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Proceedings of the National Academy of... Nov 1998To investigate the contribution of individual serotonin (5-hydroxytryptamine; 5-HT) receptors to mood control, we have used homologous recombination to generate mice...
To investigate the contribution of individual serotonin (5-hydroxytryptamine; 5-HT) receptors to mood control, we have used homologous recombination to generate mice lacking specific serotonergic receptor subtypes. In the present report, we demonstrate that mice without 5-HT1A receptors display decreased exploratory activity and increased fear of aversive environments (open or elevated spaces). 5-HT1A knockout mice also exhibited a decreased immobility in the forced swim test, an effect commonly associated with antidepressant treatment. Although 5-HT1A receptors are involved in controlling the activity of serotonergic neurons, 5-HT1A knockout mice had normal levels of 5-HT and 5-hydroxyindoleacetic acid, possibly because of an up-regulation of 5-HT1B autoreceptors. Heterozygote 5-HT1A mutants expressed approximately one-half of wild-type receptor density and displayed intermediate phenotypes in most behavioral tests. These results demonstrate that 5-HT1A receptors are involved in the modulation of exploratory and fear-related behaviors and suggest that reductions in 5-HT1A receptor density due to genetic defects or environmental stressors might result in heightened anxiety.
Topics: Animals; Anxiety Disorders; Autoradiography; Brain; Disease Models, Animal; Female; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Mice, Knockout; Motor Activity; Neurons; Receptors, Serotonin; Receptors, Serotonin, 5-HT1; Recombination, Genetic; Serotonin; Tritium
PubMed: 9826725
DOI: 10.1073/pnas.95.24.14476 -
Trends in Pharmacological Sciences Mar 1995The current classification for 5-HT2 receptors accommodates three subtypes. In addition to the originally defined 5-HT2 receptor, sanctuary is now provided for the... (Review)
Review
The current classification for 5-HT2 receptors accommodates three subtypes. In addition to the originally defined 5-HT2 receptor, sanctuary is now provided for the structurally related 5-HT1c receptor (now 5-HT2c) and at least one atypical 5-HT receptor subtype. The strong functional union of this family is reflected in the paucity of ligands that will discriminate between its subtypes and prompts some re-evaluation of the activities of compounds which may now be regarded as nonselective for the receptor subtypes in this class. In this article, Gordon Baxter and colleagues examine the pharmacology of both officially recognized and atypical 5-HT2 receptor subtypes. A number of novel selective agents are highlighted, some of which may prove useful for 5-HT2 receptor classification and, ultimately, clarify the mechanistic basis for current and future therapeutic strategies which target this receptor family.
Topics: Animals; Drug Design; Humans; Psychotic Disorders; Receptors, Serotonin; Recombinant Proteins; Sequence Homology, Amino Acid; Serotonin Antagonists; Serotonin Receptor Agonists; Structure-Activity Relationship
PubMed: 7792930
DOI: 10.1016/s0165-6147(00)88991-9 -
Neuroscience Letters Jul 1999Serotonin (5-HT) has been shown to influence the development of the rodent barrel field by affecting the patterning of thalamic axons in the somatic sensory cortex. To...
Serotonin (5-HT) has been shown to influence the development of the rodent barrel field by affecting the patterning of thalamic axons in the somatic sensory cortex. To determine whether this is a direct effect on thalamocortical neurones, we analyzed primary thalamic cultures taken from E15 mouse embryos. We show that 5-HT enhances neurite outgrowth of thalamic neurones. The sodium channel blocker, TTX, blocks these effects, whereas the selective 5-HT1B agonist CGS-12066A maleate reproduced 5-HT's effect. Using PCR and immunocytochemistry, we found that 5-HT1B receptors are already expressed by thalamic neurones at E15, and that this expression is maintained in vitro. These results suggest that 5-HT-1B receptor activation directly affects the growth of thalamocortical axons.
Topics: Animals; Cells, Cultured; Embryo, Mammalian; Immunohistochemistry; Mice; Neurites; Neurons; Receptors, Serotonin; Reverse Transcriptase Polymerase Chain Reaction; Serotonin Antagonists; Serotonin Receptor Agonists; Thalamus
PubMed: 10430511
DOI: 10.1016/s0304-3940(99)00422-x -
Progress in Molecular Biology and... 2010Contemporary receptor theory was developed to account for the existence of constitutive activity, as defined by the presence of receptor signaling in the absence of any... (Review)
Review
Contemporary receptor theory was developed to account for the existence of constitutive activity, as defined by the presence of receptor signaling in the absence of any ligand. In vitro studies with a variety of cell types have revealed the existence of constitutive activity and inverse agonism at a large number of receptors and also additional complexities of ligand-receptor interactions. Thus, ligands acting at a constitutively active receptor can act as agonists, antagonists, and/or inverse agonists, and these pharmacological characteristics can differ for an individual ligand depending upon the receptor response measured and the physiological state of the system under study. Studies with a variety of cell types have established that the serotonin 5-HT(2A) and 5-HT(2C) receptors and the cannabinoid CB1 receptor demonstrate constitutive activity and inverse agonism in vitro. Serotonin and cannabinoid receptors are involved in a large number of physiological and behavioral functions. The possible existence of constitutive activity and inverse agonism at these receptors in vivo would provide new avenues for drug development. Recent studies have provided compelling evidence that both the serotonin 5-HT(2A) and 5-HT(2C) receptors and cannabinoid CB1 receptor demonstrate inverse agonism and constitutive activity also in vivo. This chapter describes our current knowledge of constitutive activity in vitro and then examines the evidence for constitutive activity in vivo.
Topics: Animals; Cannabinoid Receptor Agonists; Humans; In Vitro Techniques; Ligands; Models, Biological; Receptors, Cannabinoid; Receptors, Serotonin; Serotonin Receptor Agonists
PubMed: 20691957
DOI: 10.1016/S1877-1173(10)91001-6 -
Neuropsychopharmacology : Official... 1990Both the 5-hydroxytryptamine2 (5-HT2) and 5-HT1c receptors may be regulated by a large number of endogenous and exogenous factors. The 5-HT2 receptors, for example, may... (Review)
Review
Both the 5-hydroxytryptamine2 (5-HT2) and 5-HT1c receptors may be regulated by a large number of endogenous and exogenous factors. The 5-HT2 receptors, for example, may be decreased by acute and chronic treatment with many antipsychotic agents, some antidepressants, and receptor-specific agonists. Similar to the 5-HT2 receptor, the 5-HT1c receptors may be decreased by acute and chronic treatment with the antidepressant mianserin. The 5-HT2 receptors appear to increase during perinatal development and are reported to be elevated in the frontal cortex and hippocampus of victims of suicide; the 5-HT1c receptors display supersensitivity following ablation of serotonergic terminals with 5,7-dihydroxytryptamine. The molecular details responsible for these changes remain unknown, though with the recent cloning of the cDNAs for the 5-HT2 and 5-HT1c receptors the occasion is particularly favorable for mechanistic studies aimed at determining how these alterations occur. Preliminary information suggests that developmentally induced alterations in 5-HT2 and 5-HT1c receptors may be due to transcriptional regulation while changes caused by mianserin treatment might be due to posttranslational processes (e.g., proteolysis, internalization, phosphorylation, covalent alterations). Insights into the molecular means by which 5-HT receptors are regulated could have profound influences on our understanding of pharmacologic, developmental, and psychopathologic processes.
Topics: Animals; Humans; Receptors, Serotonin
PubMed: 2078277
DOI: No ID Found -
Acta Physiologica Scandinavica Nov 2000There is mounting evidence that increased brain serotonin during exercise is associated with the onset of CNS-mediated fatigue. Serotonin receptor sensitivity is likely...
There is mounting evidence that increased brain serotonin during exercise is associated with the onset of CNS-mediated fatigue. Serotonin receptor sensitivity is likely to be an important determinant of this fatigue. Alterations in brain serotonin receptor sensitivity were examined in Wistar rats throughout 6 weeks of endurance training, running on a treadmill four times a week with two exercise tests per week to exhaustion. Receptor sensitivity was determined indirectly as the reduction in exercise time in response to a dose of a serotonin (1A) agonist, m-chlorophenylpiperazine (m-CPP). The two groups of controls were used to examine (i) the effect of the injection per se on exercise performance and (ii) changes in serotonin receptor sensitivity associated with maturation. In the test group, undrugged exercise performance significantly improved by 47% after 6 weeks of training (4518 +/- 729 to 6640 +/- 903 s, P=0.01). Drugged exercise performance also increased significantly from week 1 to week 6 (306 +/- 69-712 +/- 192 s, P = 0.04). Control group results indicated that the dose of m-CPP alone caused fatigue during exercise tests and that maturation was not responsible for any decrease in receptor sensitivity. Improved resistance to the fatiguing effects of the serotonin agonist suggests desensitization of central serotonin receptors, probably the 5-HT1A receptors. Endurance training appears to stimulate an adaptive response to the fatiguing effects of increased brain serotonin, which may enhance endurance exercise performance.
Topics: Adaptation, Physiological; Animals; Exercise Test; Fatigue; Physical Conditioning, Animal; Physical Endurance; Piperazines; Rats; Rats, Wistar; Receptors, Serotonin; Serotonin Receptor Agonists; Time Factors
PubMed: 11167306
DOI: 10.1046/j.1365-201x.2000.00774.x -
Pharmacology & Therapeutics May 1995Recent, rapid progress in the molecular biology of serotonin (5-HT) receptors requires conceptual re-thinking with respect to receptor classification. Thus, based on... (Review)
Review
Recent, rapid progress in the molecular biology of serotonin (5-HT) receptors requires conceptual re-thinking with respect to receptor classification. Thus, based on operational criteria (agonist and antagonist rank order), as well as transduction mechanisms involved and the structure of the receptor protein, the Nomenclature Committee of the Serotonin Club has proposed the following classification and nomenclature: the main receptor types 5-HT1 to 5-HT4, recombinant receptors (e.g. 5-ht5 to 5-ht7) and 'orphan' receptors. The aim of the present review is to discuss the events leading to this classification, the criteria for and functional responses mediated by various 5-HT receptors, as well as the therapeutic possibilities with 5-HT ligands.
Topics: Animals; Anxiety Disorders; Depressive Disorder; Humans; Receptors, Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists
PubMed: 7667401
DOI: 10.1016/0163-7258(94)00005-n -
Molecular Endocrinology (Baltimore, Md.) Jan 2006Serotonin (5-HT), the endogenous nonselective 5-HT receptor agonist, activates the inositol 1,4,5-triphosphate/calcium (InsP3/Ca2+) signaling pathway and exerts both...
Serotonin (5-HT), the endogenous nonselective 5-HT receptor agonist, activates the inositol 1,4,5-triphosphate/calcium (InsP3/Ca2+) signaling pathway and exerts both stimulatory and inhibitory actions on cAMP production and GnRH release in immortalized GnRH neurons. The high degree of similarity between the signaling and secretory responses elicited by GnRH and 5-HT prompted us to target specific 5-HT receptor subtypes to deconvolute the complex actions of these agonists on signal transduction and GnRH release. Specific mRNA transcripts for 5-HT1A, 5-HT2C, 5-HT4, and 5-HT7 were identified in immortalized GnRH neurons (GT1-7). The rate of firing of spontaneous action potentials (APs) by hypothalamic GnRH neurons and cAMP production and pulsatile GnRH release in GT17 cells were profoundly inhibited during activation of the Gi-coupled 5-HT1A receptor. Treatment with a selective agonist to activate the Gq-coupled 5-HT2C receptor increased the rate of firing of spontaneous APs, stimulated InsP3 production and caused a delayed increase in GnRH release. Selective activation of the Gs-coupled 5-HT4 receptor also increased the rate of firing of APs, stimulated cAMP production, and caused a sustained and robust increase in GnRH release. The ability of 5-HT receptor subtypes expressed in GnRH neurons to activate single or multiple G proteins in a time- and dose-dependent manner differentially regulates the phospholipase C/InsP3/Ca2+, and adenylyl cyclase/cAMP signaling pathways, and thereby regulates the frequency and amplitude of pulsatile GnRH release. This process, in conjunction with the modulation of spontaneous electrical activity of the GnRH neuron, contributes to the control of the pulsatile mode of neuropeptide secretion that is characteristic of GnRH neuronal function in vivo and in vitro.
Topics: Action Potentials; Animals; Cells, Cultured; Cyclic AMP; Fetus; GTP-Binding Protein alpha Subunits; Gonadotropin-Releasing Hormone; Hypothalamus; Neurons; Neurosecretion; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT1A; Receptor, Serotonin, 5-HT2C; Receptors, Serotonin; Receptors, Serotonin, 5-HT4; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Signal Transduction; Type C Phospholipases
PubMed: 16109737
DOI: 10.1210/me.2005-0109 -
Current Drug Targets. CNS and... Feb 2004The 5-hydroxytryptamine(6) (5-ht(6)) was one of the most recent additions to the 5-HT receptor family, selective antagonists have recently been developed and potential... (Review)
Review
The 5-hydroxytryptamine(6) (5-ht(6)) was one of the most recent additions to the 5-HT receptor family, selective antagonists have recently been developed and potential functional roles are now becoming apparent. The high affinity of a wide range of psychiatric drugs for the 5-ht(6)receptor, together with its almost exclusive expression in the CNS, being abundant in limbic and cortical regions, has stimulated significant research interest. The 5-ht(6)receptor appears to regulate glutamatergic and cholinergic neuronal activity, and increasing evidence suggests that it may be involved in the regulation of cognition, feeding and, possibly, affective state and seizures. The current article will review all aspects of the discovery, genetics, distribution, pharmacology and function of the 5-ht(6)receptor. Taken together, this wealth of information warrants the use of the upper case nomenclature for the 5-ht(6) receptor to be approved and its true status recognised.
Topics: Animals; Brain; Cloning, Molecular; Drug Evaluation; Feeding Behavior; Humans; Learning; Mental Disorders; Mice; Neurons; Polymorphism, Genetic; Rats; Receptors, Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Signal Transduction; Structure-Activity Relationship; Tissue Distribution
PubMed: 14965245
DOI: 10.2174/1568007043482561 -
Progress in Neuro-psychopharmacology &... Oct 2003Serotonin (5-HT)-receptor-based mechanisms have been postulated to play a critical role in the action of the new generation of antipsychotic drugs (APDs) that are... (Review)
Review
Serotonin (5-HT)-receptor-based mechanisms have been postulated to play a critical role in the action of the new generation of antipsychotic drugs (APDs) that are usually referred to as atypical APDs because of their ability to achieve an antipsychotic effect with lower rates of extrapyramidal side effects (EPS) compared to first-generation APDs such as haloperidol. Specifically, it has been proposed by Meltzer et al. [J. Pharmacol. Exp. Ther. 251 (1989) 238] that potent 5-HT2A receptor antagonism together with weak dopamine (DA) D2 receptor antagonism are the principal pharmacologic features that differentiate clozapine and other apparent atypical APDs from first-generation typical APD. This hypothesis is consistent with the atypical features of quetiapine, olanzapine, risperidone, and ziprasidone, which are the most common treatments for schizophrenia in the United States and many other countries, as well as a large number of compounds in various stages of development. Subsequent research showed that 5-HT1A agonism may be an important consequence of 5-HT2A antagonism and that substitution of 5-HT1A agonism for 5-HT2A antagonism may also produce an atypical APD drug when coupled with weak D2 antagonism. Aripiprazole, the most recently introduced atypical APD, and a D2 receptor partial agonist, may also owe some of its atypical properties to its net effect of weak D2 antagonism, 5-HT2A antagonism and 5-HT1A agonism [Eur. J. Pharmacol. 441 (2002) 137]. By contrast, the alternative "fast-off" hypothesis of Kapur and Seeman [Am. J. Psychiatry 158 (2001) 360] applies only to clozapine and quetiapine and is inconsistent with the "slow" off rate of most atypical APDs, including olanzapine, risperidone and ziprasidone. 5-HT2A and 5-HT1A receptors located on glutamatergic pyramidal neurons in the cortex and hippocampus, 5-HT2A receptors on the cell bodies of DA neurons in the ventral tegmentum and substantia nigra and GABAergic interneurons in the cortex and hippocampus, and 5-HT1A receptors in the raphe nuclei are likely to be important sites of action of the atypical APDs. At the same time, evidence has accumulated for the important modulatory role of 5-HT2C and 5-HT6 receptors for some of the effects of some of the current APDs. Thus, 5-HT has joined DA as a critical target for developing effective APDs and led to the search for novel drugs with complex pharmacology, ending the exclusive search for single-receptor targets, e.g., the D3 or D4 receptor, and drugs that are selective for them.
Topics: Animals; Antipsychotic Agents; Brain; Dopamine; Dopamine Agents; Dose-Response Relationship, Drug; Drug Interactions; Humans; Receptors, Serotonin; Schizophrenia; Serotonin Antagonists; Serotonin Receptor Agonists
PubMed: 14642974
DOI: 10.1016/j.pnpbp.2003.09.010