawley; Receptors, Serotonin; Serotonin; Species Specificity

Choroid plexus epithelial cells are enriched in mRNA for proteins such as the iron carrier transferrin, which acts as a trophic factor in the brain. Choroid plexus epithelial cells also have a high density of 5-HT1C receptors linked to activation of the phosphoinositide (PI) hydrolysis second messenger system. The present studies show that the 5-HT1C/5-HT2 receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) potently increases PI hydrolysis and the levels of transferrin in primary cultures of rat choroid plexus epithelial cells. These effects are blocked by the 5-HT1C/5-HT2 receptor antagonists mesulergine and mianserin, but not by the 5-HT2 receptor-selective antagonist spiperone. Similarly, mesulergine and mianserin, but not spiperone, block the increases in transferrin levels and PI hydrolysis elicited by 5-carboxamidotryptamine (5-CT), a 5-HT1 receptor-selective agonist, and by serotonin. We conclude, therefore, that 5-HT1C receptor activation in the choroid plexus leads to an increase in the production of transferrin. By promoting transferrin synthesis in the choroid plexus, 5-HT may indirectly influence brain development and differentiation.

Topics: Amino Acid Isomerases; Animals; Blotting, Northern; Carrier Proteins; Cells, Cultured; Choroid Plexus; Cyclosporins; Epithelium; Ergolines; Fibroblasts; Kinetics; Male; Mianserin; Peptidylprolyl Isomerase; Phosphatidylinositols; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Receptors, Serotonin; RNA Probes; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Spiperone; Thymidine; Time Factors; Transferrin

Quantitative receptor autoradiography was used to determine the distribution patterns of 5-CT-sensitive and 5-CT-insensitive binding of [3H]5-HT to high-affinity sites in human cortex, putamen, and globus pallidus. The binding of 3H-5-HT was limited to 5-HT1D sites (5-CT-sensitive) by co-incubating pindolol and mesulergine with [3H]5-HT, and by using 10 microM 5-HT to determine non-specific binding. The difference in the levels of binding between tissues exposed to the 5-CT-containing incubation media and tissue exposed to [3H]5-HT in the presence of 100 nM 5-CT was defined as 5-CT-insensitive binding (5-HT1E). The 5-HT1D receptor density in the frontal cortex was 189 fmol/mg, 226 fmol/mg was present in the globus pallidus, while the density in the putamen was only 28 fmol/mg. The 5-HT1E receptor density was 146 fmol/mg in frontal cortex, 224 fmol/mg in putamen and 140 fmol/mg in globus pallidus. The differential distribution patterns of the high-affinity, 5-CT-sensitive and 5-CT-insensitive [3H]5-HT binding sites indicate that these sites are expressed independently in human brain tissues. These data are supportive of and consistent with previous pharmacological data that led to the division of 5-HT1D receptors into 5-HT1D and 5-HT1E receptors and do not support the division of 5-HT1D receptors into 5-CT-sensitive and 5-CT-insensitive states.

Topics: Antiparkinson Agents; Autoradiography; Brain Chemistry; Ergolines; Humans; In Vitro Techniques; Pindolol; Receptors, Serotonin; Serotonin

1. 5-Hydroxytryptamine (5-HT) was applied by microiontophoresis in the vicinity of identified sympathetic preganglionic neurones in the upper thoracic spinal cord of the rat, in vivo. 2. Sympathetic preganglionic neurones responded in one of three ways to 5-HT: by (a) excitation (76%), (b) inhibition (4%) or (c) in a biphasic manner (5%). 3. The excitatory responses evoked by 5-HT were mimicked by 5-carboxamidotryptamine (5-CT) and alpha-methyl-5-hydroxytryptamine (alpha-Me-5-HT). The inhibitory and biphasic responses evoked by 5-HT were mimicked by 2-methyl-5-hydroxytryptamine (2-Me-5-HT). The observed responses evoked by 5-HT and selective agonists may be different on the same cell. In several instances a single neurone excited by one agonist was inhibited by another agonist. 4. The 5-HT2-receptor antagonists, ketanserin and LY 53857, failed to abolish selectively the excitatory responses evoked by 5-HT and alpha-Me-5-HT, when applied by microiontophoresis. The antagonists non-selectively reduced the excitatory responses evoked by 5-HT, 5-CT, alpha-Me-5-HT, D,L-homocysteic acid (DLH) and noradrenaline (NA). A reduction in synaptically evoked activity was also observed. 5. The 5-HT3-receptor antagonist, ICS 205-930, failed to abolish the inhibitory responses evoked by 5-HT. 6. It was concluded that the excitatory responses evoked by 5-HT are mediated by a receptor that is neither 5-HT2 or 5-HT3, but shows similarities to the 5-HT1-like receptor profile. The inhibitory actions of 5-HT are mimicked by 2-Me-5-HT, but the receptor is not 5-HT3, or 5-HT1-like or 5-HT2.

Topics: Anesthesia; Animals; Electric Stimulation; Ergolines; Ganglia, Sympathetic; Homocysteine; Indoles; Iontophoresis; Ketanserin; Male; Neurons; Norepinephrine; Rats; Rats, Inbred Strains; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Tropisetron