摘要:

AbstractFour serotonin receptor clones have now been isolated and characterized. They encode the serotonin 5‐HT1A, 5‐HT1C, 5‐HT1D, and 5‐HT2receptors. The serotonin 5‐HT1Creceptor, which was originally classified as a 5‐HT1receptor, is now seen to be a member of the 5‐HT2receptor subfamily. Within the current 5‐HT1receptor subfamily, the two clones that have been described (5‐HT1Aand 5‐HT1D) show similarities in amino acid sequence and function but are not as closely related as might have been expected. The human 5‐HT1Dreceptor clone, when expressed in mouse fibroblast cells, displays pharmacological binding properties in agreement with human cortical membrane preparations. Sumatriptan, a new antimigraine medication, exhibits an apparent dissociation constant of 3.4 nM at this human receptor site. This represents the highest affinity interaction yet identified for this drug, and suggests that significant species differences may exist in the binding of this compound to 5‐HT1Dreceptors. Similar species differences in ergot drug affinities have been described for the 5‐HT2receptor. Deduced amino acid sequence homologies between serotonin and other monoamine receptor clones are discussed, leading to a classification scheme for serotonin receptors involving superfamily, family, and subfamily relationship

ISSN:0272-4391    

DOI:10.1002/ddr.430260302

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractFive sites (5HT1A, 5HT1B, 5HT1C, 5HT1D, and 5HT1E) have been detected using3H‐5HT radioligand methodology and mammalian brain tissue. We report herein that high‐affinity3H‐5HT binding to homogenates of bovine and rat caudate and cortical tissues cannot be interpreted without including at least one additional 5HT receptor. Competition studies were performed in rat frontal cortex tissues, using pharmacological blockade of 5HT1A, 5HT1B, and 5HT1Creceptors to facilitate examination of other possible sites. Ergotamine, under these conditions, produced a low‐affinity competition K1= 1.2 1μM with a Hill coefficient of 1.0. 5‐carboxyamidotryptamine (5CT), under these conditions, produced a complex competition curve, with an overall K1value of 101 nM and a Hill coefficient of 0.55. Computer‐assisted analysis of the 5CT competition curve revealed a high‐affinity site (K1= 16nM) and a low‐affinity site (K1= 802 nM). Therefore, competition curves produced using ergotamine and 5‐CT indicate that there is a site in rat frontal cortical tissue with high affinity for 5HT, 5CT, and low affinity for ergotamine as well as a site with high affinity for 5HT and low affinity for 5CT and ergotamine. The site with high affinity for 5HT, and low affinity for 5CT and ergotamine resembles the 5HT1Ereceptor, insofar as these three drugs are concerned. There is no reported site with high affinity for 5HT and 5CT and low affinity for ergotamine (heretofore referred to as 5HT1F). The lack of a high‐affinity ergotamine competition for3H‐5HT binding to non‐5HT1A, 5HT1B, and 5HT1Csites indicates that there is no detectable 5HT1Dbinding in this tissue. In rat striatal tissue both 5CT and ergotamine produced complex competition curves with Hill coefficients less than unity (0.6 and 0.65, respectively). Computer‐assisted analysis indicated that a minority of sites (approximately 35%) displayed high affinity for both ergotamine and 5CT, while 65% of the sites displayed low affinity for both 5CT and ergotamine. The site labeled with3H‐5HT displaying high affinity for 5CT and ergotamine coincides with the pharmacological profile of a 5HT1Dsite. The site labeled with3H‐5HT displaying low affinity for 5CT and ergotamine coincides with the pharmacological profile of the 5HT1Esite. Results from bovine cortical and striatal tissues reinforce the conclusions drawn from the rat brain data. In summary, detailed studies of specific3H‐5HT binding to non 5HT1A‐1Csites indicate that (1) there are detectable 5HT1Dsites in rat striatal tissue but not in rat cortical tissue, (2) there are detectable 5HT1Esites in rat brain tissue, and (c) a novel high‐affinity3H‐5HT binding site possessing high affinity for 5CT and low affinity for ergotamine has been detected in rat and bovine

ISSN:0272-4391    

DOI:10.1002/ddr.430260303

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractSumatriptan is a highly selective 5‐HT1receptor agonist and an effective treatment for migraine. It causes constriction of cranial blood vessels. In anaesthetised animals, it selectively constricts parts of the carotid vasculature and has been shown to inhibit plasma protein extravasation from blood vessels of the dura mater induced by antidromic stimulation of the trigeminal nerve. This effect may result from a localised vasoconstriction of the meningeal vessels and/or a direct inhibitory effect on adventitial nerve endings. Sumatriptan penetrates the blood brain barrier poorly. These findings are consistent with the view that the locus of action of sumatriptan is at the level of the wall of cranial blood vessels that are distended and edematous during a migraine headache. © 1992 Wiley‐Liss,

ISSN:0272-4391    

DOI:10.1002/ddr.430260304

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractCP‐94,253, 3‐(1,2,5,6‐tetrahydro‐4‐pyridyl)‐5‐propoxypyrrolo[3,2‐b]pyridine, a new serotonergic ligand, was found to exhibit significantly greater binding affinity at 5‐HT1Breceptors than at 5‐HT1Aor 5‐HT1Creceptors. Saturation studies showed CP‐94,253 to be a competitive inhibitor of [125l]iodocyanopindolol binding to 5‐HT1Bsites. Its competition curve with this radioligand was shifted to the right (decreased affinity) in the presence of Gpp(NH)p, indicating an agonist function for CP‐94,253. Oral administration of CP‐94,253 to rats caused inhibition of food intake, decrease in body weight gain, and hyperlocomotion, effects apparently elicited via activation of 5‐HT1Bre

ISSN:0272-4391    

DOI:10.1002/ddr.430260305

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractThe accessibility and use of a standard 5‐HT1Aagonist radioligand ([3H]8‐hydroxy‐2‐(dipropylaminotetralin) has resulted in the availability of a large amount of binding data on various serotonergic agents. This, in turn, has permitted the formulation of structure—affinity relationships (SAFIR). By contrast, much less information is available concerning the agonist and antagonist activity of these agents. This is primarily due to a lack of standard evaluation procedures, controversy regarding the presynaptic versus postsynaptic nature of certain models, and the recent realization that many 5‐HT1Aagents are partial agonists. Thus, it has been difficult to formulate structure—activity relationships (SAR) for these agents. The present review examines the various classes of 5‐HT1Aserotonergic agents and the available data on their 5‐HT1Aagonist and antagonist activity with the aim of formulating SAR. These SAR should provide useful information for the subsequent design of 5‐HT1A‐selective agonists and antagonists.

ISSN:0272-4391    

DOI:10.1002/ddr.430260306

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractElectrophysiological recordings from hippocampus and cortex have demonstrated that one of the most prominent effects of serotonin in these regions is a membrane hyperpolarization that effectively inhibits neuronal activity. The use of the in vitro brain slice preparation has allowed for detailed pharmacological and physiological studies of this response. Pharmacological analysis using agonists and antagonists indicates that these responses are mediated by activation of receptors of the 5‐HT1Asubtype. Buspirone, ipsapirone and 8‐OHDPAT are all partial agonists at this receptor with 8‐OHDPAT exhibiting an intrinsic activity approximately one‐fourth that of serotonin. The ability of 5‐HT1Areceptor agonists to elicit a hyperpolarization is dependent on intracellular GTP, suggesting the involvement of a G protein in the transmembrane signalling mechanism. In agreement with this idea, injection of the stable GTP analog GTPγS renders the serotonin induced hyperpolarization irreversible, while GDPβS blunts its effects and pertussis toxin pretreatment blocks it. The 5‐HT1Areceptor induced hyperpolarization is mediated by an increase in potassium conductance. While the identity of the potassium channel remains to be determined, its basic characteristics identify it as belonging to a general class of inwardly rectifying G protein activated potassium channels ubiquitously distributed in neuronal and cardiac muscle tissues. In the rat hippocampus and cortex, most pyramidal cells co‐express 5‐HT1Awith either 5‐HT4or 5‐HT2receptors, respectively, which in turn act to increase the ability of strong stimuli to excite these cells. As a result the net effect of serotonin on membrane excitability is dependent on the strength of incoming stimuli. Weak stimuli are depressed by the coactivation of these receptor subtypes while strong stimuli are enhanced. Thus the effects of selective 5‐HT1Aligands are likely to depend not only on their direct effect on membrane excitability but also on how they alter ongoing serotonergic neurotransmission.

ISSN:0272-4391    

DOI:10.1002/ddr.430260307

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractSeveral agents that downregulate 5‐HT2receptors produce anxiolytic effects in humans, but the role of 5‐HT2receptor downregulation has been difficult to assess because of their other actions. To test the effects of pharmacological downregulation of 5‐HT2receptors on exploratory behavior in the mouse, mianserin, a drug known to downregulate 5‐HT2receptors after a single dose, was administered 30 min, 48 hr, or 18 days prior to testing in the elevated plus‐maze. Following testing in the elevated maze, the head‐shake response to 4‐iodo‐R‐(—)‐2,5‐dimethoxyphenylisopropylamine (DOI), a selective 5‐HT2/5‐HT1Cagonist was assessed, and in a separate group of animals 5‐HT1A, 5‐HT1B, 5‐HT1C, β1,β2, and 5‐HT2agonist and antagonist binding was quantified autoradiographically. Mianserin pretreatment resulted in a significant dose‐related anxiolytic effect in the elevated plus maze evidenced by increases in the percentage of entries to, and time spent on the open arms. Head‐shakes induced by DOI were also dose‐dependently decreased as a result of mianserin pretreatment. At this time, the binding of the 5‐HT2receptor antagonist, 7‐amino‐8[125I]ketanserin was decreased by 50%. Binding of DOI to 5‐HT2receptors was decreased by 46%, and to 5‐HT1Creceptors was decreased by 53%, but no other changes were found in any of the other receptor types examined. These findings demonstrate that the 5‐HT2receptor plays at least a permissive role in anxiety‐like behaviors, since an intact 5‐HT2system is necessary for the full expression of the anxiety‐like response, but the role of 5‐HT1Creceptor downregulation in the effects of mia

ISSN:0272-4391    

DOI:10.1002/ddr.430260308

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractA number of compounds with high receptor binding affinity for the 5‐hydroxytryptamine (5‐HT) receptor subtype designated as 5‐HT1Acan produce anxiolytic and/or antidepressant effects in humans. In contrast to the traditional benzodiazepine anxiolytics, many of the clinically efficacious 5‐HT1Adrugs are either ineffective or produce inconsistent results in traditional preclinical anxiolytic screens using behavioral procedures with rodents. In preclinical antidepressant models with these animals, however, effects of the 5‐HT1Adrugs, as well as those of traditional antidepressant compounds, are predictive of their antidepressant activity in humans. In contrast, 5‐HT1Adrugs are quite effective in pigeons studied under a rather conventional punishment or conflict‐type procedure that is also sensitive to the benzodiazepine anxiolytics. However, traditional antidepressant compounds, such as the tricyclic drugs amitriptyline and imipramine, as well as the 5‐HT reuptake blockers such as fluoxetine, do not show effects similar to the newer 5‐HT1Adrugs in this procedure. Thus, in rodents, current antidepressant models are sensitive to drugs that appear to function through different mechanisms, whereas conflict‐type procedures typically do not reveal anxiolytic‐like effects with 5‐HT1Adrugs. The pigeon conflict procedure, however, discriminates between the 5‐HT1Aantidepressants and antidepressant drugs functioning through other systems, whereas the effects of known anxiolytics in this procedure are quite similar. Increases in punished responding with 5‐HT1Adrugs correlates highly (r= +0.83) with affinity for the 5‐HT1Areceptor in pigeons. This paper reviews behavioral studies conducted with the pigeon in which the focus has been on the analysis of 5‐HT1Acompounds and addresses additional work that is required to answer many of the outstanding questions about this new class of anxiolytic and/or antidepressan

ISSN:0272-4391    

DOI:10.1002/ddr.430260309

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractActivation of 5‐HT receptors via reuptake inhibition, precursor loading, or inhibition of catabolism have consistently resulted in decreases in ethanol preference in rats. The objective of the present studies was to determine whether activation of the 5‐HT1Areceptor with gepirone, a selective agonist, decreases ethanol preference. Preference was first evaluated for ethanol solutions from 3 to 11%, in a free‐choice situation with ethanol solution or tapwater available in the home cage. Male Sprague‐Dawley rats consumed the most ethanol solution relative to water at a concentration of 6%. When ethanol (6% solution) was available to ethanol‐habituated rats in a 1‐hr restricted access situation, subjects consumed 5.9 ± 0.4 ml. Pretreatment with gepirone (0.46–4.6 mg/kg IP) resulted in a dose‐dependent reduction in ethanol consumption in the restricted‐access paradigm. The 5‐HT reuptake inhibitor fluoxetine also resulted in dose‐related decreases in ethanol consumption in restricted access. A subsequent experiment using a lower dose of fluoxetine also found a suppressive effect on ethanol intake. A single daily dose of gepirone failed to decrease the consumption of 6% ethanol when it was continuously available in the home cage. The short half‐life of gepirone might explain its lack of effect in continuous access with only one daily dose. Gepirone decreased open‐field activity at higher (2.3 to 4.6‐mg/kg) doses, but did not affect rotorod performance at any dose (4.6–9.2 mg/kg) tested, whereas haloperidol (0.025–1.0 mg/kg) significantly decreased time on the rotorod. These results suggest that 5‐HT1Areceptor activation decreases ethanol intake in limited access and that the motorically disrupting effects of gepirone are not manifest under these

ISSN:0272-4391    

DOI:10.1002/ddr.430260310

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY

摘要:

AbstractA series of experiments was performed to investigate the effects on aggression of various drugs affecting serotonergic transmission in rats. Using ethologically derived behavioural categories, the behaviour of treated animals was described. Drug effects were observed in two aggression models: resident–intruder aggression (RI) in male rats, and maternal aggression in lactating females during the postpartum period (MA). The 5‐HT1Aagonists, buspirone, iosapirone, and 8‐OH‐DPAT, decreased aggression in RI and MA but simultaneously led to a marked decrease in social interest and activity, indicative of a nonspecific anti‐aggressive profile. Nonselective 5‐HT agonists, such as RU 24969, eltoprazine (DU 28853), and TEMPP, reduced aggression quite specifically and did not decrease social interest or exploration, but sometimes even increased these behaviours. In RI and MA, the behavioural effects of these drugs were roughly similar. By contrast, MA was more sensitive to the treatment with the 5‐HT reuptake blocker fluvoxamine, which blocked RI aggression only nonspecifically at the highest dose. DOI, a 5‐HT2and 5‐HT1Cagonist, decreased aggressive behaviour and increased inactivity, without affecting social interest and exploration in RI as well as MA. This was, however, accompanied by “wet dog shaking,” characteristic of 5‐HT2‐receptor stimulation. The nonspecific 5‐HT agonist (and 5‐HT3antagonist) quipazine also induced “wet dog shaking” at doses that suppressed aggression, social interest and exploration but increased inactive behaviours (sitting and lying). The discussion attempts to delineate a role for 5‐HT receptor subtype involvement in the modulation of aggression, with the restrictions we clearly face with regard to the lack of specific serotonergic agonists and antagonists for certain receptor subtypes. By and large, male and female rats react similarly to treatment with serotonergic drugs stressing the consistent role of 5‐HT in different forms

ISSN:0272-4391    

DOI:10.1002/ddr.430260311

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1992

数据来源: WILEY