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1.
Br J Pharmacol ; 172(17): 4331-41, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26040667

RESUMO

BACKGROUND AND PURPOSE: The opioid system plays a crucial role in several physiological processes in the CNS and in the periphery. It has also been shown that selective opioid receptor agonists exert potent inhibitory action on pruritus and pain. In this study we examined whether two analogues of Salvinorin A, PR-37 and PR-38, exhibit antipruritic properties in mice. EXPERIMENTAL APPROACH: To examine the antiscratch effect of PR-37 and PR-38 we used a mouse model of compound 48/80-induced pruritus. In order to elucidate the mechanism of action of tested compounds, specific antagonists of opioid and cannabinoid receptors were used. The effect of PR-37 on the CNS was assessed by measuring motor parameters and exploratory behaviours in mice. KEY RESULTS: PR-37 and PR-38, jnjected s.c., significantly reduced the number of compound 48/80-induced scratching behaviours in mice in a dose- and time-dependent manner. PR-38 was also active when orally administered. The antiscratch activity of PR-37 was blocked by the selective κ opioid receptor antagonist, nor-binaltorphimine, and that of PR-38 by the selective µ opioid receptor antagonist, ß-funaltrexamine. CONCLUSION AND IMPLICATIONS: In conclusion, a novel framework for the development of new antipruritic drugs derived from salvinorin A has been validated.


Assuntos
Diterpenos Clerodânicos/química , Diterpenos Clerodânicos/uso terapêutico , Prurido/induzido quimicamente , Prurido/prevenção & controle , p-Metoxi-N-metilfenetilamina/toxicidade , Analgésicos Opioides/uso terapêutico , Animais , Relação Dose-Resposta a Droga , Feminino , Masculino , Camundongos , Antagonistas de Entorpecentes/uso terapêutico
2.
Neuroscience ; 297: 22-37, 2015 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-25818050

RESUMO

Neural function within the medial prefrontal cortex (mPFC) regulates normal cognition, attention and impulse control, implicating neuroregulatory abnormalities within this region in mental dysfunction related to schizophrenia, depression and drug abuse. Both serotonin-2A (5-HT2A) and -2C (5-HT2C) receptors are known to be important in neuropsychiatric drug action and are distributed throughout the mPFC. However, their interactive role in serotonergic cortical regulation is poorly understood. While the main signal transduction mechanism for both receptors is stimulation of phosphoinositide production, they can have opposite effects downstream. 5-HT2A versus 5-HT2C receptor activation oppositely regulates behavior and can oppositely affect neurochemical release within the mPFC. These distinct receptor effects could be caused by their differential cellular distribution within the cortex and/or other areas. It is known that both receptors are located on GABAergic and pyramidal cells within the mPFC, but it is not clear whether they are expressed on the same or different cells. The present work employed immunofluorescence with confocal microscopy to examine this in layers V-VI of the prelimbic mPFC. The majority of GABA cells in the deep prelimbic mPFC expressed 5-HT2C receptor immunoreactivity. Furthermore, most cells expressing 5-HT2C receptor immunoreactivity notably co-expressed 5-HT2A receptors. However, 27% of 5-HT2C receptor immunoreactive cells were not GABAergic, indicating that a population of prelimbic pyramidal projection cells could express the 5-HT2C receptor. Indeed, some cells with 5-HT2C and 5-HT2A receptor co-labeling had a pyramidal shape and were expressed in the typical layered fashion of pyramidal cells. This indirectly demonstrates that 5-HT2C and 5-HT2A receptors may be commonly co-expressed on GABAergic cells within the deep layers of the prelimbic mPFC and perhaps co-localized on a small population of local pyramidal projection cells. Thus a complex interplay of cortical 5-HT2A and 5-HT2C receptor mechanisms exists, which if altered, could modulate efferent brain systems implicated in mental illness.


Assuntos
Córtex Pré-Frontal/metabolismo , Receptor 5-HT2A de Serotonina/metabolismo , Receptor 5-HT2C de Serotonina/metabolismo , Animais , Contagem de Células , Glutamato Descarboxilase/metabolismo , Masculino , Neurônios/metabolismo , Parvalbuminas/metabolismo , Córtex Pré-Frontal/citologia , Ratos , Ratos Sprague-Dawley
3.
Transl Psychiatry ; 1: e33, 2011 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-22832607

RESUMO

Caveolin-1 (Cav-1) is a scaffolding protein important for regulating receptor signaling cascades by partitioning signaling molecules into membrane microdomains. Disruption of the CAV1 gene has recently been identified as a rare structural variant associated with schizophrenia. Although Cav-1 knockout (KO) mice displayed no baseline behavioral disruptions, Cav-1 KO mice, similar to schizophrenic individuals, exhibited increased sensitivity to the psychotomimetic N-methyl-D-aspartate receptor antagonist phencyclidine (PCP). Thus, PCP disruption of prepulse inhibition (PPI) and PCP-induced mouse locomotor activity were both enhanced by genetic deletion of Cav-1. Interestingly, genetic deletion of Cav-1 rendered the atypical antipsychotics clozapine and olanzapine and the 5-HT(2A)-selective antagonist M100907 ineffective at normalizing PCP-induced disruption of PPI. We also discovered that genetic deletion of Cav-1 attenuated 5-HT(2A)-induced c-Fos and egr-1 expression in mouse frontal cortex and also reduced 5-HT(2A)-mediated Ca(2+) mobilization in primary cortical neuronal cultures. The behavioral effects of the 5-HT(2A) agonist (2,5-dimethoxy-4-iodoamphetamine) including head twitch responses and disruption of PPI were also attenuated by genetic deletion of Cav-1, indicating that Cav-1 is required for both inverse agonist (that is, atypical antipsychotic drug) and agonist actions at 5-HT(2A) receptors. This study demonstrates that disruption of the CAV1 gene--a rare structural variant associated with schizophrenia--is not only pro-psychotic but also attenuates atypical antipsychotic drug actions.


Assuntos
Antipsicóticos/farmacologia , Comportamento Animal/efeitos dos fármacos , Caveolina 1/genética , Esquizofrenia/etiologia , Esquizofrenia/genética , Animais , Antipsicóticos/administração & dosagem , Comportamento Animal/fisiologia , Caveolina 1/deficiência , Caveolina 1/fisiologia , Modelos Animais de Doenças , Camundongos , Camundongos Knockout , Receptor 5-HT2A de Serotonina/genética , Esquizofrenia/fisiopatologia
4.
Mol Psychiatry ; 12(10): 904-22, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17667958

RESUMO

While the current antipsychotic medications have profoundly impacted the treatment of schizophrenia over the past 50 years, the newer atypical antipsychotics have not fulfilled initial expectations, and enormous challenges remain in long-term treatment of this debilitating disease. In particular, improved treatment of the negative symptoms and cognitive dysfunction in schizophrenia which greatly impact overall morbidity is needed. In this review we will briefly discuss the current pipeline of drugs for schizophrenia, outlining many of the strategies and targets currently under investigation for the development of new schizophrenia drugs. Many of these compounds have great potential as augmenting agents in the treatment of negative symptoms and cognition. In addition, we will highlight the importance of developing new paradigms for drug discovery in schizophrenia and call for an increased role of academic scientists in discovering and validating novel drug targets. Indeed, recent breakthroughs in genetic studies of schizophrenia are allowing for the development of hypothesis-driven approaches for discovering possible disease-modifying drugs for schizophrenia. Thus, this is an exciting and pivotal time for the development of truly novel approaches to drug development and treatment of complex disorders like schizophrenia.


Assuntos
Antipsicóticos/uso terapêutico , Desenho de Fármacos , Esquizofrenia/tratamento farmacológico , Animais , Humanos , Modelos Biológicos
5.
Pharmacogenomics J ; 6(1): 42-51, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-16314884

RESUMO

The 5-HT(2A)-serotonin receptor is a major molecular target for most atypical antipsychotic drugs as well as most hallucinogens, which can exacerbate psychotic symptoms. In this study, we examined whether random sequence variations in the gene (single nucleotide polymorphisms, SNPs) encoding the 5-HT(2A)-serotonin receptor could explain inter-individual variability in atypical antipsychotic and agonist drug response. We examined the in vitro pharmacology of four non-synonymous SNPs, which give rise to T25N, I197V, A447V, and H452Y variant 5-HT(2A)-serotonin receptors. Our data indicate that these non-synonymous SNPs exert statistically significant, although modest, effects on the affinity and functional effects of several currently approved atypical antipsychotics (aripiprazole, clozapine, olanzapine, quetiapine, risperidone, and ziprasidone). Also, the 5-HT(2A) receptor SNPs slightly altered the potency and relative efficacy of a small number of selected agonists (2,5-dimethoxy-4-iodoamphetamine, tryptamine, 5-hydroxytryptamine, m-chlorophenylpiperazine, and 5-methoxy-N, N-dimethyltryptamine). In all, our results show that the in vitro pharmacological effects of the SNPs are drug specific.


Assuntos
Antipsicóticos/farmacologia , Polimorfismo de Nucleotídeo Único , Receptor 5-HT2A de Serotonina/genética , Agonistas do Receptor de Serotonina/farmacologia , Ligação Competitiva , Linhagem Celular , Clonagem Molecular , Relação Dose-Resposta a Droga , Humanos , Ligantes , Ensaio Radioligante , Receptor 5-HT2A de Serotonina/biossíntese , Agonistas do Receptor 5-HT2 de Serotonina , Transfecção
6.
Bioorg Med Chem Lett ; 15(23): 5298-302, 2005 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-16183286

RESUMO

An examination of several amine-substituted analogs of N(1)-benzenesulfonylindoles reveals that although they bind at human 5-HT(6) serotonin receptors with high affinity, they are likely to bind in a dissimilar manner.


Assuntos
Indóis/química , Receptores de Serotonina/química , Aminas/química , Humanos , Ligação Proteica
7.
J Neurochem ; 91(5): 1057-66, 2004 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-15569249

RESUMO

Disruptions of glutamatergic and noradrenergic signaling have been postulated to occur in depressive disorders. Glutamate provides excitatory input to the noradrenergic locus coeruleus (LC). In this study, the location of immunoreactivity against neuronal nitric oxide synthase (nNOS), an intracellular mediator of glutamate receptor activation, was examined in the normal human LC, and potential changes in nNOS immunoreactivity that might occur in major depression were evaluated. Tissue containing LC, and a non-limbic, LC projection area (cerebellum) was obtained from 11 to 12 matched pairs of subjects with major depression and control subjects lacking major psychiatric diagnoses. In the LC region, nNOS immunoreactivity was found in large neuromelanin-containing neurons, small neurons lacking neuromelanin, and glial cells. Levels of nNOS immunoreactivity were significantly lower in the LC (- 44%, p < 0.05), but not in the cerebellum, when comparing depressed with control subjects. nNOS levels were positively correlated with brain pH values in depressed, but not control, subjects in both brain regions. Low levels of nNOS in the LC may reflect altered excitatory input to this nucleus in major depression. However, pH appears to effect preservation of nNOS immunoreactivity in subjects with depression. This factor may contribute, in part, to low levels of nNOS in depression.


Assuntos
Transtorno Depressivo Maior/enzimologia , Locus Cerúleo/enzimologia , Óxido Nítrico Sintase/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Western Blotting/métodos , Estudos de Casos e Controles , Cerebelo/enzimologia , Feminino , Humanos , Concentração de Íons de Hidrogênio , Imuno-Histoquímica/métodos , Masculino , Pessoa de Meia-Idade , Óxido Nítrico Sintase Tipo I , Mudanças Depois da Morte , Fatores de Tempo
8.
Neuroscience ; 122(4): 907-20, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-14643760

RESUMO

The 5-HT(2A) serotonin receptor represents an important molecular target for atypical antipsychotic drugs and for most hallucinogens. In the mammalian cerebral cortex, 5-HT(2A) receptors are enriched in pyramidal neurons, within which 5-HT(2A) receptors are preferentially sorted to the apical dendrites. In primary cortical cultures, 5-HT(2A) receptors are sorted to dendrites and not found in the axons of pyramidal neurons. We identified a sorting motif that mediates the preferential targeting of 5-HT(2A) receptors to the dendrites of cortical pyramidal neurons in vitro. We constructed green fluorescent protein-tagged 5-HT(2A) receptors wherein potential sorting motifs were disrupted, and subsequently employed either the Semliki Forest virus or calcium phosphate for the transient expression of recombinant 5-HT(2A) receptors in cultured cortical pyramidal neurons. Using dual-labeling immunofluorescent confocal microscopy, we quantified the axonal and dendritic sorting patterns of endogenous and recombinant 5-HT(2A) receptors. We discovered that disruption of the PDZ-binding domain of the 5-HT(2A) receptor greatly attenuates the dendritic targeting of 5-HT(2A) receptors without inappropriately sorting 5-HT(2A) receptors to axons. The PDZ-binding domain is therefore a necessary signal for the preferential targeting of the 5-HT(2A) receptor to the dendritic compartment of cultured cortical pyramidal neurons, the first such role ascribed to this protein-protein interaction motif of any G protein-coupled receptor.


Assuntos
Córtex Cerebral/metabolismo , Dendritos/metabolismo , Células Piramidais/metabolismo , Receptor 5-HT2A de Serotonina/metabolismo , Animais , Sítios de Ligação/fisiologia , Linhagem Celular , Córtex Cerebral/fisiologia , Cricetinae , Humanos , Proteínas do Tecido Nervoso/metabolismo , Ligação Proteica/fisiologia , Estrutura Terciária de Proteína/fisiologia , Células Piramidais/fisiologia , Ratos , Ratos Sprague-Dawley , Receptor 5-HT2A de Serotonina/genética , Agonistas do Receptor 5-HT2 de Serotonina , Agonistas do Receptor de Serotonina/farmacologia , Transfecção
9.
Ann N Y Acad Sci ; 1009: 419-26, 2003 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-15028621

RESUMO

The human I(1)-imidazoline receptor candidate gene, iras, has previously been cloned and mapped to locus 3p21.1-9 (also known as Nischarin; accession No. AC006208). By comparison to a database of expressed sequence tags (ESTs), three alternatively spliced transcripts have been deduced. A map of 21 exons was constructed for the medium-length transcript (IRAS-M) containing 5,232 base pairs (bp) and encoding 1,504 amino acids (aas). Introns 13B and 13C are inserted into the two alternative transcripts, forming IRAS-S and IRAS-L mRNA (short and long isoforms). Northern blots confirmed the existence of these mRNA isoforms. In most brain regions the order of mRNA abundance was IRAS-M > IRAS-L > IRAS-S mRNA. Although aas 1 through 510 are theoretically identical, truncated proteins could be derived from IRAS-S (2,678 bp transcript yields 515 aas) and IRAS-L (9,457 bp transcript yields 583 aas). Because exon-16 of the iras gene has been proposed to encode the functional domains of imidazoline and a-5 integrin binding, only IRAS-M is expected to possess I(1) receptor properties. Subtype-selective cDNA expression constructs were therefore generated and used to transfect CHO cells. High-affinity I(1) binding was endowed by IRAS-M and IRAS-L, but not by IRAS-S transfection.


Assuntos
Processamento Alternativo , Proteínas de Transporte/genética , Peptídeos e Proteínas de Sinalização Intracelular , Receptores de Droga/genética , Proteínas de Transporte/metabolismo , Éxons , Humanos , Receptores de Imidazolinas , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , RNA Mensageiro/metabolismo , Ensaio Radioligante , Receptores de Droga/metabolismo
10.
Neuroscience ; 113(1): 23-35, 2002.
Artigo em Inglês | MEDLINE | ID: mdl-12123681

RESUMO

As visualized by light and electron microscopic immunocytochemistry, the distribution of the neuronal serotonin-2A (5-HT(2A)) receptor is mainly intracellular throughout adult rat brain. This localization is particularly striking in the pyramidal cells of cerebral cortex, the dendrites of which are intensely immunoreactive, but without any labeling of their spines. In view of recent yeast two-hybrid and biochemical results suggesting an association of 5-HT(2A) receptors with the cytoskeletal microtubule-associated protein MAP1A, the respective subcellular distributions of the receptors and of MAP1A were compared by quantitative electron microscopic immunocytochemistry in dendrites of adult rat frontoparietal cortex. Counts of silver-intensified immunogold particles revealed a higher density of 5-HT(2A) receptors in smaller rather than larger dendrites, and an apportionment between pre-defined compartments representing the plasma membrane and the cytoplasm that was proportional to the relative surface area of these compartments. MAP1A immunoreactivity also predominated in smaller versus larger dendrites, but with a slightly lower proportion of labeling in the plasma membrane versus cytoplasmic compartment. The co-localization of 5-HT(2A) receptors and MAP1A protein in the same dendrites could be demonstrated in double immunolabeling experiments. These results confirmed the predominantly somato-dendritic, intracellular localization of 5-HT(2A) receptors in cerebral cortex, showed their higher concentration in distal as opposed to proximal dendrites, and suggested their potential association to the cytoskeleton in cortical neurons in vivo. Such a distribution of 5-HT(2A) receptors reinforces our earlier hypothesis that 5-HT(2A) receptors participate in intraneuronal signaling processes involving the cytoskeleton, and raises the possibility that their activation could be dependent upon that of another co-localized, plasma membrane-bound, 5-HT receptor.


Assuntos
Dendritos/química , Proteínas Associadas aos Microtúbulos/análise , Neocórtex/química , Receptores de Serotonina/análise , Animais , Anticorpos Monoclonais/análise , Imuno-Histoquímica , Masculino , Microscopia Eletrônica , Proteínas Associadas aos Microtúbulos/imunologia , Ratos , Ratos Sprague-Dawley , Receptor 5-HT2A de Serotonina , Receptores de Serotonina/imunologia , Distribuição Tecidual
11.
Neuroscience ; 111(1): 163-76, 2002.
Artigo em Inglês | MEDLINE | ID: mdl-11955720

RESUMO

Considerable evidence suggests that a dysfunction of the dopamine and serotonin (5-hydroxytryptamine or 5-HT) neurotransmitter systems contributes to a diverse range of pathological conditions including schizophrenia, depression and drug abuse. Recent electrophysiological and behavioral studies suggest that 5-HT modulates dopaminergic neurons in the ventral tegmental area via activation of 5-HT(2A) receptors. It is currently unknown if 5-HT(2A) receptors mediate their actions on dopaminergic neurons in the ventral tegmental area via direct or indirect mechanisms. This study investigated whether 5-HT(2A) receptors were localized on dopamine cells within the A10 dopamine subnuclei of the rat, including the ventral tegmental area. We discovered that 5-HT(2A) receptor-like immunoreactivity colocalized with tyrosine hydroxylase, a marker for dopamine neurons, throughout the A10 dopamine cell population. Colocalization was most prominent in rostral and mid A10 regions, including the paranigral, parabrachial, and interfascicular subnuclei. Though more rare, non-dopaminergic neurons also expressed 5-HT(2A) receptor immunoreactivity in the ventral tegmental area. Additionally, although a dense population of 5-HT(2A) immunoreactive cells was observed in the rostral dorsal raphe nucleus, rarely were these cells immunoreactive for tyrosine hydroxylase. The linear raphe A10 dopamine subdivisions also displayed a low degree of 5-HT(2A) receptor and tyrosine hydroxylase colocalization. These findings provide an anatomical basis for the physiological modulation of dopamine neurons in the rostral ventral tegmental area either directly, by 5-HT(2A) receptors localized on dopamine cells, or indirectly, through a non-dopaminergic mechanism. Interestingly, 5-HT(2A) receptors were expressed on dopamine neurons in several A10 subnuclei that project to mesolimbic forebrain regions implicated in drug addiction, and recent evidence indicates that ventral tegmental area 5-HT(2A) receptor activation may modulate reward-related behavior in rodents. 5-HT(2A) receptors were also expressed on dopamine cells in A10 subnuclei that project to forebrain areas that have been implicated in schizophrenia, and atypical antipsychotic drugs have high affinities for 5-HT(2A) receptors. Thus, findings in this study could have important implications for understanding 5-HT and dopamine circuitry dysfunction in schizophrenia.


Assuntos
Dopamina/metabolismo , Mesencéfalo/metabolismo , Neurônios/metabolismo , Receptores de Serotonina/metabolismo , Animais , Anticorpos Monoclonais , Membrana Celular/metabolismo , Membranas Intracelulares/metabolismo , Masculino , Mesencéfalo/citologia , Ratos , Ratos Sprague-Dawley , Receptor 5-HT2A de Serotonina , Distribuição Tecidual , Tirosina 3-Mono-Oxigenase/metabolismo
12.
J Neurosci ; 21(24): 9856-66, 2001 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-11739593

RESUMO

We examined the in vivo effects of the hallucinogen 4-iodo-2,5-dimethoxyamphetamine (DOI). DOI suppressed the firing rate of 7 of 12 dorsal raphe (DR) serotonergic (5-HT) neurons and partially inhibited the rest (ED(50) = 20 microg/kg, i.v.), an effect reversed by M100907 (5-HT(2A) antagonist) and picrotoxinin (GABA(A) antagonist). DOI (1 mg/kg, s.c.) reduced the 5-HT release in medial prefrontal cortex (mPFC) to 33 +/- 8% of baseline, an effect also antagonized by M100907. However, the local application of DOI in the mPFC increased 5-HT release (164 +/- 6% at 100 microm), an effect antagonized by tetrodotoxin, M100907, and BAY x 3702 (5-HT(1A) agonist) but not by SB 242084 (5-HT(2C) antagonist). The 5-HT increase was also reversed by NBQX (AMPA-KA antagonist) and 1S,3S-ACPD (mGluR 2/3 agonist) but not by MK-801 (NMDA antagonist). AMPA mimicked the 5-HT elevation produced by DOI. Likewise, the electrical-chemical stimulation of thalamocortical afferents and the local inhibition of glutamate uptake increased the 5-HT release through AMPA receptors. DOI application in mPFC increased the firing rate of a subgroup of 5-HT neurons (5 of 10), indicating an enhanced output of pyramidal neurons. Dual-label fluorescence confocal microscopic studies demonstrated colocalization of 5-HT(1A) and 5-HT(2A) receptors on individual cortical pyramidal neurons. Thus, DOI reduces the activity of ascending 5-HT neurons through a DR-based action and enhances serotonergic and glutamatergic transmission in mPFC through 5-HT(2A) and AMPA receptors. Because pyramidal neurons coexpress 5-HT(1A) and 5-HT(2A) receptors, DOI disrupts the balance between excitatory and inhibitory inputs and leads to an increased activity that may mediate its hallucinogenic action.


Assuntos
Ácido Glutâmico/metabolismo , Picrotoxina/análogos & derivados , Córtex Pré-Frontal/metabolismo , Receptores de Serotonina/metabolismo , Serotonina/metabolismo , Anfetaminas/farmacologia , Animais , Relação Dose-Resposta a Droga , Agonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Feminino , Fluorbenzenos/farmacologia , Antagonistas GABAérgicos/farmacologia , Alucinógenos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Microdiálise , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Picrotoxina/farmacologia , Piperidinas/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Núcleos da Rafe/efeitos dos fármacos , Núcleos da Rafe/metabolismo , Ratos , Ratos Wistar , Receptor 5-HT2A de Serotonina , Receptores de Serotonina/efeitos dos fármacos , Receptores 5-HT1 de Serotonina , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , Sesterterpenos , Tetrodotoxina/farmacologia , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/metabolismo
13.
Brain Res Bull ; 56(5): 441-51, 2001 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-11750789

RESUMO

5-Hydroxytryptamine(2A) (serotonin(2A), 5-HT(2A)) receptors are important for many physiologic processes including platelet aggregation, smooth muscle contraction, and the modulation of mood and perception. A large number of pharmaceutical agents mediate their actions, at least in part, by modulating the number and/or activity of 5-HT(2A) receptors. Drugs with action at 5-HT(2A) receptors are used in the treatment of many disorders, including schizophrenia, depression, and anxiety disorders. This review summarizes over two decades of research on the regulation of 5-HT(2A) receptors and provides a comprehensive review of numerous in vivo studies describing the paradoxical phenomenon of 5-HT(2A) receptor down-regulation by chronic treatment with antidepressants and antipsychotics. In addition, studies reporting antagonist-induced internalization of 5-HT(2A) receptors and other G protein-coupled receptors will be highlighted as a possible mechanism to explain this paradoxical down-regulation. Finally, a review of the cellular and molecular mechanisms that may be responsible for agonist-mediated desensitization and internalization of 5-HT(2A) receptors will be presented.


Assuntos
Sistema Nervoso Central/metabolismo , Regulação para Baixo/efeitos dos fármacos , Proteínas de Ligação ao GTP/efeitos dos fármacos , Transporte Proteico/efeitos dos fármacos , Receptores de Serotonina/metabolismo , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , Serotonina/metabolismo , Animais , Regulação para Baixo/fisiologia , Proteínas de Ligação ao GTP/metabolismo , Humanos , Transporte Proteico/fisiologia , Receptor 5-HT2A de Serotonina , Receptores de Serotonina/efeitos dos fármacos
14.
Mol Pharmacol ; 60(5): 1020-30, 2001 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-11641430

RESUMO

The effect of endocytosis inhibitors on 5-hydroxytryptamine(2A) (5-HT(2A)) receptor desensitization and resensitization was examined in transiently transfected human embryonic kidney (HEK) 293 cells and in C6 glioma cells that endogenously express 5-HT(2A) receptors. In HEK-293 cells, 5-HT(2A) receptor desensitization was unaffected by cotransfection with a dominant-negative mutant of dynamin (DynK44A), a truncation mutant of arrestin-2 [Arr2(319-418)], or by two well-characterized chemical inhibitors of endocytosis: concanavalin A (conA) and phenylarsine oxide (PAO). In contrast, beta 2-adrenergic receptor desensitization was significantly potentiated by each of these treatments in HEK-293 cells. In C6 glioma cells, however, DynK44A, Arr2(319-418), conA, and PAO each resulted in the potentiation of 5-HT(2A) and beta-adrenergic receptor desensitization. The cell-type-specific effect of Arr2(319-418) on 5-HT(2A) receptor desensitization was not related to the level of GRK2 or GRK5 expression. Interestingly, although beta 2-adrenergic receptor resensitization was potently blocked by cotransfection with DynK44A, 5-HT(2A) receptor resensitization was enhanced, suggesting the existence of a novel cell-surface mechanism for 5-HT(2A) receptor resensitization in HEK-293 cells. In addition, Arr2(319-418) had no effect on 5-HT(2A) receptor resensitization in HEK-293 cells, although it attenuated the resensitization of the beta 2-adrenergic receptor. However, in C6 glioma cells, both DynK44A and Arr2(319-418) significantly reduced 5-HT(2A) receptor resensitization. Taken together, these results provide the first convincing evidence of cell-type-specific roles for endocytosis inhibitors in regulating GPCR activity. Additionally, these results imply that novel GRK and arrestin-independent mechanisms of 5-HT(2A) receptor desensitization and resensitization exist in HEK-293 cells.


Assuntos
Arrestina/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , GTP Fosfo-Hidrolases/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Receptores de Serotonina/metabolismo , Animais , Arrestinas/farmacologia , Células Cultivadas , Dinaminas , Endocitose/efeitos dos fármacos , Quinase 5 de Receptor Acoplado a Proteína G , Glioma/metabolismo , Humanos , Rim/citologia , Rim/embriologia , Fosfoproteínas/farmacologia , Ratos , Receptor 5-HT2A de Serotonina , Receptores Adrenérgicos beta 2/efeitos dos fármacos , Receptores Adrenérgicos beta 2/metabolismo , Receptores de Serotonina/efeitos dos fármacos , Células Tumorais Cultivadas , Quinases de Receptores Adrenérgicos beta
15.
J Pharmacol Exp Ther ; 299(1): 83-9, 2001 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-11561066

RESUMO

Atypical antipsychotic drugs, which are distinguished from typical antipsychotic drugs by a lower incidence of extra-pyramidal side effects and less propensity to elevate serum prolactin levels (e.g., clozapine, olanzapine, risperidone, quetiapine, ziprasidone), have become the most widely used treatments for schizophrenia, although their precise mechanism of action remains controversial. It has been suggested that this group of atypical antipsychotic drugs is characterized by preferentially high affinities for 5-hydroxytryptamine (5-HT)2A serotonin receptors and relatively low affinities for D2-dopamine receptors. It has recently been proposed that these atypical antipsychotic drugs may also be distinguished from typical antipsychotic drugs (e.g., haloperidol, fluphenazine, chlorpromazine, and so on) by inverse agonist actions at the 5-HT2C-INI RNA edited isoform of the human 5-HT2C receptor transiently expressed in COS-7 cells. We have examined the relationship among 5-HT2C inverse agonist potency, efficacy, and atypical antipsychotic drug status in HEK-293 cells of a large number of typical and atypical antipsychotic drugs using human embryonic kidney (HEK)-293 cells stably transfected with the h5-HT2C-INI receptor. Inverse agonist actions at h5-HT2C-INI receptors were measured for both typical and atypical antipsychotic drugs. Thus, some typical antipsychotic drugs (chlorpromazine, mesoridazine, fluphenazine, and loxapine) were efficient inverse agonists, whereas several clinically effective atypical antipsychotic drugs (remoxapride, quetiapine, sulpiride, melperone, amperozide) were not. Additionally, several drugs without significant antipsychotic actions (M100907, ketanserin, mianserin, ritanserin, and amitriptyline) were potent inverse agonists at the 5-HT2C-INI isoform expressed in HEK-293 cells. Taken together, these results demonstrate that both typical and atypical antipsychotic drugs may exhibit inverse agonist effects at the 5-HT2C-INI isoform of the human 5-HT2C receptor and that no relationship exists between inverse agonist actions and atypicality.


Assuntos
Antipsicóticos/farmacologia , Receptores de Serotonina/efeitos dos fármacos , Agonistas do Receptor de Serotonina/farmacologia , Células 3T3 , Animais , Células COS , Humanos , Hidrólise , Camundongos , Fosfatidilinositóis/química , Edição de RNA/efeitos dos fármacos , Receptor 5-HT2C de Serotonina , Transfecção
16.
Psychopharmacology (Berl) ; 157(1): 111-4, 2001 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-11512051

RESUMO

RATIONALE: s-Fluorocarazolol [(S)-FCZ] is the major positron emission tomography (PET) ligand currently used to visualize central beta-adrenergic receptors in vivo, although its pharmacology is incompletely known. OBJECTIVE: Our objective was to comprehensively characterize the in vitro pharmacology of (S)- and (R)-FCZ to determine its suitability for study of central and peripheral beta-adrenergic receptors. METHODS: We characterized the in vitro pharmacology of (S)-FCZ at 42 biogenic amine receptors and transporters in vitro using the resources of the National Institute of Mental Health Psychoactive Drug Screening Program. RESULTS: As expected (R)- and (S)-FCZ had high affinities for beta-adrenergic receptors (Ki values=0.08-0.45 nM) and negligible affinities (Ki values>100 nM) for nearly all other tested receptors and transporters with the exception of the h5-HT1A receptor for which (S)-FCZ had high affinity (Ki=34 nM). Interestingly, (R)-FCZ had low affinity for the h5-HT1A receptor (Ki=342 nM). CONCLUSION: The high affinity of (S)-FCZ for the h5-HT1A receptor is not likely to interfere with studies of peripheral beta-adrenergic receptors, since 5-HT1A receptors are expressed at very low levels outside the central nervous system. Indeed, computer simulations predict that even at low ligand concentrations, 5-HT1A binding in brain regions like hippocampus are likely to be substantial. Thus, (S)-FCZ may not be a suitable PET ligand for studies of central nervous system beta-adrenergic receptors unless the contribution by 5-HT1A sites can be shown to be negligible.


Assuntos
Antagonistas Adrenérgicos beta/metabolismo , Carbazóis/metabolismo , Propanolaminas/metabolismo , Receptores Adrenérgicos beta/metabolismo , Receptores de Serotonina/metabolismo , Tomografia Computadorizada de Emissão , Humanos , Ligantes , Receptores 5-HT1 de Serotonina , Proteínas Recombinantes/metabolismo , Estereoisomerismo
17.
Bioorg Med Chem Lett ; 11(8): 955-9, 2001 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-11327599

RESUMO

In view of its role in tumor promotion and signal transduction, protein kinase C (PKC) has proven to be an exciting target for cancer therapy. With the aid of molecular modeling, we rationally designed and stereoselectively synthesized a new class of rigidified pyrrolidone-based PKC activators. Pyrrolidone 15 was found to exhibit reasonable affinity for PKCdelta, with lower affinity for the other isozymes tested. Pyrrolidone 2 causes the dose-dependent induction of apoptosis in LNCaP prostate cancer cells. This apoptotic effect could be markedly potentiated by the use of LNCaP cells overexpressing the PKCalpha or delta isozymes.


Assuntos
Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Ativadores de Enzimas/síntese química , Isoenzimas/efeitos dos fármacos , Neoplasias da Próstata/fisiopatologia , Proteína Quinase C/efeitos dos fármacos , Pirrolidinonas/síntese química , Antineoplásicos/farmacologia , Apoptose/fisiologia , Relação Dose-Resposta a Droga , Desenho de Fármacos , Ativadores de Enzimas/farmacologia , Humanos , Isoenzimas/genética , Isoenzimas/metabolismo , Masculino , Próstata/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Proteína Quinase C/genética , Proteína Quinase C/metabolismo , Proteína Quinase C-alfa , Proteína Quinase C-delta , Pirrolidinonas/farmacologia , Estereoisomerismo , Células Tumorais Cultivadas
18.
Bioorg Med Chem Lett ; 11(11): 1375-7, 2001 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-11378358

RESUMO

A series of dopamine D(4) antagonists was synthesized and evaluated as potential candidates for development as positron emission tomography (PET) radioligands. All new compounds display high affinity and selectivity for the D(4) receptors and compounds 5b, 5d, and 5e were identified as candidates for radioligand development.


Assuntos
Antagonistas de Dopamina/síntese química , Antagonistas dos Receptores de Dopamina D2 , Sítios de Ligação , Antagonistas de Dopamina/química , Antagonistas de Dopamina/farmacologia , Piridinas/síntese química , Piridinas/química , Piridinas/farmacologia , Pirróis/síntese química , Pirróis/química , Pirróis/farmacologia , Ensaio Radioligante , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D4 , Receptores de Serotonina/efeitos dos fármacos , Receptores de Serotonina/metabolismo , Tomografia Computadorizada de Emissão/métodos
19.
Bioorg Med Chem Lett ; 11(5): 655-8, 2001 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-11266163

RESUMO

Comparison of the serotonin 5-HT2A receptor affinities of chain lengthened and N-alkylated analogues of the novel ligand 9-aminomethyl-9,10-dihydroanthracene (AMDA) and a structurally similar prototypical tricyclic amine imipramine suggests that the two agents bind to the receptor in different fashions. The demonstration that AMDA is highly selective for serotonin receptors (5-HT2A, K = 20nM; 5-HT2C, Ki=43nM) versus the dopamine D2 receptor (Ki>10,000nM), as well as the serotonin and norepinephrine transporters (Ki>10,000nM) further suggests that AMDA and the nonselective ligand imipramine interact with these target macromolecules in different ways.


Assuntos
Antracenos/química , Receptores de Serotonina/metabolismo , Antagonistas da Serotonina/química , Animais , Antracenos/metabolismo , Linhagem Celular , Ligantes , Conformação Molecular , Estrutura Molecular , Ensaio Radioligante , Receptor 5-HT2A de Serotonina , Antagonistas da Serotonina/metabolismo
20.
Bioorg Med Chem Lett ; 11(4): 563-6, 2001 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-11229772

RESUMO

Comparison of the serotonin 5-HT2A receptor affinities of a parallel series of structural analogues of the novel ligand 9-aminomethyl-9,10-dihydroanthracene (AMDA) and a structurally similar prototypical tricyclic amine cyproheptadine suggests that the two agents bind to the receptor in different fashions. Examination of ligand-receptor model complexes supports the experimental data and suggests a potential origin for the differences in binding modes.


Assuntos
Antracenos/metabolismo , Ciproeptadina/metabolismo , Receptores de Serotonina/metabolismo , Antagonistas da Serotonina/metabolismo , Células 3T3 , Animais , Camundongos , Modelos Moleculares , Conformação Molecular , Receptor 5-HT2A de Serotonina , Relação Estrutura-Atividade
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