Localization of serotonin receptors in the rat thalamus by electrophysiology and the action of 5-HTP-DP-hex (original) (raw)
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Substance P enhances the release of endogenous serotonin from rat ventral spinal cord
European Journal of Pharmacology, 1989
The effect of the tachykinin neuropeptides, substance P (SP), neurokinin A (NKA) and the neurokinin B (NKB) receptor agonist, senktide, on the potassium-evoked release of endogenous serotonin (5-hydroxytryptamine, 5-HT) was investigated in superfused tissue slices of rat ventral spinal cord, where 5-HT is known to coexist with SP. Endogenous 5-HT was assayed by HPLC with electrochemical detection. The evoked release of 5-HT was significantly enhanced by 10-4 M SP (190% increase) and 10-5 M SP (74% increase) but not by 10-6 M SP. NKA (10-5 and 10-4 M) and senktide (10-5 and 10-4 M) had no significant effect on the 5-HT release. The results suggest that, in the rat ventral spinal cord, where most of the 5-HT and SP is stored in the same nerve endings, SP but not NKA nor NKB potentiates the evoked release of 5-HT in a dose-dependent manner.
British Journal of Pharmacology, 1990
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 a-methyl-5-hydroxytryptamine (a-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 a-Me-5-HT, when applied by microiontophoresis. The antagonists nonselectively reduced the excitatory responses evoked by 5-HT, 5-CT, a-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.
Neuroscience, 1978
with the indirect immunofluorescence technique of Coons and collaborators a possible coexistence of 5-hydroxytryptamine (S-HT) and substance P in neurons of the lower medulla oblongata was exptored. Antisera to 5-HT and to dopadecarboxylase (aromatic t-aminoacid decarboxylase), an enzyme probably present in immunologically indistinguishable forms both in catechoiamine and 5-HT neurons, were used as markers for 5.HT neurons and an antiserum raised to synthetic substance P conjugated with bovine serum albumin for substance P-containing neurons. Five or IOfirn thick, consecutive sections were stained with the three antisera. Numerous cell somata in nucleus raphe magnus, nucleus raphe obscurus, nucleus raphe pallidus, pars a of the nucleus reticularis gigantocellularis and nucleus interfasci~ularis hypoglossi contained both substance P-like immunoreactivity and 5-HT (and dopadecarboxylase) immunoreactive material. After intraventricular or intracisternal injections of $6. or 5,7-dihydroxytryptamine, two neurotoxins assumed to cause= degeneration mainly of 5-HT neurons, enlarged substance P and S-HT (and dopadecarboxylase) positive fibres were seen in, around and lateral to the olivary complex. Furthermore, in these rats both substance P and 5-HT positive nerve terminals in the ventral horns of the spinal cord disappeared.
Brain Research, 1992
Intracellular recordings from dorsal raph e neurones in slices from rat brains were used to study the actions of x-opioid receptor agonists on an excitatory postsynaptic potential (epsp) evoked by local electrical stimulation of afferent terminals. The epsp was observed on all 5-HT-sensitive neurones and was blocked by 1 /LM TIX. The epsp was reduced in a dose-dependent manner by the specific x-opioid receptor agonist [5R-(5a,7a,8(3)}-N-methyl-N-[7-(I-pyrrolidinyl)-l-oxaspiro[4.5]dec-8-yl)-4-benzofuranacetamide monohydrochloride (CI-977) (1-100 nM). The effects of CI-977 were blocked by the specific x-opioid receptor antagonist norbinaltorphimine (NorBNI) (0.1-1 /LM). In the presence of the GABA A receptor antagonists picrotoxin and bicuculline (30 /LM), CI-977 still had its depressant action on the epsp. Application of the excitatory amino acid receptor antagonists either kynurenic acid <0.5-1 mM) or 6-cyano•2,3-dihydro-7-nitro-quinoxaline-2,3-dione (CNQX) (30~M) and DL•2-amino-5-phoshonovaleric acid (APV) reduced both the peak and area of the epsp suggesting that the main component of the epsp evoked by electrical stimulation was largely due to release of excitatory amino acids from afferent terminals. Using potassium chloride-filled recording electrodes an epsp which was only part ially occluded by kynurenic acid or CNQX and APV was seen on some neurones, this residual epsp was insensitive to CI-977 but was blocked by 30~M picrotoxin and bicuculline. The specific~-opioid receptor agonist, DAGOL, had no consistent effect on the fast epsp. Longer durat ion electrical stimuli produced a slow inhibitory postsynaptic potential (ipsp) and a long duration increase in firing. CI-977 did not affect either the slow 5-HT-mediated ipsp which was blocked by spiperone or the slow noradrenaline-mediated increase in firing which was sensitive to prazosin. CI-977 did not change the depolarizing response to brief applications of either glutamic acid or N•methyl-D-aspartic acid (NMDA). CI-977, NorBNI, naloxone, DAGOL, picrotoxin, bicuculline and kynurenic acid had no consistent effects on the resting postsynaptic membrane potential or conductance. Under voltage-clamp conditions CI-977 had no effect on a membrane current resembling IA-These results suggest that x-opioid receptors are present on the terminals of afferents which release excitatory amino acids onto the 5-HT•sensitive neurones in the raphe.
Analgesic properties of a systemically-administered synthetic dipeptide of 5-hydroxytryptophan
Peptides, 1986
Analgesic properties of a systemically-administered synthetic dipeptide of 5-hydroxytryptophan. PEPTIDES 7(6) [995][996][997][998][999] 1986.--Synthetic peptides of 5-hydroxytryptophan (5-HTP), including N-acetyl-5-HTP-5-HTP amide (5-HTP-ACETYL-DP), specifically inhibit the binding of serotonin to serotonin binding protein. 5-HTP-ACETYL-DP also produces a long-lasting, opiatesensitive analgesia following central, but not systemic administration. The present study evaluated an apolar derivative of 5-HTP dipeptide, N-hexanoyl-5-HTP-5-HTP amide (5-HTP-HEX-DP), for its analgesic properties in rats following systemic administration. 5-HTP-HEX-DP (5-50 mg/kg) significantly increased jump thresholds in a dose-dependent manner with peak analgesia occurring at 2.5 hr after injection, and lasting up to 5 hr. In the tail-flick assay, 5-HTP-HEX-DP (20 mg/kg) produced a significant antinociceptive effect at 1 hr post-injection using both high and low intensity levels of radiant heat. While 5-HTP-HEX-DP and morphine each elicited analgesia following acute administration, chronic (14 days) incremental dosing with 5-HTP-HEX-DP or morphine resulted in persistent analgesia in 5-HTP-HEX-DP-treated animals, and a loss of analgesia in morphine-treated rats. Thus, significant tolerance to morphine, but not 5-HTP-HEX-DP analgesia developed using this protocol. Hence, 5-HTP-HEX-DP is a systemically-active analgesic which fails to develop tolerance when administered daily over 14 days.
Pre- and postsynaptic actions of serotonin on rat suprachiasmatic nucleus neurons
Brain Research, 2000
Serotoninergic transmission is implicated in the photic and non-photic regulation of circadian rhythms. 5-HT (1-100 mM), carboxamidotryptamine (5-CT 0.1-10 mM) and (1)-8-hydroxy-dipropylaminotetraline (8-OH-DPAT, 1-30 mM) dose-dependently activated an outward current (5-100 pA) in 30% of neurons voltage-clamped at 260 mV in the suprachiasmatic nucleus (SCN) in vitro slice. EC values were 7.0 mM for 5-HT and 0.2 mM for 5-CT. Serotonin-induced outward current was associated with an increase in 50 21 input conductance, and the current was blocked by Ba (1 mM). The amplitude of the current was enhanced by depolarization, reduced by hyperpolarization, and reversed its polarity during a hyperpolarization beyond the potassium equilibrium potential. Mean amplitudes of the 5-HT outward current changed with time of the subjective circadian day. The value near CT2 (23.8 pA) was about 4 times greater than that around CT14 (6.7 pA). Cells that responded with an outward current showed four types of morphology: monopolar, simple bipolar, curly bipolar and radial shaped; they were localized in all parts of the SCN. The EPSC evoked by retino-hypothalamic-tract (RHT) stimulation was inhibited 26% but the inward current induced by exogenously applied glutamate or NMDA was not affected by serotonin agonists. Focal stimulation-induced and spontaneous IPSC but not the exogenous GABA-induced outward current were inhibited by 5-HT agonists in a subpopulation of cells. In conclusion, 5-HT regulates SCN neurons by both pre-and post-synaptic inhibitory mechanisms; the latter may play a key role in modulating SCN circadian rhythm by activation of 5-HT receptors and opening of a potassium channel.
Characterization of 5-hydroxytryptamine-induced depolarizations in rat isolated vagus nerve
European Journal of Pharmacology, 1994
An additional component of the depolarization induced by 5-hydroxytryptamine (5-HT) in the rat isolated vagus nerve has recently been attributed to activation of 5-HT 4 receptors. To confirm and extend this finding, extracellular recordings of D.C. potentials were made using the 'grease-gap' technique during continuous superfusion of the isolated nerve. Beginning at 1 nM, 5-HT induced small depolarizations that displayed a slow onset. At concentrations > 1 tzM, large depolarizations with rapid onset were elicited. In the presence of the 5-HT 3 receptor antagonists, granisetron or ondansetron, 5-HT responses were diminished and exhibited an increased latency to peak. These small, slow depolarizations were not reduced by 5-HT 1 or 5-HT receptor antagonists, but were potently inhibited by the 5-HT 4 receptor antagonist GR 113808 (pA 2 = 9.3), and mimicked by 5-methoxytryptamine (pECs0 = 5.3). 5-HTa-mediated responses were larger at 37°C than at 31°C, but also showed marked diminution with repeated 5-HT applications at concentrations greater than 1 /zM. Conversely, 5-HT 3 receptor responses were potentiated at lower temperatures (< 31°C). Consistent with the reported positive coupling of 5-HT 4 receptors to adenylyl cyclase, forskolin and 8-Br-cAMP produced slowly developing depolarizations which were qualitatively similar to 5-HT 4 receptor activation. Pre-depolarization of nerves with 10 /xM forskolin or 300 IzM 8-Br-cAMP diminished the effect of 5-HT 4 receptors.This study has confirmed the presence of 5-HT 4 receptors on the vagus nerve of the rat and defined some conditions that optimize their pharmacological isolation. The rat isolated vagus nerve constitutes a simple and robust preparation for studying 5-HT 4 receptors in the peripheral nervous system.
British Journal of Pharmacology, 2009
Electrically evoked release of [3H]‐noradrenaline ([3H]‐NA) or [3H]‐5‐hydroxytryptamine ([3H]‐5‐HT) in slices of human and the rat neocortex was used to characterize presynaptic opioid receptors. Release of [3H]‐NA in rat neocortical slices was reduced only by the μ‐receptor agonist DAMGO (pIC50: 7.27, CI95: [7.22, 7.32]; Imax: 77.6±1.6%; antagonized by naloxone: pA2: 8.88, CI95: [8.78, 8.98]). Release of [3H]‐NA in human neocortical slices was unaffected by DAMGO, but inhibited by the δ‐receptor agonist DPDPE (Imax: 25.7±2.2%) and the κ‐receptor agonist U‐50,488H (19.7±2.7% inhibition at 1 μM). Both effects were antagonized by naltrindole (1 μM). Release of [3H]‐5‐HT in rat neocortical slices, was inhibited by DAMGO (10 μM) and U‐50,488H (1 and 10 μM) only in the presence of the 5‐HT receptor antagonist methiotepin (1 μM). Release of [3H]‐5‐HT in human neocortical slices was unaffected by DPDPE, but U‐50,488H (Imax: 40.8±8.3%; antagonized by 0.1 μM norbinaltorphimine) and DAMGO (16...
Quantitative data on serotonin nerve terminals in adult rat neocortex
Brain Research, 1976
Serotonin (5-HT) nerve terminals, specifically labeled with [aH]5-HT have been counted in light microscope radioautographs from the fronto-parietal neocortex of adult rats, following prolonged superfusions with relatively high concentrations of tracer (10 a M or 10 4 M), and after 15 or 30 days of radioautographic exposure. Comparative analysis of the results indicated that all 5-HT varicosities did not possess the same capacity to accumulate the exogenous amine. Nevertheless, superfusions with 10 -4 M [aH]5-HT provided a sufficient loading of 5-HT boutons to allow their complete detection within any given layer of the neocortex.