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)

The behavioural element, stretched attend posture (SAP), is an important component of the "risk-assessment" repertoire of defensive behaviour in rodents. The present experimental paradigm was devised as a novel and simple method of eliciting high levels of SAP in mice and rats. The SAP test apparatus comprised an elevated black Perspex circular platform. A smaller clear red Perspex circular "Canopy" was supported directly above the platform by a central pillar, thus dividing the platform into an inner, dimly lit covered zone and an outer, brightly lit exposed zone. In both the rat and mouse version of this model, vehicle-treated animals exhibited a marked preference for exploring the covered zone and also exhibited high baseline levels of SAP, particularly at the covered zone boundary whilst they investigated the exposed zone. In the mouse SAP test, the benzodiazepine receptor agonists, diazepam (0.5 mg/kg s.c.) and chlordiazepoxide (2 mg/kg s.c.), and the 5-HT1A receptor agonists, buspirone (1 and 3 mg/kg s.c.), ipsapirone (3 mg/kg s.c.) and 8-OH-DPAT (0.2 mg/kg s.c.), all significantly decreased the frequency of SAP without impairing motor activity. In the rat SAP test, diazepam (0.5 mg/kg s.c.) significantly decreased, whilst the anxiogenic 5-HT2C/1B receptor agonist, mCPP (0.25 and 0.5 mg/kg s.c.), significantly increased, the frequency of SAP. Ipsapirone (3 mg/kg s.c.) induced a non-specific behavioural inhibition. These data suggest that the "Canopy" SAP test is a useful paradigm to investigate risk assessment behaviour in both rats and mice, and may provide a sensitive novel rodent model of anxiety.
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PMID:Behavioural and pharmacological characterisation of the canopy stretched attend posture test as a model of anxiety in mice and rats. 933 77

A drug discrimination procedure was used to characterize the ethanol-like effects of a variety of 5-HT1 agonists. Previous studies found that the degree of substitution of the 5-HT1B/2C agonist TFMPP (m-trifluoromethylphenylpiperazine) depended on the training dose of ethanol. The present studies extend this initial finding to four additional 5-HT agonists with different selectivity for 5-HT1A, 5-HT1B, or 5-HT2C receptors: CGS 12066B (7-trifluoromethyl-4(4-methyl-1-piperazinyl)-pyrrolo[1,2a]quinoxaline maleate), mCPP [1-(3-chlorophenyl)piperazine diHCl], RU 24969 [5-methoxy-3(1,2,3,4-tetrahydro-4-pyridinyl]-1H-indole succinate and 8-OH DPAT [(+/-)-8-hydroxy-2-(di-n-propylamino)tetralin HBr]. Separate groups of rats were trained to discriminate 1.0 g/kg (n = 7), 1.5 g/kg (n = 6) or 2.0 g/kg (n = 8) ethanol from water. Following training, three to five doses of each 5-HT agonist were tested twice in each rat. The most selective 5-HT1B agonist tested, CGS 12066B (3-17 mg/kg; IP), completely substituted for the 1.0 g/kg ethanol, but not for 1.5 or 2.0 g/kg ethanol. Likewise, the 5-HT1B/2C agonist mCPP (0.56-1.7 mg/kg; IP) completely substituted only in the 1.0 g/kg ethanol training group. The 5-HT1A/1B agonist RU 24969 (0.1-3.0 mg/kg; IP) substituted for all training doses of ethanol, although in a lower proportion of the rats tested in the 2.0 g/kg ethanol training group. Finally, the 5-HT1A agonist 8-OH DPAT (0.1-1.0 mg/kg, IP) did not substitute completely for any ethanol training dose. The results consistently show that agonists with 5-HT1B activity produce discriminative stimulus effects similar to low and intermediate, but not high, ethanol training doses.
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PMID:Characterization of the ethanol-like discriminative stimulus effects of 5-HT receptor agonists as a function of ethanol training dose. 934 79

The new antidepressant mirtazapine was tested in two experimental procedures which can reveal direct or indirect 5-HT1A receptor agonistic effects. These procedures were observation for induction of lower lip retraction in rats and comparison of stimulus properties in cross-familiarization experiments with conditioned taste aversion in mice. Mirtazapine induced lower lip retraction in rats, as did the 5-HT1A receptor agonist (+/-)-8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT). However, the response to mirtazapine at doses up to 22 mg/kg remained below the maximum score obtained with 8-OH-DPAT (0.46 mg/kg). Blockade of the 5-HT1A receptors with pindolol (10 mg/kg) caused a strong reduction of the lower lip retraction induced both with mirtazapine and 8-OH-DPAT. In the cross-familiarization conditioned taste aversion experiments it was found that the conditioned taste aversion induced by mirtazapine (0.32 mg/kg) could be prevented if the mice were pre-exposed to injections with mirtazapine (0.22 and 0.46 mg/kg), 8-OH-DPAT (0.22 and 0.46 mg/kg) and after pre-exposure to the 5-HT reuptake inhibitor fluoxetine (22 mg/kg). No familiarization for the mirtazapine stimulus was obtained by pre-exposure to (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl (DOI) (0.46-4.6 mg/kg) and MK212 (2.2-22 mg/kg), being agonists for the 5-HT2A and 5-HT2C receptors, respectively. With the reversed sequence, the conditioned taste aversion induced by 8-OH-DPAT (0.22 mg/kg), DOI (1.0 mg/kg) and fluoxetine could be prevented only partially by pre-exposure to mirtazapine in a dose of 1 mg/kg. The conditioned taste aversion induced by MK 212 (4.6 mg/kg) was not affected by pre-exposure to mirtazapine (0.1-1.0 mg/kg). On the basis of these results, it can be concluded that mirtazapine has indirect 5-HT1A receptor agonistic properties which may play an important role in the therapeutic effect of this compound.
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PMID:Indirect in vivo 5-HT1A-agonistic effects of the new antidepressant mirtazapine. 936 34

Effects of 5-hydroxytryptamine (5-HT) on inspiration-related nerve activity and membrane potential of respiratory neurons in the ventrolateral medulla were studied in brainstem-spinal cord preparations isolated from newborn rats. Bath application of 5-100 microM 5-HT induced a biphasic response in inspiratory nerve activity: a transient increase in respiratory frequency followed by a decrease in the rate of discharge. The excitatory effect of 5-HT was particularly prominent in preparations with a respiratory rate of less than 3 min-1, whereas the inhibitory effect was more pronounced in preparations with a higher respiratory rate. In pre-inspiratory (Pre-I) and inspiratory (Insp) neurons, 20 microM 5-HT induced a membrane depolarization of up to 10 mV accompanied by a significant decrease in the input resistance. Membrane depolarization by 5-HT was also evident in the presence of tetrodotoxin. In Pre-I neurons, 5-HT caused an increase in the burst rate, which was followed by a decrease in the intraburst firing frequency and burst amplitude, although the burst rate remained high. The burst rate in Insp neurons first increased and subsequently decreased without significant change in the intraburst firing frequency. Simultaneous intra- and extracellular recordings (in the contralateral medulla) of Pre-I/Pre-I neuron or Pre-I/Insp neuron pairs revealed that 5-HT disturbed the correlation between these neuron bursts. Increase in the respiratory rate induced by 20 microM 5-HT was completely blocked by pretreatment (5-15 min) with 5 microM ketanserin or 1 microM methysergide, but not by 10 microM propranolol. None of these antagonists blocked the inhibitory effects of 5-HT. A 5-HT2 agonist, 1-(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI, 10-100 microM) increased the respiratory rate. Perfusion with a 5-HT1A agonist, 8-hydroxy-dipropylaminotetralin hydrobromide (8-OH-DPAT, 20-100 microM) induced an increase or a decrease in the respiratory rate. A 5-HT2C agonist, 1-(3-chlorophenyl)piperazine (m-CPP, 2-10 microM) induced an initial decrease in the respiratory rate followed by a further long- lasting decrease. Burst activity of Pre-I neurons was suppressed upon administration of 10 microM m-CPP and enhanced with 20 microM DOI. The results suggest that changes in the bursting properties of Pre-I and Insp neurons induced by 5-HT lead to modulation of the respiratory network, thus causing biphasic modulation of the respiratory rhythm. In addition to effects via 5-HT1A receptors, activation of 5-HT2A and 5-HT2C receptor subtypes might be involved in excitatory effects and inhibitory effects of 5-HT respectively.
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PMID:Modulation of respiratory rhythm by 5-HT in the brainstem-spinal cord preparation from newborn rat. 944 95

Audiogenic seizures can be induced in DBA/2J mice following intense auditory stimulation. A number of neurotransmitters, including 5-hydroxytryptamine (5-HT), are believed to be involved in mediating this effect since it has been shown previously that depletion of 5-HT or blockade of 5-HT receptors protects DBA/2J mice from these audiogenic seizures. The present study was undertaken to determine whether antagonism of the newly identified 5-HT7 receptor may protect DBA/2J mice from audiogenic seizures by attempting to correlate in vivo potency of compounds with their affinity at the 5-HT7 receptor. All compounds used in the correlation were shown to be antagonists at the 5-HT7 receptor and a statistically significant correlation was observed between 5-HT7 affinity and doses for half-maximal response (ED50) for protection of DBA/2J mice from sound-induced seizures (r = 0.80; P < 0.05). No significant correlation was observed between in vivo activity and affinity at either 5-HT1A, 5-HT2A or 5-HT2C receptors. It is also unlikely that interactions between the 5-ht5 receptor will protect DBA/2J mice from audiogenic seizures since metergoline and mesulergine which are both active in this in vivo model have no affinity for the 5-ht5 receptor. There are similarities between the pharmacology of the 5-HT7 receptor and that of the 5-HT1A receptor, however the correlation between the in vivo potency in DBA/2J mice and 5-HT1A affinity was not significant. Furthermore, the 5-HT1A receptor antagonist WAY 100135 did not protect DBA/2J mice from audiogenic seizures at doses that antagonise 5-HT1A receptor-mediated effects in mice. These data suggest that antagonism of 5-HT7 receptors may protect against audiogenic seizures in DBA/2J mice although a definitive conclusion must await studies with selective 5-HT7 antagonists.
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PMID:Correlation between 5-HT7 receptor affinity and protection against sound-induced seizures in DBA/2J mice. 945 69

Environmental enrichment augments neuronal plasticity and cognitive function and possible mediators of these changes are of considerable interest. In this study, male rats were exposed to environmental enrichment or single housing for 30 days. Rats from the enriched group had significantly higher 5-HT1A receptor mRNA expression in the dorsal hippocampus (62%, 59% and 44% increase in the CA1, CA2 and CA3 subfields, respectively). This was associated with significantly higher [3H]8-OH-DPAT binding in the inferior part of CA1. No changes were seen for 5-HT2A or 5-HT2C receptor mRNAs. The neuronal plasticity detected after environmental change may be mediated, in part, through 5-HT1A receptors.
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PMID:Environmental enrichment selectively increases 5-HT1A receptor mRNA expression and binding in the rat hippocampus. 947 97

1. The release of glutamic acid and its modulation by 5-hydroxytryptamine (5-HT) in the human brain has been investigated in synaptosomal preparations from fresh neocortical samples obtained from patients undergoing neurosurgery to reach deeply sited tumours. 2. The Ca2+-dependent K+ (15 mM)-evoked overflow of glutamate was inhibited by 5-HT in a concentration-dependent manner (EC50 = 2.9 nM; maximal effect approximately 50%). The inhibition caused by 5-HT was antagonized by the 5-HT1/5-HT2 receptor antagonist methiothepin. The 5-HT1B/5-HT1D receptor agonist sumatriptan mimicked 5-HT (EC50 = 6.4 nM; maximal effect approximately 50%); the effect of sumatriptan was also methiothepin-sensitive. Selective 5-HT1A receptor antagonists could not prevent the inhibition of glutamate release by 5-HT. 3. The 5-HT1B/5-HT1D receptor ligand GR 127935 and the 5-HT2C/5-HT1B/5-HT1D receptor ligand metergoline were unable to prevent the 5-HT effect; instead they inhibited glutamate release, their effects being abolished by methiothepin. Some 5-HT1A receptor antagonists also displayed intrinsic agonist activity. 4. The effect of sumatriptan was prevented by ketanserin, a drug known to display much higher affinity for recombinant h 5-HT1D than for h 5-HT1B receptors. 5. We propose that neocortical glutamatergic nerve terminals in human brain cortex possess release-inhibiting presynaptic heteroreceptors that appear to belong to the h 5-HT1D subtype.
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PMID:Glutamate release in human cerebral cortex and its modulation by 5-hydroxytryptamine acting at h 5-HT1D receptors. 948 53

The aminomethylchroman derivative BAY x 3702 (R-(-)-2-[4-[(chroman-2-ylmethyl)-amino]-butyl]-1,1-dioxo-benzo[d] isothiazolone hydrochloride) is a new high affinity 5-hydroxytryptamine (5-HT)1A receptor ligand [calf hippocampus: Ki: 0.19 nM; reference compounds 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) and ipsapirone: 0.98 and 2.56, respectively; rat cortex: 0.24 nM; rat hippocampus: 0.58 nM; human cortex and recombinant 5-HT1A receptors: 0.25 and 0.4 nM, respectively]. BAY x 3702 bound also with relatively high to moderate affinity to the following receptors: alpha-1 and alpha-2 adrenergic (Ki: 6 and 7 nM, respectively); 5-HT7- and 5-HT1D (7 and 36 nM); dopamine D2- and D4 (48 and 91 nM); sigma sites (176 nM) and 5-HT2C (310 nM); others: > 10 microM, as obtained in more than 50 different binding assays. In the forskolin-stimulated adenylate cyclase assay in rat hippocampal tissue, a model of postsynaptic 5-HT1A receptor function, BAY x 3702 was a potent 5-HT1A receptor full agonist (IC50: 1.9 nM; 8-OH-DPAT: 25.3 nM, full agonist; ipsapirone: partial agonist) and its effects could be completely blocked by the 5-HT1A receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohe xan e carboxamide trihydrochloride (WAY-100635). At those receptors where BAY x 3702 bound with lower affinity, the compound appeared to be either an agonist (5-HT1D receptors) or an antagonist (alpha-1, alpha-2 and D2 receptors). In a rat brain slice preparation containing the dorsal raphe nucleus (DRN), a model of somatodendritic 5-HT1A receptor function, BAY x 3702 inhibited potently (1 nM) neuronal firing. Also in vivo, BAY x 3702 (0.5 microgram/kg, i.v.) was found to suppress 5-HT neuronal firing in the DRN of anesthetized rats. In both electrophysiological assays BAY x 3702 was more potent than 8-OH-DPAT and ipsapirone; the potency difference being about 1 and 2 orders of magnitude, respectively. In rats trained to discriminate 8-OH-DPAT (0.1 mg/kg, i.p.) in a drug discrimination procedure, complete generalization was obtained with BAY x 3702 (ED50: 0.022 mg/kg, i.p. and 0.38 mg/kg, p.o.; 8-OH-DPAT: 0.028 mg/kg, i.p. and ipsapirone: 0.44 mg/kg, i.p.). In the rat hypothermia model BAY x 3702 induced a WAY-100635-reversible effect and the compound had a higher potency and intrinsic activity than 8-OH-DPAT and ipsapirone (ED50: 0.25 mg/kg, i.p. and 5.4 mg/kg, p.o., respectively; 8-OH-DPAT: 1.1 mg/kg, i.p. and ipsapirone: 6.2 mg/kg, i.p.). BAY x 3702 induced a stimulation of plasma ACTH levels in the rat; the effect being again more pronounced than that of ipsapirone (ED50: 7.5 and 25.3 mg/kg, p.o., respectively). It is concluded that BAY x 3702 is a relatively selective 5-HT1A receptor agonist with high potency and intrinsic activity.
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PMID:Characterization of the aminomethylchroman derivative BAY x 3702 as a highly potent 5-hydroxytryptamine1A receptor agonist. 949 70

In vivo microdialysis was used to compare the effects of serotonergic drugs on morphine- and cocaine-induced increases in extracellular dopamine (DA) concentrations in the rat nucleus accumbens (NAc). Systemic administration of the 5-HT2A/2C agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) (2.5 mg/kg, s.c. ) prevented the increase in extracellular DA in the NAc produced by morphine (5 mg/kg, i.p.). In contrast, this dose of DOI had no effect on the ability of cocaine (10 mg/kg, i.p.) to increase extracellular DA concentrations in the NAc. A 5-HT2C selective agonist, 6-chloro-2-[1-piperazinyl]-pyrazine (MK-212, 5 mg/kg, s.c.) also inhibited morphine-induced increases in extracellular DA concentrations in the NAc. Pretreatment of rats with the selective 5-HT2A antagonist, amperozide, had no effect on morphine-induced elevation of NAc DA concentrations. In order to determine if inhibition of the firing of 5-HT neurons contributes to the serotonin agonist-mediated inhibition of morphine-induced accumbens DA release, rats were pretreated with the 5-HT1A agonist, 8-OHDPAT. At a dose of 100 microg/kg (sc), 8-OHDPAT did not interfere with morphine's ability to increase DA concentrations in the NAc. These results suggest that the activation of 5-HT2C receptors selectively inhibits morphine-induced DA release in the NAc in a manner which is independent of the inhibition of 5-HT neurons.
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PMID:Serotonin 5-HT2C agonists selectively inhibit morphine-induced dopamine efflux in the nucleus accumbens. 950 67

The influence of serotonin (5-HT) antagonists and a selective serotonin reuptake inhibitor (SSRI) on cocaine-induced locomotor activity, rears, and head bobs was investigated in female Glaxo Wistar rats. The SSRI, fluoxetine (10 mg/kg), and the nonselective 5-HT agent, methysergide, at the dose range of 5 and 15 mg/kg enhanced the behaviors produced by cocaine (15 mg/kg) to a similar extent. Moreover, the potentiation of cocaine-induced locomotor activity, rears, and head bobs was even greater after the combined administration of methysergide ( 15 mg/kg) and fluoxetine (10 mg/kg). In order to investigate a possible involvement of 5-HT1A receptors in the observed potentiation by methysergide and fluoxetine, the potent and selective 5-HT1A antagonist, WAY 100635, was used. WAY 100635 (0.1 and 1.5 mg/kg) markedly reduced the behaviors induced by cocaine preceded by fluoxetine (10 mg/kg) and methysergide (5 and 15 mg/kg) pretreatment, respectively, suggesting an involvement of 5-HT1A receptors in the action of fluoxetine and methysergide on cocaine-induced behaviors. An attenuation of the fluoxetine-enhanced cocaine-induced behaviors was also observed after pretreatment with the 5-HT2A antagonist ketanserin (0.1 and 1.0 mg/kg). Coadministration of ketanserin (1.0 mg/kg) and WAY 100635 (1.5 mg/kg) resulted in the greatest blockade of the fluoxetine-enhanced cocaine-induced behaviors. The antagonists and the SSRI, fluoxetine, did not alter the behaviors in comparison to that of saline-treated animals. These results provide evidence for an involvement of 5-HT1A receptors in the enhancing effect of fluoxetine and methysergide on cocaine-induced locomotor activity, rears, and head bobs, and suggest a stimulatory action of methysergide at the 5-HT1A receptor. In addition, some of the actions may also be mediated by activation of the 5-HT2A receptor and/or inhibition of the 5-HT2C receptor.
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PMID:Involvement of serotonin in the modulation of cocaine-induced locomotor activity in the rat. 951 61


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