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)

A series of 1-(pyrimidin-2-yl)piperazine derivatives were prepared and evaluated in receptor binding assays and in in vivo behavioral paradigms as potential atypical antipsychotic agents. Compound 16 (BMS 181100 (formerly BMY 14802)) emerged as the lead compound from within the series on the basis of its good activity and duration of action in the inhibition of both conditioned avoidance responding and apomorphine-induced stereotopy in the rat. Compound 16 not only failed to induce catalepsy in the rat but was quite effective in reversing the cataleptic effect of neuroleptic agents, thus indicating a low propensity for causing extrapyramidal side effects. In comparison to reference antipsychotic agents, 16 appeared to be less sedating and was relatively weaker in causing muscle incoordination. The compound was essentially inactive in binding to dopamine D2 receptors and its chronic administration to rats did not result in dopamine receptor supersensitivity. It exhibited modest to weak affinity for 5-HT1A and alpha 1 receptors but was found to be a fairly potent ligand for sigma binding sites (IC50 vs (+)-[3H]-3-PPP = 112 nM). Although the resolved enantiomers of racemic 16 did not show dramatic differences from racemate or from each other in most tests, the R(+) enantiomer was up to 11-fold more potent than its antipode in binding to sigma sites. Several studies have indicated that 16 may be a limbic-selective agent which may modulate dopaminergic activity by an indirect mechanism. The compound has been selected for clinical evaluation in the treatment of psychosis.
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PMID:Synthesis and biological characterization of alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazinebutanol and analogues as potential atypical antipsychotic agents. 136 78

Repeated cocaine intoxication can result in the development of behavioral sensitization in animals and psychosis in humans, phenomena that have been associated with alterations in dopamine (DA) function. Using electrophysiologic and autoradiographic techniques, modifications of central serotonin (5-hydroxytryptamine; 5-HT) systems were investigated in rats treated with a regimen of cocaine administration that produced behavioral sensitization. The inhibitory response of single 5-HT neurons in the dorsal raphe (DR) to (-)-cocaine, the 5-HT uptake inhibitor fluoxetine or the 5-HT1A agonist 8-hydroxy-2-[di-N-propylamino]tetralin (8-OHDPAT) was significantly enhanced in cocaine-treated rats. Furthermore, several brain areas that contain either cell bodies (DR) or terminals for 5-HT (medial and sulcal prefrontal cortex, frontal cortex) showed cocaine-induced elevations in [3H]imipramine-labeled 5-HT uptake sites, while [3H]-8-OHDPAT-labeled 5-HT1A receptors were decreased only in the central medial amygdala. These results suggest that modifications of autoregulatory mechanisms secondary to alterations of 5-HT uptake processes may contribute to the development of cocaine sensitization.
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PMID:Chronic cocaine enhances serotonin autoregulation and serotonin uptake binding. 138 62

An experimental method to test the hypothesis that antipsychotic (neuroleptic) agents influence gene expression in the mouse brain has been developed using the cis and trans stereoisomers of flupenthixol. The cis form of the drug is known to be clinically effective against some of the psychotic symptoms of schizophrenia as opposed to the trans isomer which is relatively inactive. A 2- to 3-fold increase in the abundance of dopamine 2 receptor mRNA was observed in the cis treated mice after a period of ten weeks. No change was observed in the expression of the dopamine D2 receptor gene upon treatment with the trans isomer. No change in the amount of 5-HT1A, 5-HT1C, alpha 1 adrenergic, beta 1 and beta 2 adrenergic neuroreceptor mRNA was found in the mice treated with active drug. The results show a long-term adaptation to D2 antagonism at the level of gene expression which occurs over a similar time scale to that of the clinical response to neuroleptic treatment of schizophrenia.
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PMID:Stereospecific effect of flupenthixol on neuroreceptor gene expression. 164 66

Ziprasidone (CP-88,059) is a combined 5-HT (serotonin) and dopamine receptor antagonist which exhibits potent effects in preclinical assays predictive of antipsychotic activity. Whereas the compound is a dopamine antagonist in vitro and in vivo, its most potent action is antagonism of 5-HT2A receptors, where its affinity is an order of magnitude greater than that observed for dopamine D2 sites. Laboratory and clinical findings have led to a hypothesis that antagonism of 5-HT2A receptors in the brain limits the undesirable motor side effects associated with dopamine receptor blockade and improves efficacy against the negative symptoms of schizophrenia. Ziprasidone possesses an in vitro 5-HT2A/dopamine D2 receptor affinity ratio higher than any clinically available antipsychotic agent. In vivo, ziprasidone antagonizes 5-HT2A receptor-induced head twitch with 6-fold higher potency than for blockade of d-amphetamine-induced hyperactivity, a measure of central dopamine D2 receptor antagonism. Ziprasidone also has high affinity for the 5-HT1A, 5-HT1D and 5-HT2C receptor subtypes, which may further enhance its therapeutic potential. The prediction of antipsychotic efficacy without severe motor side effects is supported by the relatively weak potency of ziprasidone to produce catalepsy in animals, contrasted with its potent antagonism of conditioned avoidance responding and dopamine agonist-induced locomotor activation and stereotypy. The compound is well tolerated in animals at doses producing effective dopamine antagonism in the brain. Ziprasidone should be a valuable addition to the treatment of psychotic disorders.
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PMID:Ziprasidone (CP-88,059): a new antipsychotic with combined dopamine and serotonin receptor antagonist activity. 756 37

Psychopharmacotherapy of the elderly must take into account the effects of age-related changes in the structure and function of the brain and various organs. In general, older people are more sensitive than young people to both the therapeutic and toxic effects of psychotropic medications, necessitating lower doses and longer dosage intervals. This holds true for the treatment of 5 major types of psychiatric illness (depression, bipolar disorder, anxiety, psychotic disorders and dementia). The tricyclic antidepressants, although efficacious, inexpensive, and backed by 30 years of experience, are less well tolerated by the elderly than are newer antidepressants such as the selective serotonin uptake inhibitors. Problems with monoamine oxidase (MAO) inhibitors, including orthostatic hypotension and restrictions in diet and other medication use, have been overcome by the advent of reversible selective inhibitors of MAO-A, but the efficacy of these in the elderly has yet to be proven in clinical trials. Lithium remains the mainstay for the treatment of bipolar disorder. However, careful dosing and monitoring of plasma lithium concentrations are required in the elderly due to changes in pharmacokinetics and pharmacodynamics which make older patients very sensitive to the toxic effects of this medication. Similarly, age-related changes in the pharmacokinetics and pharmacodynamics of the benzodiazepines, the most frequently prescribed medications for anxiety in the elderly, result in recommendations for lower doses and preferential use of those agents metabolised by conjugation (e.g. oxazepam). Buspirone, a partial serotonin 5-HT1A-agonist which is better tolerated than benzodiazepines in the elderly, may be used as an alternative. The elderly are extremely sensitive to extrapyramidal adverse effects which the typical antipsychotics (neuroleptics) exhibit to varying extents. The selection of a suitable agent for the treatment of a psychotic disorder should be based upon the adverse effect profile of the drug and the specific symptoms and situation of the patient. The newer atypical antipsychotics, clozapine and risperidone, have yet to be well-studied in the elderly. Dementia, exemplified by Alzheimer's disease, is almost exclusively an illness of the elderly. Only one medication, tacrine, has been approved for its treatment, based on extensive basic research and positive results of several clinical trials. Its long-term benefits have yet to be determined and it has several adverse effects, including a tendency to increase liver enzymes to the extent that the medication has to be discontinued.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Recent advances in geriatric psychopharmacology. 853 49

As noted previously, it is likely that the tendency to lash out verbally or physically at others is influenced by an interaction among multiple complex biologic factors. We need to investigate how these systems interact with each other to develop a more thorough understanding of the brain's influence over aggressive behavior. We are at a very early stage in our understanding of the neurobiology of aggression. There are no simple tools for studying the complex neurophysiology of the human brain. The studies cited in this article include techniques limited in their utility. As our technologies improve, discovering a more thorough picture of the brain's influence over aggressive behavior may be possible. For example, functional neuroimaging may help to localize abnormal neurotransmitter functioning in the brains of individuals with impulsive aggressive behavior. Our technologies are beginning to reveal the differential effects of subsystems of neurotransmitter regulation. Subtypes of serotonin receptors may differentially mediate impulsive aggressive behaviors. Animal studies suggest that 5-HT 1A receptor stimulation results in a decrease in aggressive behavior. As noted previously, aggressive personality-disordered patients show a blunted prolactin response to the 5-HT1A agonist buspirone. Antagonism of 5-HT 2 receptors appears to decrease aggression, and this effect may explain the ability of newer antipsychotic agents (which, unlike older antipsychotic medications, block 5-HT 2 receptors) to produce a dramatic reduction in aggression and agitation independent of effects on psychotic symptoms. Neglecting psychosocial factors in the causes of aggressive behavior would also be naive. Although environmental factors account for much of the predisposition to aggression, there have been few systematic studies to explore the relationship between life experiences and aggression. In addition, there have been no well-designed studies of the interaction between biology and an individual's environment in the genesis of aggressive behavior. There is some evidence of an association between childhood abuse and neglect and adult antisocial personality disorder, but this relationship might be merely an artifact of the genetic relationship between parental and offspring antisocial personality disorder. As we discussed in the introduction, one of the biggest hurdles in the study of the neurobiology of aggression is the lack of a consensus on definitions. "Intermittent Explosive Disorder" is the only category in DSM-IV that directly addresses individuals with problems with aggression, but the criteria are vague and only focus on a handful of the many patients who exhibit problems with aggressive behavior. It is our hope that investigators in this field can work together toward developing more precise and encompassing diagnostic criteria to study effectively both the neurobiology and treatment of these disorders.
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PMID:The neurobiology of impulsive aggression. 919 21

The ergoline derivative, LEK-8829 (9,10-didehydro-N-methyl-(2-propynyl)-6-methyl-8-aminomethylerg oline), has been proposed as a potential atypical antipsychotic drug with antagonistic actions at dopamine D2 and serotonin 5-HT2 and 5-HT1A receptors (Krisch et al., 1994, 1996). LEK-8829 also induces contralateral turning in rats with 6-hydroxydopamine-induced unilateral lesion of dopamine nigrostriatal neurons. Turning is blocked by SCH-23390 (R(+)-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzaze pine), a dopamine D1 receptor antagonist. It has been suggested that LEK-8829 could have beneficial effects in parkinsonian patients suffering from psychotic episodes induced as a side-effect of antiparkinsonian treatment with dopamine D2 receptor agonists. Therefore, we now investigated the interaction of LEK-8829 with the dopamine D2 receptor agonist bromocriptine (2-bromo-alpha-ergokryptine) in 6-hydroxydopamine-lesioned rats. Treatment with either LEK-8829 (3 mg kg(-1)) or bromocriptine (3 mg kg(-1)) induced a vigorous contralateral turning response. The cumulated number of turns induced by the treatment with both drugs combined was not significantly different from the cumulated number of turns induced by single-drug treatment. The pretreatment with SCH-23390 (1 mg kg(-1)) did not have a significant effect on the bromocriptine-induced turning but significantly decreased the turning observed after the combined LEK-8829/bromocriptine treatment. We conclude that in the 6-hydroxydopamine model, the turning behaviour mediated by the LEK-8829/bromocriptine combination may be the result of opposing activity of both drugs at dopamine D2 receptors with concomitant stimulation of dopamine D1 receptors by LEK-8829. Therefore, LEK-8829 may have a potential for the therapy of parkinsonism complicated by dopamine D2 receptor agonist drug-induced psychosis.
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PMID:Antiparkinsonian potential of interaction of LEK-8829 with bromocriptine. 967 Oct 92

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

The novel atypical antipsychotic ziprasidone has a pharmacologic profile notable for potent agonism of serotonin (5-HT)1A receptors, antagonism at 5-HT1D receptors, and reuptake inhibition of norepinephrine. 5-HT1A receptor agonism, in particular, suggests anxiolytic activity, and ziprasidone has shown preliminary efficacy in treating the symptoms of anxiety associated with psychotic disorders. In this study, the anxiolytic efficacy of ziprasidone was evaluated in nonpsychotic subjects who were anxious before undergoing minor dental surgery. We compared a single oral dose of 20 mg ziprasidone (N = 30) with that of 10 mg diazepam (N = 30) and placebo (N = 30) in a randomized, parallel-group, double-blind study. The peak anxiolytic effect of ziprasidone compared with that of placebo was similar to that of diazepam but had a later onset. At 3 hours postdose, the anxiolytic effect of ziprasidone was significantly greater than that of placebo (p < 0.05) and somewhat greater than that of diazepam. Diazepam showed a significantly greater anxiolytic effect than placebo at 1 hour (p < 0.05) but not at 3 hours. The sedative effect of ziprasidone was never greater than that of placebo, whereas that of diazepam was significantly greater than that of placebo 1 to 1.5 hours postdose. Ziprasidone was generally well tolerated. Only one patient reported treatment-related adverse events (nausea and vomiting) and, unlike diazepam, ziprasidone did not cause reductions in blood pressure. Dystonia, extrapyramidal syndrome, akathisia, and postural hypotension were not seen with ziprasidone. Thus, ziprasidone may possess anxiolytic effects in addition to its antipsychotic properties.
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PMID:The anxiolytic effect of the novel antipsychotic ziprasidone compared with diazepam in subjects anxious before dental surgery. 1191 Feb 68

It has been well-known that abuse of psychostimulants such as amphetamine and methamphetamine (MAP) induces behavioral sensitization (reverse tolerance) to MAP, resulting in psychotic effects such as hallucinatory-delusional state. Animals treated with MAP repeatedly also show the behavioral sensitization to MAP. This paper focuses on the pathogenesis and mechanism underlying sensitization to MAP after repeated treatment with MAP. MAP is known to release dopamine (DA), noradrenalin (NA) and serotonin (5-HT), and bind with the same sites on DA-, NA- and 5-HT-transporters as do these monoamines, thereby inhibiting re-uptake of these substances. As a result, these monoamines accumulate in the synaptic areas unnerved by the monoamine systems. An increase in the monoamines also occurs in the dendritic areas of DA, NA and 5-HT cells probably by a mechanism similar to those in the presynaptic terminals of monoamines. Releases and syntheses of DA, NA and 5-HT are inhibited by the monoamine per se via their autoreceptors such as D2, alpha 2 and 5-HT1A receptors, respectively. It is noteworthy that repeated MAP treatment results in the reduction of DA transporters, and such a decrease in transporters has been also found in MAP abusers by PET studies, suggesting a decrease in DA transporters is related with the appearance of reverse tolerance. Repeated MAP administration induces immediate early gene such as c-fos, c-jun and arc, and the increase in arc is inhibited by D1 and NMDA antagonists, suggesting an important role of such genes in inducing reverse tolerance. In electrophysiological studies using anesthetized rats treated with MAP repeatedly, hyposensitivities and hypersensitivities to DA and MAP have been found in nucleus accumbens receiving dopaminergic input from ventral tegmental area, 24-30 h and 5 days after the final administration of MAP, respectively, although the sensitivities recovered to the normal level 10 days after the treatment. The hypersensitivities were probably mediated via D1/D2 receptors. Thus, the hypersensitivities of nucleus accumbens neurons to DA and MAP are actually completed after repeated treatment of MAP. Therefore, it is of great interest to elucidate the molecular mechanism responsible for the DA receptor hypersensitivity.
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PMID:[Alteration of neuronal activities following repeated administration of stimulants]. 1191 3


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