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)

In this study, we examined the response of spontaneously active as well as quiescent cells (L-glutamate-activated) in the rat medial prefrontal cortex (mPFc) to the iontophoresis of 2-methylserotonin (2-Me-5-HT, 5-HT3 receptor agonist), (+/-)-2,5-dimethoxy-(4-iodo-phenyl)-2-aminopropane (DOI, 5-HT2A,2C receptor agonist), 8-hydroxy-N,N-di-propylamino tetralin (8-OH-DPAT, 5-HT1A receptor agonist) and gamma-aminobutyric acid (GABA, a non-selective GABA receptor agonist) after the intracerebral administration of pertussis toxin, an inactivator of the Gi/o protein. This was accomplished using the techniques of extracellular single cell recording and iontophoresis. The administration of pertussis toxin (0.5 microgram, 24 hours before the experiment) into the mPFc did not alter the response of mPFc cells to the iontophoresis of DOI, 2-Me-5HT or GABA compared to saline treated controls. However, the response of mPFc cells to the iontophoresis of 8-OH-DPAT was significantly attenuated in the animals pretreated with pertussis toxin compared to controls. These results suggest that the 5-HT1A but not 5-HT2A,2C or 5-HT3 receptor is coupled to the Gi/o protein.
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PMID:Effect of pertussis toxin on the response of rat medial prefrontal cortex cells to the iontophoresis of serotonin receptor agonists. 786 72

This paper describes pharmacological treatments that can reverse the anxiogenic response detected in animal tests when rats are withdrawn from chronic treatment with diazepam. Concurrent treatment with the calcium channel antagonist verapamil prevented this withdrawal response and the benzodiazepine-receptor antagonist flumazenil reversed the anxiogenic response and restored the system to a drug-naive state. Other treatments that reversed the anxiogenic response were the GABAB agonist baclofen, the 5-HT1A receptor agonist buspirone, and the 5-HT3 receptor antagonist (R,S)-zacopride (GABA = gamma-aminobutyric acid; 5-HT = 5-hydroxytryptamine). Both the enantiomers of zacopride contributed to this reversal. These behavioural reversals are interpreted in the light of biochemical studies showing increased 45Ca2+ flux and [3H]5-HT release from the hippocampus, during benzodiazepine withdrawal (Fig. 1).
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PMID:Benzodiazepine withdrawal: behavioural pharmacology and neurochemical changes. 791 Jul 43

Benzodiazepines (BDZ), the most popular drug of choice for treating anxiety disorders, present side-effects such as sedation, muscular disorders, abuse liability and synergistic effect with alcohol and CNS depressant drugs. At present, pharmacological research is focusing to find anxiolytic drugs as efficacious as benzodiazepines but without side-effects. This review reports the status of the pharmaceutical research and development on novel drugs for the treatment of anxiety disorders. A close analysis of the items selected by the N5C "Pharmaprojects" search (anxiolytic class) yielded the following classification: A) Drugs interacting with the GABA-A receptor complex, which includes BDZ-like drugs, partial BDZ agonists (beta-carbolines) and drugs interacting with the GABA-A complex through an as yet unidentified mechanism (15 compounds), B) Drugs acting as CCK-B antagonists (5 compounds), C) Drugs interacting with serotonergic function (30 compounds) subdivided into: (i) agonists at the 5-HT1A receptor, (ii) antagonists at the 5-HT2 receptor, and (iii) antagonists at the 5-HT3 receptor; D) Drugs with other mechanisms (22 compounds). Based on these results, it is not possible to identify a common mechanism through which the selected drugs under development exert their anxiolytic effect. Therefore, it appears that different biological mechanisms are specifically involved in the different anxiety disorders.
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PMID:New anxiolytics in development. 791 35

The present study was undertaken to investigate the nature of the effect of pertussis toxin on the responsiveness of two potentially distinct subgroups of postsynaptic serotonin1A (5-HT1A) receptors of rat hippocampus CA3 pyramidal neurons: those located at the level of the cell body, which can be activated by microiontophoretically-applied 5-HT1A receptor agonists, and those located on dendrites, which can be activated by endogenous serotonin released by the stimulation of the ascending serotoninergic pathway. The former receptors (denoted as extrasynaptic) have been previously demonstrated to be sensitive to pertussis toxin, whereas the latter (denoted as intrasynaptic) have been shown to be pertussis toxin-insensitive. Rats treated with the 5-HT1A receptor agonists flesinoxan or BMY 42568 were used to determine whether tonic activation of extrasynaptic 5-HT1A receptors would prevent their inactivation by pertussis toxin. A pretreatment with p-chlorophenylalanine was used to determine whether a serotonin depletion would render the intrasynaptic 5-HT1A receptors sensitive to pertussis toxin. The responsiveness of CA3 pyramidal neurons to the suppressant effects of microiontophoretically-applied serotonin, 8-hydroxy-2-(di-n-propylamin)-tetralin, baclofen and GABA or to endogenously-released serotonin, elicited by the stimulation of the ascending serotoninergic pathway, was studied one to 10 days after the intrahippocampal injection of pertussis toxin. When compared to control saline-treated rats, the treatments with flesinoxan (5 mg/kg/day, s.c.) and BMY 42568 (5 mg/kg/day, s.c.) delivered for 14 days by osmotic minipumps, starting three days prior to the injection of pertussis toxin, significantly attenuated the effect of pertussis toxin on the responsiveness of CA3 pyramidal neurons to microiontophoretic applications of serotonin and 8-hydroxy-2-(di-n-propylamino)-tetralin, as well as baclofen, an agonist of GABAB receptors, which share the same G proteins with 5-HT1A receptors. The two-day pretreatment with p-chlorophenylalanine (350 mg/kg/day, i.p.) did not render the intrasynaptic 5-HT1A receptors sensitive to pertussis toxin, as indicated by the unchanged efficacy of the stimulation of the ascending serotonin pathway in the suppressing the firing activity of CA3 dorsal hippocampus pyramidal neurons. Our results suggest that the sustained activation of extrasynaptic 5-HT1A receptors prevents the pertussis toxin-induced ADP ribosylation of G protein alpha subunit, and thereby protects an amount of G proteins sufficient to maintain the function, not only of 5-HT1A, but also of GABAB receptors.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Agonist occupation of serotonin1A receptors in the rat hippocampus prevents their inactivation by pertussis toxin. 796 92

The amygdala (AM) and the periaqueductal gray (PAG) represent the rostral and the caudal pole, respectively, of a longitudinally organized neural system, that is responsible for the integration of behavioral and physiological manifestations of defensive reactions against innate and learned threats. Microinjection of benzodiazepine (BZD) anxiolytics, GABAA receptor agonists or 5-HT receptor antagonists into the AM has anxiolytic effects in conflict tests and other models of conditioned fear, while similar administration of 5-HT or of a 5-HT1A receptor agonist has anxiogenic effects. On the other hand, in the test of electrical stimulation of the PAG, microinjection of 5-HT, 5-HT mimetics, or of drugs that enhance the action of endogenous 5-HT into the same brain area has an antiaversive effect, like BZD and GABAA agonists. Furthermore, microinjection of midazolam, of the NMDA receptor antagonist AP-7, or of the 5-HT1A/1B receptor blocker propranolol increased the exploration of the open arms of the elevated plus-maze, having therefore an anxiolytic effect. These results point to an inhibitory role of the GABA-BZD system in both the AM and the PAG. In contrast, 5-HT seemingly enhances conditioned fear in the AM, while inhibiting unconditioned fear in the PAG. Thus, 5-HT2/1C antagonists reportedly release punished behavior when injected into the AM, whereas they antagonized the antiaversive effect of 5-HT, zimelidine and 5-HT1A/1B receptor blockers in the PAG. Since reported clinical studies revealed that one of such compounds, ritanserin, relieves generalized anxiety but tends to aggravate panic disorder, a relationship may be established between the AM and anxiety and the PAG and panic.
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PMID:Role of the amygdala and periaqueductal gray in anxiety and panic. 813 40

Experimental lesions and quantitative autoradiography were used to investigate the cellular localisation of receptors. Lesions were produced by intrastriatal injections of either volkensin or ricin, only the former is retrogradely transported. Volkensin treatment caused significant losses in Fr1/Fr2 of neocortex in the number of infragranular pyramidal neurones and binding to deep cortical layers of both [3H]pirenzepine (muscarinic cholinergic m1 receptors) and [3H]kainate (kainate sensitive glutamate receptors). In common with previous findings, which also showed sparing of interneurones, supragranular pyramidal neurones were not reduced in number and the binding to deep cortical layers of [3H]8-hydroxy-2-(n-dipropylamino)tetralin (serotonin 1A receptors) was reduced. Significant increases in [3H]prazosin binding to both total alpha adrenoceptors and the alpha 1b subtype were observed in superficial layers. Adrenoceptors were not decreased in any layer. The binding of [3H] GABA to GABAA receptors was not affected at all. Muscarinic receptors and pyramidal neurones were also reduced in deep cortical layers of Par1/Par2 in common with serotonin 1A (5-HT1A) receptors and total alpha receptors were significantly decreased in the middle layers. Overall m1 and kainate receptors were less affected than 5-HT1A receptors. The results are discussed in terms of the biology of cortical pyramidal neurones, drugs for Alzheimer's disease and novel ligands for improving human brain in vivo scanning techniques.
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PMID:Localisation of muscarinic (m1) and other neurotransmitter receptors on corticofugal-projecting pyramidal neurones. 814 48

The possible involvement of ATP-sensitive potassium channels in the control of the electrical activity of central serotoninergic neurons was investigated by recording their firing rate in the dorsal raphe nucleus of rat brain stem slices exposed to various blockers and openers of these channels. Whereas the channel openers lemakalim and aprikalim produced no change in the firing rate of these neurons, the channel blockers glibenclamide and gliquidone were strongly inhibitory. As expected from an effect through ATP-sensitive potassium channels, the inhibition by glibenclamide could be prevented in a competitive manner by lemakalim and aprikalim. In contrast, the inactive isomer of the latter drug, RP 61499, did not alter the glibenclamide effect. In addition to the channel openers, the GABA receptor antagonists, bicuculline and phaclofen, but not the antagonist of somato-dendritic 5-HT1A autoreceptors, (-)tertatolol, prevented the negative influence of glibenclamide on the firing rate of serotoninergic neurons. This suggests that GABA acting at both GABAA and GABAB receptors (but not serotonin through the possible stimulation of autoreceptors) was responsible for the effect of glibenclamide. Accordingly, the blockade by the latter drug of ATP-sensitive potassium channels on GABAergic interneurons probably triggered the release of GABA, which in turn, inhibited serotoninergic neurons. In agreement with this hypothetical mechanism, autoradiographic studies demonstrated that ATP-sensitive potassium channels are not located on serotoninergic neurons (but probably on GABAergic interneurons) as the extensive lesion of these neurons by 5,7-dihydroxytryptamine did not reduce the specific labelling of the dorsal raphe nucleus by [3H]glibenclamide.
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PMID:Possible involvement of K(ATP) channels in the control of 5-HT neurons. 839 88

First defined as a residual diagnostic category in the third edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM), Generalized Anxiety Disorder (GAD) was until recently one of the least studied and least clearly conceptualized of the anxiety disorders. The clinical definition of GAD has however improved up to the fourth edition of the DSM where the disorder is now characterized as a chronic state of apprehensive expectation and uncontrollable worry concerning multiple daily life events or activities and accompanied with at least 3 symptoms belonging to a list of six common manifestations of psychic or motor tension. Clinical research demonstrating the stability and the specificity of somatic symptoms clearly support the validity of the diagnosis of GAD despite possible difficulties in the differential diagnosis with other chronic conditions or axis II disorders such as dysthymia or mixed anxiety-depressive disorder. After benzodiazepines (BZD) and 5-HT1A agonists like buspirone, several other types of new anxiolytic drugs have been developed for the treatment of GAD. Partial agonists at GABA-BZD receptor sites may offer the advantage of a better efficacy vs side-effects ratio over classical BZDs; however, systematic comparative clinical trials will have to demonstrate the clinical relevance of the encouraging results obtained with these drugs, at the experimental level, during studies in healthy volunteers and during the first placebo-controlled trials. Furthermore, the recent description of GABA-receptor's subunits clearly suggest that the development of drugs acting at this level and devoided of psychomotor or withdrawal side-effects is a target that is worth pursuing. On the other hand, the development of 5-HT2 and 5-HT3 antagonists is also of interest for the treatment of GAD since it could provide new anxiolytic drugs without these side-effects and thus easier to administer on a long-term basis corresponding to the chronicity of GAD. However, it will also be important to know if wether or not the efficacy of these new drugs, like that of buspirone, is associated with some effects on depressive symptomatology, develops only progressively over time and is different in previous BZD users compared to GAD patients who did not receive BZD before the new drug. Among these drugs in development for GAD, the most likely to reach the market in a near future are a BZD partial agonist (abecarnil), 5-HT1A agonists like ipsapirone and 5-HT3 antagonists like ondansetron. However, another area of new developments concerning the drug treatment of GAD is the use of antidepressants, which have demonstrated efficacy in this indication even in patients without depressive features or panic attacks symptoms. Considering the chronic nature of GAD, these drugs, like those acting on the 5-HT-system, would be more adapted than BZD for the long-term management of this condition. If confirmed by clinical trials involving antidepressants other than tricyclics, the efficacy of these drugs in GAD may suggest that common neurobiological mechanisms are involved in the pathogenesis of both anxiety and depressive disorders. Despite the potential interest of these new treatments of GAD, recent years have shown that the development of new anxiolytic drugs often appears limited by high-rates of placebo response in numerous clinical trials. This phenomenon may be related--in part--to the increasingly sophisticated designs used in such trials, such as extensive diagnostic workups, repeated evaluations and inclusion criteria selecting the less severe types of anxiety. As emphasized by other authors, much more research needs to be done to establish what effects various ways of conducting a trial have on the trial's results in order to facilitate the emergence of new psychopharmacological approaches in the treatment of GAD.
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PMID:[Treatment of generalized anxiety: new pharmacologic approaches]. 867 71

Effects on environmentally induced oral stereotypies (object pecking and drinker-directed activity) and other behavior (sitting, standing, pacing, preening), of preferential antagonists and agonists of central 5-HT and GABA receptor subtypes, were examined in individually caged broiler breeder fowls subjected to chronic food restriction. All drugs were injected intravenously at three doses, and their effects compared with a saline control treatment. The only significant (p < 0.05) effect of 5-HT antagonists [NAN-190 (5-HT1A), ketanserin (5-HT2), MDL-72222 (5-HT3)] was an increase in pacing with ketanserin (0.8 mg/kg). With 5-HT agonists, 8-OH-DPAT (5-HT1A) suppressed the two oral stereotypies and increased standing (all 1.0 mg/kg) and preening (0.2 mg/kg), alpha-methylserotonin (5-HT2) suppressed the oral stereotypies and increased sitting (all 1.0 mg/kg), and m-CPBG (5-HT3) suppressed drinker-directed activity (1.0 mg/kg). The GABA antagonists (bicuculline (GABAA), 5-aminovaleric acid (GABAB) had no effect, and of the GABA agonists [muscimol (GABAA), baclofen (GABAB)], muscimol suppressed preening and increased sitting, standing (all 1.0 mg/kg), and pacing (0.2 mg/kg). Most of the significant effects of serotonergic and GABAergic agents on behavior here appeared to reflect at least some degree of sedation, and there was no real evidence of any specific influence of these compounds on the oral stereotypies within the range of doses tested.
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PMID:Behavioral responses of restricted-fed fowls to pharmacological manipulation of 5-HT and GABA receptor subtypes. 880 8

Social conflict between mice produces analgesia in the attacked mouse. Both the magnitude and type (opioid or nonopioid) of this analgesia have been related to attack intensity and strain of mouse. In the present study low intensity social conflict (7 bites) did not produce analgesia, whereas high intensity - 30 and 60 bites - interactions produced, respectively, short-lasting (5 min) and very short-lasting (1 min) analgesia in Swiss albino mice, when compared with nonaggressive interaction (0 bite). The 30 bites aggressive interaction induced analgesia (AIIA) was not affected by IP injection of either naloxone (5.0 and 7.5 mg/kg) or diazepam (0.5, 1.0, 2.0 and 4.0 mg/kg). However, this attack-induced analgesia was reduced after IP administration of the 5-HT1A agonists, gepirone (0.3 and 3.0 mg/kg) and BAY R 1531 (0.01 mg/kg). These results indicate that the analgesia induced by 30 bites social conflict in Swiss albino mice does not involve opioid and GABA-benzodiazepine (GABA-BZD) mechanisms. In addition, they suggest that high-intensity social conflict activates serotonergic pain modulatory systems that act through 5-HT1A receptors.
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PMID:High intensity social conflict in the Swiss albino mouse induces analgesia modulated by 5-HT1A receptors. 907 86


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