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 serotonin (5-hydroxytryptamine, 5-HT) receptor 1A is involved in many physiological functions, including the regulation of learning and memory by acting either as an autoreceptor located on 5-HT neurons (raphe nuclei) or as a heteroreceptor on non-5-HT neurons, mainly in the hippocampal formation. To investigate whether the effects of 5-HT via 5-HT1A receptors on learning are age-sensitive, we evaluated the performance of young-adult (3 months old) and aged (22 months old) 5-HT1A knockout (KO) mice and their homologous wild types (WT) in the hippocampal-dependent spatial reference memory version of the Morris water maze. We demonstrated that young-adult 5-HT1AKO mice exhibit an impairment in learning and retention of the spatial task, as compared to WT mice, without showing any sign of change in their sensori-motor and locomotor abilities or motivation. This genotype effect does not persist during aging. In fact, aged 5-HT1AKO mice seem to be slightly facilitated during the early stages of learning. These results are consistent with a possible prevalence of 5-HT1A raphe functions in learning and memory abilities of young-adult animals, since the effects of the mutation on mice performance (impairment) are opposite to those found after intra-raphe injection of 5-HT1A agonists (facilitation), and with data showing increased activity of 5-HT neurons in 5-HT1AKO mice. The reduced effect of the mutation in aged animals possibly reflects the lower efficacy of autoreceptors due to aging and/or a prevalence of hippocampal heteroreceptors.
Brain Res Mol Brain Res 2004 Nov 04
PMID:Age-dependent effects of serotonin-1A receptor gene deletion in spatial learning abilities in mice. 1551 75

Serotonin 5-HT1 receptors are implicated in anxiety and depression. These receptors belong to the family A of G-protein-coupled receptors and couple to inhibitory G-proteins. Recent studies show that chronic activation of 5-HT1A receptors leads to proliferation of hippocampal neurons suggesting that neurogenesis contributes to the effects of antidepressants. However, the molecular mechanisms and pathways involved are not understood. We used Neuro 2A cells transfected with 5-HT1A receptors and SK-N-SH cells endogenously expressing the receptor to examine the effect of receptor activation on neuronal survival and neurite outgrowth. We find that receptor activation leads to increased neurite outgrowth that can be blocked by the receptor selective antagonist and by treatment with pertussis toxin or lactacystin implicating inhibitory G-proteins and proteasomal degradation in this process. Interestingly, the small G-protein Rap and the transcription factor STAT-3 are also involved since reducing the levels of Rap1 (using small interfering RNA) or STAT-3 (using dominant negative STAT3) significantly blocks 5-HT1A-receptor-mediated neurite outgrowth. The observed increase in the phosphorylation of Src and STAT-3, at sites leading to their activation, further supports a crucial role for these proteins in neurite outgrowth. We also find that prolonged activation of endogenous 5-HT1A receptors leads to increased cell survival even under starving conditions; this is completely blocked by co-treatment with the antagonist. Taken together, these findings indicate that activation of the 5-HT1A receptor leads to a number of neurotropic events by activating a series of signal transduction molecules leading to long-term changes required for neurogenesis.
Brain Res Mol Brain Res 2005 Aug 18
PMID:Serotonin receptor activation leads to neurite outgrowth and neuronal survival. 1592 28

Serotonin (5-HT) has long been implicated in a number of neurodevelopmental processes including neuronal cell division, migration, neurite outgrowth, and synapse formation. However, relatively little is known about how these effects are mediated during normal brain development in vivo and the identity of the receptor subtypes involved in mediating these effects. In recent years, a number of pharmacological studies have suggested a role for the serotonin 1A (5HT1A) receptor subtype in mediating the developmental effects of 5-HT in the hippocampus. These studies, however, have been difficult to interpret due to lack of information regarding the expression and distribution of 5HT1A in the developing brain and hippocampus in particular. In the current study, specific anti-5-HT1A antibodies, developed in our laboratory [F.C. Zhou, T.D. Patel, D. Swartz, Y. Xu, M.R. Kelley, Production and characterization of an anti-serotonin 1A receptor antibody which detects functional 5-HT1A binding sites, Brain Res Mol Brain Res, 69 (1999) 186-201], were utilized to map the ontogeny and distribution of the 5HT1A receptor protein in the developing rat hippocampus through embryonic and early postnatal life. This is the first such study of 5-HT1A expression in the developing rat brain. Our findings revealed that expression of the 5HT1A receptor emerges during the initial stages of embryonic hippocampal development. Remarkably, most if not all hippocampal neurons begin to express 5HT1A shortly upon completion of their terminal mitosis. We found that 5HT1A is initially concentrated around the cell bodies and later becomes more sparsely distributed along the dendrites after the neurons have matured. In addition to postmitotic neurons, we have observed that S100 and GFAP positive glia transiently express 5HT1A during early postnatal development of the hippocampus. These findings demonstrate that the 5-HT1A receptor is positioned to mediate developmental effects of serotonin in the hippocampus. Furthermore, the temporal patterns of expression suggest a role for 5-HT1A in postmitotic events such as neuronal migration, neurite outgrowth, and phenotypic differentiation.
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PMID:Ontogeny of 5-HT1A receptor expression in the developing hippocampus. 1593 84

The present review paper describes results indicating the influence of nitric oxide (NO) on motor control. Our last studies showed that systemic injections of low doses of inhibitors of NO synthase (NOS), the enzyme responsible for NO formation, induce anxiolytic effects in the elevated plus maze whereas higher doses decrease maze exploration. Also, NOS inhibitors decrease locomotion and rearing in an open field arena. These results may involve motor effects of this compounds, since inhibitors of NOS, NG-nitro-L-arginine (L-NOARG), N(G)-nitro-L-arginine methylester (L-NAME), N(G)-monomethyl-L-arginine (L-NMMA), and 7-Nitroindazole (7-NIO), induced catalepsy in mice. This effect was also found in rats after systemic, intracebroventricular or intrastriatal administration. Acute administration of L-NOARG has an additive cataleptic effect with haloperidol, a dopamine D2 antagonist. The catalepsy is also potentiated by WAY 100135 (5-HT1a receptor antagonist), ketanserin (5HT2a and alfal adrenergic receptor antagonist), and ritanserin (5-HT2a and 5HT2c receptor antagonist). Atropine sulfate and biperiden, antimuscarinic drugs, block L-NOARG-induced catalepsy in mice. L-NOARG subchronic administration in mice induces rapid tolerance (3 days) to its cataleptic effects. It also produces cross-tolerance to haloperidol-induced catalepsy. After subchronic L-NOARG treatment there is an increase in the density NADPH-d positive neurons in the dorsal part of nucleus caudate-putamen, nucleus accumbens, and tegmental pedunculupontinus nucleus. In contrast, this treatment decreases NADPH-d neuronal number in the substantia nigra compacta. Considering these results we suggest that (i) NO may modulate motor behavior, probably by interfering with dopaminergic, serotonergic, and cholinergic neurotransmission in the striatum; (ii) Subchronic NO synthesis inhibition induces plastic changes in NO-producing neurons in brain areas related to motor control and causes cross-tolerance to the cataleptic effect of haloperidol, raising the possibility that such treatments could decrease motor side effects associated with antipsychotic medications. Finally, recent studies using experimental Parkinson's disease models suggest an interaction between NO system and neurodegenerative processes in the nigrostriatal pathway. It provides evidence of a protective role of NO. Together, our results indicate that NO may be a key participant on physiological and pathophysiological processes in the nigrostriatal system.
Cell Mol Neurobiol 2005 Mar
PMID:Role of nitric oxide on motor behavior. 1604 47

1. Serotonin is an intrinsically fluorescent biogenic amine that acts as a neurotransmitter and is found in a wide variety of sites in the central and peripheral nervous system. Serotonergic signaling appears to play a key role in the generation and modulation of various cognitive and behavioral functions. 2. Serotonin exerts its diverse actions by binding to distinct cell surface receptors which have been classified into many groups. The serotonin1A (5-HT1A) receptor is the most extensively studied of the serotonin receptors and belongs to the large family of seven transmembrane domain G-protein coupled receptors. 3. The tissue and sub-cellular distribution, structural characteristics, signaling of the serotonin1A receptor and its interaction with G-proteins are discussed. 4. The pharmacology of serotonin1A receptors is reviewed in terms of binding of agonists and antagonists and sensitivity of their binding to guanine nucleotides. 5. Membrane biology of 5-HT1A receptors is presented using the bovine hippocampal serotonin1A receptor as a model system. The ligand binding activity and G-protein coupling of the receptor is modulated by membrane cholesterol thereby indicating the requirement of cholesterol in maintaining the receptor organization and function. This, along with the reported detergent resistance characteristics of the receptor, raises important questions on the role of membrane lipids and domains in the function of this receptor.
Cell Mol Neurobiol 2005 Jun
PMID:The serotonin1A receptor: a representative member of the serotonin receptor family. 1607 79

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.
Mol Endocrinol 2006 Jan
PMID:Serotonin (5-HT) receptor subtypes mediate specific modes of 5-HT-induced signaling and regulation of neurosecretion in gonadotropin-releasing hormone neurons. 1610 37

In this work, a hierarchic system of QSAR models from 1D to 4D is considered on the basis of the simplex representation of molecular structure (SiRMS). The essence of this system is that the QSAR problem is solved sequentially in a series of the improved models of the description of molecular structure. Thus, at each subsequent stage of a hierarchic system, the QSAR problem is not solved ab ovo, but rather the information obtained from the previous step is used. Actually, we deal with a system of solutions defined more exactly. In the SiRMS approach, a molecule is represented as a system of different simplex descriptors (tetratomic fragments with fixed composition, structure, chirality and symmetry). The level of simplex-descriptor detail increases consecutively from 1D to 4D representations of molecular structure. It enables us to determine the fragments of structure that promote or interfere with the given biological activity easily. Molecular design of compounds with a given level of activity is possible on the basis of SiRMS. The efficiency of the method is demonstrated for the example of the analysis of substituted piperazines affinity for the 5-HT1A receptor.
J Mol Model 2005 Nov
PMID:Hierarchic system of QSAR models (1D-4D) on the base of simplex representation of molecular structure. 1623 16

cDNA sequences of serotonin (5-hydroxytryptamine, 5-HT) 1A and 1D receptors were cloned from the tilapia, Oreochromis mossambicus, brain. The influence of both gonadal steroids and temperature on the ontogenetic expression of brain 5-HT1A and 5-HT1D receptors from days 5 to 15 post-hatch, a critical period of sexual differentiation, was investigated using quantitative real-time reverse transcription-polymerase chain reaction. Neither estrogen nor methyltestosterone had an effect on the ontogenetic expression of 5-HT1A or 5-HT1D receptors. Between days 5 and 10 post-hatch, a critical period for low-temperature-induced feminization, we found no significant difference in the ontogenetic expression of 5-HT1A between exposure to low and elevated temperature. A similar result was found for 5-HT1D. Between days 10 and 15 post-hatch, a critical period for elevated-temperature-induced masculinization, the ontogenetic expression of neither brain 5-HT1A nor 5-HT1D was altered by exposure to elevated temperature. These results suggest that neither brain 5-HT1A nor 5-HT1D plays a critical role in either gonadal steroid- or temperature-induced sexual differentiation.
Comp Biochem Physiol B Biochem Mol Biol 2006 Jan
PMID:Influence of temperature and gonadal steroids on the ontogenetic expression of brain serotonin 1A and 1D receptors during the critical period of sexual differentiation in tilapia, Oreochromis mossambicus. 1635 46

Structural features of the pyrido[1,2-c]pyrimidine derivatives with arylpiperazine moiety and their affinities towards 5-HT1A, 5-HT2A and alpha1-adrenergic receptors were analyzed using the CoMFA procedure. On the basis of 3D-QSAR models for the 5-HT2A and alpha1-adrenergic receptors, four compounds with expected better affinity/selectivity were proposed and synthesized. The affinities obtained confirm experimentally the usefulness of CoMFA models. Our results suggest that active conformations adopted by the studied molecules when interacting with the receptors are neutral instead of the protonated ones.
J Mol Graph Model 2006 Nov
PMID:CoMFA methodology in structure-activity analysis of hexahydro- and octahydropyrido[1,2-c]pyrimidine derivatives based on affinity towards 5-HT1A, 5-HT2A and alpha1-adrenergic receptors. 1654 63

The mechanism of action of acetaminophen is currently widely discussed. Direct inhibition of cyclooxygenase isoforms remains the commonly advanced hypothesis. We combined behavioral studies with molecular techniques to investigate the mechanism of action of acetaminophen in a model of tonic pain in rats. We show that acetaminophen indirectly stimulates spinal 5-hydroxytryptamine (5-HT)1A receptors in the formalin test, thereby increasing transcript and protein levels of low-affinity neurotrophin receptor, insulin-like growth factor-1 (IGF-1) receptor alpha subunit, and growth hormone receptor and reducing the amount of somatostatin 3 receptor (sst3R) mRNA. Those cellular events seem to be important for the antinociceptive activity of acetaminophen. Indeed, down-regulation of sst3R mRNA depends on acetaminophen-elicited, 5-HT1A receptor-dependent increase in neuronal extracellular signal-regulated kinase 1/2 (ERK1/2) activities that mediate antinociception. In addition, spinal growth hormone (GH) and IGF-1 receptors would also be involved in the antinociceptive activity of the analgesic at different degrees. Our results show the involvement of specific 5-HT1A receptor-dependent cellular events in acetaminophen-produced antinociception and consequently indicate that inhibition of cyclooxygenase activities is not the exclusive mechanism involved. Furthermore, we propose that the mechanisms of 5-HT1A receptor-elicited antinociception and the role of the spinal ERK1/2 pathway in nociception are more intricate than suspected so far and that the GH/IGF-1 axis is an interesting new player in the regulation of spinal nociception.
Mol Pharmacol 2007 Feb
PMID:Acetaminophen recruits spinal p42/p44 MAPKs and GH/IGF-1 receptors to produce analgesia via the serotonergic system. 1708 3


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