Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P08908 (5-HT1A)
 5,574 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thirty-three years ago, Gaddum and Picarelli classified the serotonin receptors in the guinea pig ileum into D and M types based on the activity of dibenzyline and morphine to block contractions of intestinal smooth muscle caused by serotonin. The subsequent location of specific ligand binding sites for serotonin in the brain has led to the identification of at least eight serotonin receptor sub-types in rat brain. While there is some controversy over the functional importance of many of these receptor sub-types, there is evidence that they fall into two major groups according to the nature of their coupling to secondary messengers or ion channels. Thus the 5-HT1 and 5-HT2 receptors appear to occupy the G protein receptor sub-family which may be coupled either to adenylate cyclase (most 5-HT1 sub-types) or phosphatidyl inositol (5-HT2 sub-types). The central "M" receptors (now termed 5-HT3) appear to occupy a ligand gated ion channel super-family. The cloning of three of the serotonin receptor sub-types in 1989 (5-HT1A, 5-HT1C and 5-HT2) has been of importance in enabling the receptor sub-types to be classified as specific protein molecules encoded by specific genes. The problem now arises with regard to the linking of the changes in the cellular activity of the various receptor sub-types with the plethora of behavioural changes that arise as a consequence of the actions of serotonin in the brain. The present review summarizes the evidence implicating the role of specific serotonin receptor sub-types in eating disorders, sleep, sexual activity, anxiety states, aggression, schizophrenia and depression. A summary of the relationship between these receptor sub-types and their possible involvement in the aetiology of these diseases is shown in Table 2.
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PMID:Sub-types of serotonin receptors: biochemical changes and pharmacological consequences. 162 53

The intravenous administration of 2-deoxy-D-glucose (2-DG) to conscious catheterised rats dose-dependently increased the levels of glucose in plasma throughout the analysis (60 min); the levels of insulin in plasma remained unchanged, except for an early significant decrease in rats treated with the largest dose (1 g/kg). Pretreatment (10 min beforehand) with the beta 2-adrenoceptor antagonist, ICI 118,551 (3 mg/kg) or the alpha 2-adrenoceptor antagonist, idazoxan (1 mg/kg) decreased the rise in levels of glucose in plasma elicited by 2-DG (250 mg/kg). Conversely, the alpha 1-adrenoceptor antagonist, prazosin (1 mg/kg) or the dopaminergic receptor blocker, haloperidol (0.5 mg/kg) amplified the hyperglycaemic response to 2-DG. Previous administration of either the 5-HT1A/5-HT2 receptor antagonist, spiperone (3 mg/kg), the 5-HT1/5-HT2 receptor antagonist, methysergide (1 mg/kg), the 5-HT1C/5-HT2 receptor antagonist, ritanserin (1 mg/kg) or the 5-HT3 receptor antagonist, ICS 205.930 (0.1 mg/kg) did not affect 2-DG-induced hyperglycaemia. On the other hand, the mixed 5-HT1A/5-HT1B/beta-adrenoceptor antagonist, (-)-propranolol (5 mg/kg) and the 5-HT1/5-HT2 receptor antagonist, methiotepin (1 mg/kg), respectively, diminished and amplified the hyperglycaemia elicited by 2-DG. Lastly, in rats pretreated with prazosin (1 mg/kg, 30 min beforehand), an additional pretreatment (10 min beforehand) with prazosin or methiotepin (both at 1 mg/kg) did not further amplify the hyperglycaemic response to 2-DG. These results indicate that 2-DG-induced hyperglycaemia is mediated by alpha 2- and beta 2-adrenoceptors and amplified by alpha 1-adrenoceptor blockade. Conversely, neither 5-HT1, 5-HT2 nor 5-HT3 receptors played a role in the hyperglycaemic response to 2-DG.
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PMID:Influence of catecholaminergic and serotonergic receptor antagonists on the hyperglycaemic response to the neuroglucopaenic agent, 2-deoxy-D-glucose. 165 2

Trimipramine has been reported to differ from other typical tricyclic antidepressant drugs in several aspects, for instance it does not inhibit neuronal transmitter uptake and does not cause down-regulation of beta-adrenoceptors. Moreover, it may possess antipsychotic activity in schizophrenic patients. In the present investigation it was found that trimipramine did not alter the electrically-induced release of [3H]noradrenaline and [3H]5-hydroxytryptamine, from slices of the cerebral cortex of the rat, in concentrations of less than 1 microM. It did not antagonize the inhibitory effect of noradrenaline and 5-hydroxytryptamine on the release of transmitter, mediated by presynaptic autoreceptors. In radioligand binding studies, D,L-trimipramine showed fairly high affinities (KI 10-60 nM) for some dopamine (DA), noradrenaline and 5-hydroxytryptamine (5-HT) receptor subtypes (5-HT2 receptors = alpha 1A/B-adrenoceptors greater than or equal to D2 receptors), intermediate affinities (300-550 nM) for D1 receptors, alpha 2B-adrenoceptors and 5-HT1C receptors but only low affinities (greater than 1000 nM) for alpha 2A-adrenoceptors, 5-HT1A, 5-HT1D and 5-HT3 receptors. It may thus be classified as an atypical neuroleptic drug. Especially, its affinities for dopamine receptors, alpha 1-adrenoceptors and 5-HT2 receptors closely resembled the values measured for clozapine. The L-enantiomer of trimipramine showed higher affinities for these binding sites than D-trimipramine. The present findings may explain the mechanism of the potential antipsychotic action but not the antidepressant effect of trimipramine.
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PMID:Trimipramine: pharmacological reevaluation and comparison with clozapine. 166 93

1. The actions of serotonin (5-HT) and noradrenaline (NA) in the cat perigeniculate nucleus (PGN) and the guinea-pig nucleus reticularis thalami (NRT) were investigated with extracellular and intracellular recordings obtained from neurones in thalamic slices maintained in vitro. 2. Single, local application of either 5-HT or NA resulted in pronounced (5-50 Hz) and prolonged (2-10 min) excitation associated with the occurrence of single-spike activity. Serotoninergic excitation was specifically blocked by the 5-HT2/5-HT1C antagonists ketanserin and ritanserin, but not by the 5-HT1A antagonist pindolol or the 5-HT3 antagonist ICS 205-930. Furthermore, the 5-HT response was mimicked by alpha-methyl-5-HT, but not by the 5-HT1A agonist 8-hydroxydipropylaminotetralin (8-OHDPAT) or the 5-HT3 agonist 2-methyl-5-HT. Together, these results indicate that this excitatory response is mediated through 5-HT2 receptors with the possible involvement of 5-HT1C receptors. 3. Noradrenergic excitation was specifically blocked by the alpha 1-antagonist prazosin, but not by the beta-antagonist propranolol or the alpha 2-antagonist yohimbine. Similarly, the response was mimicked by the alpha-agonist phenylephrine, but not by the beta-agonist isoprenaline. These results indicate that the noradrenergic excitation is mediated by alpha 1-adrenoceptors. 4. Block of synaptic transmission either by lowering external calcium concentration ([Ca2+]o) to 0.5 mM and raising external magnesium concentration ([Mg2+]o) to 10 mM or by local application of tetrodotoxin failed to block the excitatory or depolarizing response to 5-HT or NA indicating that these responses are direct and not mediated through the release of other neurotransmitters. 5. Intracellular recordings revealed that the 5-HT- and NA-induced excitations are mediated by a pronounced slow depolarization associated with an apparent decrease in input conductance and an increase in the membrane time constant. Current versus voltage plots obtained under voltage clamp before and during the presence of 5-HT and NA revealed that these neurotransmitters induced an inward current which reversed to an outward current at -107 and -110 mV, respectively, in 2.5 mM external potassium concentration ([K+]o). This reversal potential was identical to that associated with an increase in potassium conductance activated by acetylcholine (-110 mV) in the same neurones. Plots of the amplitude of the 5-HT- or NA-induced current versus membrane potential revealed a linear relationship in the voltage range from -140 to -60 mV.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Serotonin and noradrenaline excite GABAergic neurones of the guinea-pig and cat nucleus reticularis thalami. 166 58

The effects of two antidepressant drugs, amoxapine and amitriptyline, that belong to distinct chemical classes, have been examined on various biochemical parameters related to serotoninergic and opioidergic neurotransmission in the rat brain and spinal cord. In vitro binding studies showed that both amoxapine and amitriptyline interact in the nanomolar range with 5-HT2 receptors labelled by [3H]ketanserin in cortical membranes. By contrast, neither amoxapine nor amitriptyline can be considered as possible ligands of 5-HT1A and 5-HT1B receptors because their affinities for these sites are in the micromolar range (or even worse). Interestingly, amoxapine binds with a good affinity (IC50 = 0.30 microM) to 5-HT3 receptors labelled by [3H]zacopride in cortical membranes. Complementary experiments using the 5-HT3-dependent Bezold-Jarisch reflex confirmed that amoxapine really acts in vivo as a 5-HT3 antagonist (IC50 = 50 micrograms/kg i.v.), whereas amitriptyline is essentially inactive on 5-HT3 receptors. The second part of this study consisted of looking for possible changes in central 5-HT receptors 24 h after either a single or a repeated (for 14 days) treatment with amoxapine (10 mg/kg i.p. each day) or amitriptyline (10 mg/kg i.p.). A marked decrease in the density of 5-HT2 receptors was found in the cerebral cortex in both treatment groups. By contrast, neither 5-HT1A nor 5-HT1B receptors were significantly affected in any brain region studied. Finally we explored whether acute and/or chronic administration of amoxapine or amitriptyline affected the levels of opioid peptides and the mu and delta classes of opioid receptors in various regions of the brain and the spinal cord.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Preclinical pharmacology of amoxapine and amitriptyline. Implications of serotoninergic and opiodergic systems in their central effect in rats]. 166 97

Several developments in serotonin neuropharmacology have implications for psychiatric disorders and have already begun to impact their treatment. Selective inhibitors of serotonin uptake, which enhance serotonergic function by preventing the removal of serotonin from the synaptic cleft via the membrane transporter, have been introduced for the treatment of depression and may be effective in other disorders. Precursor loading can increase serotonin concentrations in the synaptic cleft, and tryptophan--which has been available in health food stores and drug stores--had become increasingly used for self-medication of depression, insomnia, and premenstrual syndrome. Conversion to serotonin is not the major metabolic pathway for tryptophan, and large increases in other tryptophan metabolites (such as quinolinic acid, a substance that is excitotoxic at high concentrations) accompany small increases in extracellular serotonin. The recent epidemic of the eosinophilia-myalgia syndrome associated with tryptophan now appears due to a trace contaminant in the product from a single manufacturer. A major advance in serotonin pharmacology has been the elucidation of serotonin receptor heterogeneity. At least seven receptor subtypes (5-HT1A, 5-HT1B, 5-HT1C, 5-HT1D, 5-HT2, 5-HT3, 5-HT4) have been identified in brain. Direct-acting agonists and antagonists can have selective affinity for specific receptor subtypes. Selective activation of 5-HT1A receptors seems to cause anxiolytic and possibly antidepressive effects. Selective antagonists of 5-HT2 or 5-HT3 receptors may be useful in treating anxiety and schizophrenia. Drugs that enhance serotonergic function suppress aggression in animals, but the specific receptor subtypes involved are not known. The advances being made in serotonin pharmacology will help define the role of this brain neurotransmitter in psychiatric and other disorders and can be expected to lead to further therapeutic advances.
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PMID:Role of serotonin in therapy of depression and related disorders. 167 51

The prototypical 5-HT1A agonist, 8-OH-DPAT, dose-dependently (0.16-10.0 mg/kg, s.c.) elicited a pronounced antinociception in the hot-plate test in mice. This action was not affected by the 5-HT1A antagonists, BMY 7378, (-)-pindolol and (-)-alprenolol nor by selective antagonists at 5-HT1C, 5-HT2 and 5-HT3 receptors. It was also resistant to antagonists at D1, D2, alpha 1 and opioid receptors. In contrast, it was blocked by the alpha 2 antagonists, idazoxan, rauwolscine and yohimbine. L 659,066, a selective alpha 2 antagonist which does not enter the CNS, was ineffective. The action of 8-OH-DPAT was mimicked by the centrally acting alpha 2 agonists, UK 14,304 and guanabenz whereas ST 91, which does not penetrate the blood-brain barrier, was inactive. The action of UK 14,304 and guanabenz was also blocked by idazoxan, rauwolscine and yohimbine but not by L 659,066. These data indicate that the antinociceptive properties of 8-OH-DPAT in the hot-plate test in mice are mediated by CNS-localized alpha 2 receptors, rather than 5-HT1A receptors.
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PMID:Alpha 2 receptors mediate the antinociceptive action of 8-OH-DPAT in the hot-plate test in mice. 167 12

Pre-weaning rat pups emit ultrasonic vocalizations when removed from the litter. These 'separation-induced vocalizations' (SIV) are suppressed by classical benzodiazepine anxiolytics and by non-benzodiazepine anxiolytics which lack muscle relaxant and sedative properties. The present study used the SIV model to assess potential anxiolytic properties of compounds which target different sites associated with the NMDA receptor complex. Comparison was made to drugs which affect benzodiazepine or serotonin (5-HT) receptors. Muscle relaxant potential was assessed using 'TIP' (time on an inclined plane), the amount of time a pup was able to retain its position on a steeply inclined surface. Mephenesin, a centrally acting muscle relaxant, significantly suppressed TIP but not SIV. The benzodiazepine agonist diazepam suppressed both SIV and TIP, whereas the 5-HT1A partial agonists, buspirone and MDL 73,005EF, suppressed SIV without affecting TIP. The 5-HT2 antagonist MDL 11,939 suppressed TIP but not SIV, whereas neither measure was affected by the 5-HT3 antagonist MDL 73,147EF. SIV was suppressed by NMDA antagonists including those acting at the glutamate recognition site (D,L-amino-phosphonovaleric acid (AP5) and MDL 100,453) or at the ion channel (MK-801), or by the strychnine-insensitive glycine antagonist 5,7-dichlorokynurenic acid (5,7-DCKA). TIP was suppressed even more potently by AP5, MDL 100,453 and MK-801, whereas 5,7-DCKA was inactive on this measure. Thus, antagonists acting at different sites present on the glutamate recognition site exhibit potential anxiolytic activity, but the glycine antagonist was unusual in its lack of prominent muscle relaxant side effects.
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PMID:NMDA receptor complex antagonists have potential anxiolytic effects as measured with separation-induced ultrasonic vocalizations. 167 93

Cocaine inhibits the 5-HT2-mediated (+/-)-DOI-induced head-twitch response (HTR) in mice in a dose-dependent manner. In order to investigate the possible inhibitory mechanism(s) of cocaine on 5-HT2 receptor function, we studied the effects of the selective adrenergic alpha 2 receptor antagonist yohimbine and the beta-adrenergic/5-HT1 receptor antagonist alprenolol, and the 5-HT3 antagonist ICS 205-930 on the inhibitory action of cocaine on the (+/-)-DOI-induced HTR. Neither yohimbine (0.1 and 0.5 mg/kg) nor alprenolol (10 mg/kg) pretreatment had any significant effect on the (+/-)-DOI-induced HTR. However, both antagonists prevented the inhibitory effects of cocaine on the (+/-)-DOI-induced HTR. The 5-HT3 antagonist ICS 205-930 neither produced HTR nor decreased the (+/-)-DOI-induced HTR frequency. The present results suggest that cocaine inhibits 5-HT2 receptor function by increasing the synaptic concentration of norepinephrine and serotonin via inhibition of their uptake and thus indirectly stimulating the respective inhibitory adrenergic alpha 2 and serotonergic 5-HT1A receptors. Furthermore, cocaine's 5-HT3 antagonist properties appear not to play a role in the inhibition of head-twitch behavior.
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PMID:Inhibition of 5-HT2 receptor-mediated head-twitch response by cocaine via indirect stimulation of adrenergic alpha 2 and serotonergic 5-HT1A receptors. 167 73

In this study, we have identified and characterized 5-HT3-like receptors in the rat medial prefrontal cortex (mPFc), an area with a moderate density of 5-HT3 binding sites, using the techniques of single unit recording and microiontophoresis. The microiontophoresis of the 5-HT3 receptor agonist 2-methylserotonin (2-Me-5HT), similar to the action of 5-HT, produced a current-dependent (10-80 nA) suppression of the firing rate of both spontaneously active and glutamate (GLU)-activated (quiescent) mPFc cells. Phenylbiguanide (PBG), another 5-HT3 receptor agonist, suppressed the firing rate of mPFc cells but was less effective compared to 2-Me-5HT. The continuous iontophoresis (10-20 min) of 1 M magnesium chloride markedly attenuated the suppressant effect produced by electrical stimulation of the ascending 5-HT pathway, but did not alter 2-Me-5HT's action, suggesting that the action of 2-Me-5HT is a direct one. The suppressant action of 2-Me-5HT on mPFc cells was blocked by a number of structurally diverse and selective 5-HT3 antagonists, with a rank order of effectiveness as follows: ICS 205930 = (+/-)-zacopride greater than granisetron = ondansetron = LY 278584 greater than MDL 72222. Furthermore, the intravenous administration of (+/-)-zacopride antagonized the action of 2-Me-5HT and PBG on mPFc cells. In contrast to the effects of the 5-HT3 receptors antagonists, other receptor antagonists such as metergoline (5-HT1A,1B,1C.2), (+/-)-pindolol (5-HT1A,1B, beta), SCH 23390 (5-HT1C.2, D1), l-sulpiride (D2) or SR 95103 (GABAA) failed to block 2-Me-5HT's action. These results combined suggest that 2-Me-5HT's suppressive action on mPFc cells is mediated directly by 5-HT3-like receptors.
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PMID:5-HT3-like receptors in the rat medial prefrontal cortex: an electrophysiological study. 167 70


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