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)

Two operational measures of central information processing mechanisms are habituation and prepulse inhibition (PPI) of the startle response. Both measures can be assessed reliably in humans and other animals, and have been shown to be deficient in patients with schizophrenia. The three present experiments assessed the involvement of the serotonin1B (5-HT1B) receptor in modulating startle reactivity, habituation, and PPI by comparing 5-HT1B receptor gene knockout (5-HT1B knockout) with wild-type 129/Sv mice. In experiment I, female mice received saline, 2.0 mg/kg 5-methoxy-3(1,2,3,6)tetrahydropyridin-4-yl-1H-indole (RU24969), a 5-HT1A/1B agonist, and 1.0 mg/kg 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT), a selective 5-HT1A agonist. Female mice received saline, 10.0 mg/kg RU24969, and 5.0 mg/kg 8-OH-DPAT in experiment 2, and male mice received saline, 10.0 mg/kg RU24969, and 5.0 mg/kg 8-OH-DPAT in experiment 3. All three studies used identical within-subjects designs. Two phenotypic differences were observed following saline treatment: 5-HT1B knockout mice consistently exhibited a small increase in PPI that achieved significance in experiment 1; and 5-HT1B knockout male mice exhibited robust decreases in startle reactivity. Habituation was disrupted consistently by RU24969 in wild-type but not in 5-HT1B knockout mice, while 8-OH-DPAT had no effect on habituation. Consistent with the phenotypic difference in PPI, the high dose of RU24969 significantly and consistently reduced PPI in wild-type but not in 5-HT1B knockout mice. 8-OH-DPAT increased PPI in both wild-type and 5-HT1B knockout mice in every experiment. These findings suggest that 5-HT1B receptors modulate startle reactivity, habituation, and PPI in mice. Additionally, a potential species difference may exist in the behavioral effects of 5-HT1A receptor activation on PPI.
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PMID:Serotonin1B receptor modulation of startle reactivity, habituation, and prepulse inhibition in wild-type and serotonin1B knockout mice. 926 9

Previous studies have suggested a disturbance in the cortical serotonergic (5-HT) system in schizophrenia; however, these studies have been confounded by suicide in the patients groups, which in itself is associated with alterations in the 5-HT system. In this study we characterized various components of the 5-HT system in 14 areas of the frontal and parietal cortex in tissue obtained at postmortem from aged chronically hospitalized nonsuicidal schizophrenics compared to age-matched controls. We found no differences between control and schizophrenic subjects in the density of 5-HT uptake sites or other markers of 5-HT innervation. In Brodmann areas 24 and 6 the concentration of 5-HT2A,C receptors was decreased in all schizophrenics regardless of their antipsychotic treatment history. In all other areas examined 5-HT2A,C receptor concentrations were dramatically decreased in schizophrenics patients on drugs at time of death, whereas those off drugs at death showed the same values as control subjects. The density of 5-HT1A receptors was increased in areas 24, 9a (caudal part of area 9), 44, and 6 in subjects with schizophrenia. Antipsychotic treatment did not appear to have a significant effect. Thus, the specific pattern of alterations in the 5-HT system in schizophrenia may depend on the patient population and on antemortem antipsychotic treatment. These data also provide evidence that regulation of the 5-HT2 receptor may be involved in antipsychotic action.
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PMID:Alterations in the cortical serotonergic system in schizophrenia: a postmortem study. 937 49

This study investigated the neurodevelopmental basis of schizophrenia by examining an early transient population of serotonin-1A (5-HT1A) receptors using quantitative [3H]8-OH-DPAT autoradiography on sections of frozen postmortem cerebellum. Production of an ontogenetic map showed that human neonatal cerebellum acquired dense 5-HT1A receptors, most of which were eliminated by early childhood. Autoradiographic measurements on cerebellar vermis from 16 control adult subjects confirmed sparse 5-HT1A receptor binding. The data show a persistence of some vermal 5-HT1A receptors in brains from 19 adults with chronic schizophrenia in whom there may have been a slowed or arrested postnatal regression of vermal 5-HT1A receptors. Alternatively, some 5-HT1A receptors may have been re-expressed prior to, or subsequent to, the onset of the disease symptoms. The findings are not obviously explained by drug treatment and there are no data to explain how neuroleptics might promote expression of cerebellar 5-HT1A receptors. We propose that the study has identified a neurotransmitter receptor population which, in schizophrenia, undergoes misdirected reshaping during brain development. The findings support neurodevelopmental hypotheses of the disease.
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PMID:Abnormal persistence of cerebellar serotonin-1A receptors in schizophrenia suggests failure to regress in neonates. 966 Jan 9

S 16924 antagonized locomotion provoked by dizocilpine and cocaine, reduced conditioned avoidance responses and blocked climbing elicited by apomorphine, models predictive of control of the positive symptoms of schizophrenia: its median inhibitory dose (ID)50 was 0.96 mg/kg, s.c. vs. 1.91 for clozapine and 0.05 for haloperidol. Rotation elicited in unilateral, substantia nigra-lesioned rats by the D1 agonist, SKF 38393, and by the D2 agonist, quinpirole, was blocked equipotently by S 16924 (0.8 and 1. 7) and clozapine (0.6 and 2.0), whereas haloperidol preferentially blocked quinpirole (0.02) vs. SKF 38393 (1.8). S 16924 more potently inhibited the head-twitches elicited by 1-(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and the locomotion provoked by phencyclidine than it inhibited the locomotion elicited by amphetamine (ID50s = 0.15 and 0.02 vs. 2.4). Clozapine showed a similar preference (0.04 and 0.07 vs. 8.6), but not haloperidol (0. 07 and 0.08 vs. 0.04). The discriminative stimulus (DS) properties of DOI were also blocked by S 16924 (ID50 = 0.17) and clozapine (0. 05) but not by haloperidol (>0.16). S 16924 fully (100%) generalized [effective dose (ED)50 = 0.7] to a clozapine DS and clozapine (0.23) fully generalized to a S 16924 DS whereas haloperidol (>/=0.08) only partially generalized (</=50%) to their DS in each case. Power spectra analysis of electroencephalograms from frontal cortex showed that both S 16924 (2.0) and clozapine (5.0) reinforced frequencies in the 7 to 8 Hz range whereas haloperidol (0.5) preferentially reinforced frequencies in the 10 to 14 Hz range. In a model of perturbation of cognitive-attentional function, significant latent inhibition was obtained with S 16924 (0.08) and clozapine (0.16), but not haloperidol (0.0063 and 0.04): higher doses of S 16924 (2.5), clozapine (5.0) and haloperidol (0.1) all blocked disruption of latent inhibition by amphetamine (1.5). Catalepsy was provoked by haloperidol (0.04-0.63) but not by S 16924 (>/=80.0) or clozapine (>/=80.0). Further, S 16924 (ID50 = 3.2) and clozapine (5.5) inhibited induction of catalepsy by haloperidol. This action of S 16924 was abolished by the 5-HT1A receptor antagonist, WAY 100,635 (0.16), which less markedly attenuated the anticataleptic action of clozapine. Further, although gnawing elicited by methylphenidate was inhibited by S 16924 (ID50 = 8.4), clozapine (19.6) and haloperidol (0.04), only the action of S 16924 was blocked by WAY 100,635 (0.16). Haloperidol potently (0.01-0.16, approximately 24-fold) increased prolactin levels whereas they were less markedly affected by S 16924 (2.5-40.0, 4-fold) and clozapine (10.0-40.0, 3-fold). Clozapine displayed high affinity at cloned, human, muscarinic (M1) and native, histamine (H1) receptors (Kis = 4.6 and 5.4 nM, respectively), whereas S 16924 (>1000 and 158) and haloperidol (>1000 and 453) displayed low affinity. In conclusion, S 16924 displays a profile of activity in diverse models of potential antipsychotic and extrapyramidal properties similar to that of clozapine and different to that of haloperidol. In particular, reflecting its partial agonist actions at 5-HT1A receptors, S 16924 inhibits rather than induces catalepsy in rats. However, in contrast to clozapine, S 16924 displays only low affinity for muscarinic and histaminic receptors.
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PMID:S 16924 ((R)-2-[1-[2-(2,3-dihydro-benzo[1,4] dioxin-5-yloxy)-ethyl]-pyrrolidin-3yl]-1-(4-fluoro-phenyl)-ethanone), a novel, potential antipsychotic with marked serotonin (5-HT)1A agonist properties: II. Functional profile in comparison to clozapine and haloperidol. 973 99

Dysfunction of serotonin systems has been implicated in schizophrenia. In the present study, the human 5-HT1A receptor gene containing the 5' untranslated region was screened in order to detect genetic variations, through which alteration of protein function or level of expression might contribute to schizophrenia. Genomic DNAs were isolated from whole-blood samples of 61 unrelated schizophrenic patients and 100 healthy controls. Genetic variations were screened systematically by single-strand conformational polymorphism (SSCP) analysis, followed by direct sequencing of polymerase chain reaction (PCR) product as well as restriction fragment-length polymorphism (RFLP). The novel mutations (-51T --> C, -152C --> G, -321G --> C, -480delA, and -581C --> A) were found in the 5' untranslated region. Furthermore, we found a novel missense mutation (Gly272Asp) in the coding region in addition to the mutations (Pro16Leu, 294G --> A, and 549C --> T) reported previously. No significant differences in genotype frequencies as well as allele frequencies were found between patients and controls. Our data provided no evidence of association between schizophrenia and the variants in the 5' untranslated region as well as the coding region of the human 5-HT1A receptor gene.
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PMID:Novel mutations in the promoter and coding region of the human 5-HT1A receptor gene and association analysis in schizophrenia. 975 30

Sensorimotor gating of the startle reflex occurs when the presentation of a weak "prepulse" 30-500 msec prior to a startling stimulus inhibits the reflex, and is called prepulse inhibition (PPI). The study of PPI has recently been extended to mice to take advantage of recent advances in molecular genetics, because several neuropsychiatric disorders including schizophrenia, obsessive compulsive disorder, and schizotypal personality disorder are characterized by PPI deficits. Studies in wild-type and 5-HT1B knockout mice suggest that activation of 5-HT1B receptors decreases PPI. The direct 5-HT1A/1B agonist RU24969 decreases PPI in wild-type but not 5-HT1B knockout mice. Likewise, the serotonin releasing compounds MDMA(+), MBDB(+/-), and alpha-ethyltryptamine (AET) have no effect on PPI in wild-type mice, but increase PPI in 5-HT1B knockout mice. As the direct 5-HT1A agonist 8-OH-DPAT increases PPI in mice, the unmasking of these effects may also contribute to the PPI-increasing effects of 5-HT releasers in 5-HT1B knockout mice.
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PMID:5-HT1B receptor modulation of prepulse inhibition: recent findings in wild-type and 5-HT1B knockout mice. 992 42

LEK-8829 [9,10-didehydro-N-methyl-(2-propynyl)-6-methyl-8- aminomethylergoline bimaleinate] is an antagonist of dopamine D2 receptors and serotonin (5-HT)2 and 5-HT1A receptors in intact animals and a D1 receptor agonist in dopamine-depleted animals. In the present study, we used rats with unilateral striatal lesions with ibotenic acid (IA) to investigate the dopamine receptor activities of LEK-8829 in a model with innervated dopamine receptors. The IA-lesioned rats circled ipsilaterally when challenged with apomorphine, the mixed agonist on D1/D2 receptors. LEK-8829 induced a dose-dependent contralateral turning that was blocked by D1 receptor antagonist SCH-23390. The treatment with D1 receptor agonist SKF-82958 induced ipsilateral turning, whereas the treatment with D2 receptor antagonist haloperidol induced contralateral posture. The combined treatment with SKF-82958 and haloperidol resulted in a weak contralateral turning, indicating the possible receptor mechanism of contralateral turning induced by LEK-8829. Bromocriptine induced a weak ipsilateral turning that was blocked by haloperidol. The ipsilateral turning induced by bromocriptine was significantly potentiated by the coadministration of a low dose but not by a high dose of LEK-8829. The potentiation of turning was blocked either by SCH-23390 or by haloperidol. The potentiation of ipsilateral turning suggests the costimulation of D2 and D1 receptors by bromocriptine and LEK-8829, respectively, whereas the lack of potentiation by the highest dose of LEK-8829 may be explained by the opposing activity of LEK-8829 and bromocriptine at D2 receptors. We propose that the D2 and 5HT2 receptor-blocking and D1 receptor-stimulating profile of LEK-8829 is promising for the treatment of negative symptoms of schizophrenia.
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PMID:Ergoline derivative LEK-8829-induced turning behavior in rats with unilateral striatal ibotenic acid lesions: interaction with bromocriptine. 1002 46

The modulating effects of serotonin on dopamine neurotransmission are not well understood, particularly in acute psychotic states. Positron emission tomography was used to examine the effect of psilocybin on the in vivo binding of [11C]raclopride to D2-dopamine receptors in the striatum in healthy volunteers after placebo and a psychotomimetic dose of psilocybin (n = 7). Psilocybin is a potent indoleamine hallucinogen and a mixed 5-HT2A and 5-HT1A receptor agonist. Psilocybin administration (0.25 mg/kg p.o.) produced changes in mood, disturbances in thinking, illusions, elementary and complex visual hallucinations and impaired ego-functioning. Psilocybin significantly decreased [11C]raclopride receptor binding potential (BP) bilaterally in the caudate nucleus (19%) and putamen (20%) consistent with an increase in endogenous dopamine. Changes in [11C]raclopride BP in the ventral striatum correlated with depersonalization associated with euphoria. Together with previous reports of 5-HT receptor involvement in striatal dopamine release, it is concluded that stimulation of both 5-HT2A and 5-HT1A receptors may be important for the modulation of striatal dopamine release in acute psychoses. The present results indirectly support the hypothesis of a serotonin-dopamine dysbalance in schizophrenia and suggest that psilocybin is a valuable tool in the analysis of serotonin-dopamine interactions in acute psychotic states.
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PMID:5-HT modulation of dopamine release in basal ganglia in psilocybin-induced psychosis in man--a PET study with [11C]raclopride. 1019 23

Recent interest in the role of serotonin (5-HT) in antipsychotic drug action is based mainly upon the fact that antipsychotic drugs such as clozapine, olanzapine, quetiapine, risperidone, sertindole, and ziprasidone are potent 5-HT2a receptor antagonists and relatively weaker dopamine D2 antagonists. These agents share in common low extrapyramidal side effects at clinically effective doses and possibly greater efficacy to reduce negative symptoms. As a group, they also have a superior effect on cognitive function and greater ability to treat mood symptoms in both patients with schizophrenia or affective disorders than typical antipsychotic drugs. The atypical antipsychotic agents vary in their affinities for other types of 5-HT as well as dopamine, muscarinic, adrenergic, and histaminic receptors, some, or all of which, may contribute to their differences in efficacy and side effect profile. Of the other 5-HT receptor which these drugs directly, the 5-HT1a and 5-HT2c receptors are the strongest candidates for contributing to their antipsychotic action and low EPS profile. The 5-HT6 and 5-HT7 receptors may also be of some importance. Stimulation of the 5-HT1a receptor appears to produce many of the same effects as antagonism of the 5-HT2a receptor while antagonism of the 5-HT2c receptor appears to diminish some of the actions of 5-HT2a receptor antagonism. Future antipsychotic drug development can include targeting multiple serotonin receptor subtypes.
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PMID:The role of serotonin in antipsychotic drug action. 1043 96

Considerable progress has been achieved over the past 15 years in uncovering the biological basis of major psychiatric disorders. Since psychopharmacological treatment is thought to act on the underlying biological basis of the disease, brain imaging techniques enable us to understand the mechanism of action of such compounds. Positron emission tomography (PET) as well as single photon emission computerized tomography (SPECT) are important tools used to determine patterns of brain dysfunction and to uncover the mechanism of action for antipsychotic compounds. These techniques allow us to determine striatal D2 receptor as well as cortical 5-HT2A receptor occupancy rates which are linked, at least partly, to clinical efficacy as well as side effect rates. In general it has been shown that atypical antipsychotics have a lower striatal D2 receptor occupancy rate than typical antipsychotics, parallelling the more favorable extrapyramidal side effects of atypical antipsychotics, and as a group effect they have a high 5-HT2A occupancy compared to low rates for typical agents. However, there is no association between striatal D2 receptor occupancy rates and antipsychotic efficacy but 5-HT2A occupancy rates are associated with favorable treatment for depressive symptoms within schizophrenia and improvement of cognitive function. The availability of ligands for measurement of extrastriatal D2 receptors or different 5-HT receptors (e.g. 5-HT1A) will further shed light on the pathophysiology of schizophrenia as well as possible psychopharmacological treatment perspectives.
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PMID:Dopamine- and serotonin-receptors in schizophrenia: results of imaging-studies and implications for pharmacotherapy in schizophrenia. 1065 13


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