Dopamine D2 Receptor Blockade by Haloperidol 3H-Raclopride Reveals Much Higher Occupancy than EEDQ

Kapur, Shitij; Barsoum, Susan C; Seeman, Philip

doi:10.1016/s0893-133x(00)00139-1

Cited by 22 publications

(11 citation statements)

References 9 publications

(19 reference statements)

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“…Further evidence for ABT-127 D3 receptor specificity at low doses was found in experiments 2 and 3. Doses of 10 mg/kg or above were necessary for significant inhibition of (Kapur et al, 2000;McCormick et al, 2009) and -propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b] [1,4]oxazin-9-ol that was recently used in humans as a D3-preferring tool (Boileau et al, 2009;Graff-Guerrero et al, 2009) are not selective enough; therefore, additional methods/approaches are necessary. One such approach is to evaluate radioligand binding in a brain area that is enriched in one receptor subtype and not the other.…”

Section: Discussionmentioning

confidence: 99%

Double Dissociation of the Effects of Haloperidol and the Dopamine D3 Receptor Antagonist ABT-127 on Acquisition vs. Expression of Cocaine-Conditioned Activity in Rats

Banasikowski

Bespalov²,

Drescher³

et al. 2010

J Pharmacol Exp Ther

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Dopamine receptors play a critical role in reward-related learning, but receptor subtypes may be differentially involved. D2-preferring receptor antagonists, e.g., haloperidol, attenuate acquisition of cocaine-conditioned motor activity at doses that fail to block expression. We compared haloperidol [4-[4-(4--2-hydroxy-6-methoxybenzamide binding, no effects on ␥-butyrolactone-induced striatal L-3,4-dihydroxyphenylalanine; haloperidol accumulation; no attenuation of apomorphine-induced stereotypy]. We hypothesized that haloperidol and ABT-127 will produce a doubly dissociable effect on acquisition versus expression of cocaine-conditioned activity. Rats received three 1-h habituation sessions to activity monitors followed by three 1-h cocaine (10 mg/kg) conditioning sessions. The expression phase (no cocaine injections) took place 48 h later. Haloperidol (50 /kg) given during the conditioning phase blocked the acquisition of conditioned activity but failed to block the expression of conditioning when given on the test day. In contrast, ABT-127 (1.0 mg/kg), when given during conditioning, failed to block the acquisition of conditioned activity but blocked the expression of conditioning when administered on the test day. Results suggest that D2 receptors are more critically involved in acquisition than initial expression and D3 receptors are more critically involved in expression than acquisition of conditioned activity based on cocaine.

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Section: Discussionmentioning

confidence: 99%

Double Dissociation of the Effects of Haloperidol and the Dopamine D3 Receptor Antagonist ABT-127 on Acquisition vs. Expression of Cocaine-Conditioned Activity in Rats

Banasikowski

Bespalov²,

Drescher³

et al. 2010

J Pharmacol Exp Ther

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“…Turnovers by Treatment with Haloperidol-The typical antipsychotic drug haloperidol, which is a dopamine D2 receptor antagonist (43), was tested for its ability to attenuate the hyperactive behavior of Fut8 Ϫ/Ϫ mice. Haloperidol (0.1 mg/kg) effectively reduced the hyperactivity of Fut8 Ϫ/Ϫ mice to the level observed in wild-type mice (Fig.…”

Section: Amelioration Of Hopping Hyperactivity and Monoaminementioning

confidence: 99%

α1,6-Fucosyltransferase-deficient Mice Exhibit Multiple Behavioral Abnormalities Associated with a Schizophrenia-like Phenotype

Fukuda

Hashimoto

Okayasu

et al. 2011

Journal of Biological Chemistry

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Previously, we reported that ␣1,6-fucosyltransferase (Fut8)-deficient (Fut8 ؊/؊ ) mice exhibit emphysema-like changes in the lung and severe growth retardation due to dysregulation of TGF-␤1 and EGF receptors and to abnormal integrin activation, respectively. To study the role of ␣1,6-fucosylation in brain tissue where Fut8 is highly expressed, we examined Fut8 ؊/؊ mice using a combination of neurological and behavioral tests. ␣1,6-Fucosyltransferase (Fut8) 2 catalyzes the transfer of a fucose residue from GDP-fucose to position 6 of the innermost GlcNAc residue to form ␣1,6-fucose in hybrid and complex N-linked oligosaccharides of glycoproteins as shown in Fig. 1 (1). ␣1,6-Fucosylated glycoproteins are widely distributed in mammalian tissues, especially in the brain (2). In fact, the majority of N-glycans present in mouse brain tissue are ␣1,6-fucosylated (3). We recently investigated the physiological functions of ␣1,6-fucose by using Fut8-deficient (Fut8 Ϫ/Ϫ ) mice (4). Fut8 Ϫ/Ϫ mice showed severe growth retardation. They also suffered from emphysema-like changes in their lungs that appeared to be due to a lack of ␣1,6-fucosylation of the transforming growth factor-␤1 (TGF-␤1) receptor, which consequently resulted in dysregulation of TGF-␤1 receptor activation and signaling (4), and down-regulation of expression of vascular endothelial cell growth factor receptor-2 (5). In addition, deletion of the core fucose from the IgG1 molecule reportedly enhances antibody-dependent cellular cytotoxicity activity by 50 -100-fold. This result indicates that ␣1,6-fucose is an important sugar chain in terms of antibody-dependent cellular cytotoxicity activity (6). Moreover, the loss of ␣1,6-fucosylation down-regulates both EGF receptor-mediated cell signaling pathways (7) and integrin ␣3␤1-mediated cell adhesion (8). Taken together, these results suggest that ␣1,6-fucose plays a key role in regulating important physiological functions via modification of functional proteins.Complex N-glycans are required for the development of the embryo, and the complete lack of N-glycans in GnT-I-deficient mice is lethal with defects in neural tube formation (9). These observations suggest that high-mannose N-glycans are insufficient for normal ontogeny. On the other hand, restriction of N-glycan branching to the formation of only hybrid structures by GnT-II inactivation in mice results in a very low rate of * This work was supported by Scientific Research Grants-in-aid 21370059 (to J. G.) and 22590071 (to T. F.) from the Japan Society for the Promotion of Science and the Academic Frontier Project for Private Universities from the Ministry of Education, Culture, Sports, Science and Technology of Japan. 1 To whom correspondence should be addressed. Tel.: 81-22-727-0216; Fax:81-22-727-0078; E-mail: jgu@tohoku-pharm.ac.jp.2 The abbreviations used are: Fut8, ␣1,6-fucosyltransferase; PPI, prepulse inhibition; TGF-␤1, transforming growth factor-␤1; GnT-III, N-acetylglucosaminyltransferase III; GnT-V, N-acetylglucosaminyltransferase V; 5-HT, 5-h...

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“…Os estudos vêm demonstrando que um certo nível de bloqueio de receptores é necessário (>65%), 35,36 mas não suficiente para garantir resposta clínica. Muitos pacientes exibem altos níveis de bloqueio dos receptores D 2 sem apresentar resposta clínica adequada.…”

Section: Hipótese Dopaminérgicaunclassified

Hipótese glutamatérgica da esquizofrenia

Bressan

Pilowsky

2003

Rev. Bras. Psiquiatr.

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IntroduçãoA esquizofrenia é um transtorno psiquiátrico devastador que acomete aproximadamente 1% da população ao longo da vida. Os indivíduos geralmente são acometidos no auge do seu potencial produtivo e o curso da doença é crônico e debilitante. Apesar dos progressos no tratamento da esquizofrenia, como a introdução de antipsicóticos atípicos, as medicações continuam sendo bastante limitadas na sua eficácia clínica.1 Poucos são os indivíduos que voltam a ter o funcionamento compatível com as expectativas pré-morbidas. Diferentes abordagens científicas (ex: modelos animais, estudos neuroendocrinológicos, post-mortem, psicofarmacológicos, genéticos e de neuroimagem) têm sido empregadas para investigar a esquizofrenia. Entretanto, a sua A esquizofrenia é um transtorno psiquiátrico devastador cuja fisiopatologia ainda está para ser esclarecida. Apesar de uma disfunção dopaminérgica estar bem estabelecida na esquizofrenia, há uma série de evidências sugerindo o envolvimento do sistema glutamatérgico na fisiopatologia do transtorno. Este artigo faz uma breve revisão de alguns aspectos básicos do funcionamento dos receptores glutamatérgicos com ênfase nos receptores N-metil-D-aspartato (NMDA). Apresenta evidências científicas sugerindo uma disfunção do sistema glutamatérgico na esquizofrenia (hipofunção de receptores NMDA). E discute as interações entre os sistemas dopaminérgico e glutamatérgico; mais especificamente como os estados hiperdopaminérgicos encontrados na esquizofrenia podem estar associados a uma alteração glutamatérgica.Glutamato. Receptores NMDA. Esquizofrenia. Dopamina.Schizophrenia is a devastating psychiatric disorder whose pathophysiology has not been fully clarified yet. Although dopamine dysfunction in schizophrenia is unequivocal, there are many evidences suggesting the involvement of the glutamatergic system. This paper briefly describes some basic knowledge regarding the functioning of the glutamatergic receptors with emphasis on the N-methyl-D-aspartate (NMDA) receptors. Presents evidence for glutamatergic dysfunction in schizophrenia, more specifically NMDA receptor hypofunction. Finaly the paper discusses the interaction between the dopaminergic and the glutamatergic systems; in special how hyperdopaminergic state found in schizophrenia can be associated to glutamatergic dysfunctions.Glutamate. NMDA receptors. Schizophrenia. Dopamine. fisiopatologia ainda está para ser esclarecida. Uma melhor compreensão da fisiopatologia da esquizofrenia é essencial para que tratamentos mais eficazes sejam desenvolvidos.Apesar de inúmeros achados científicos demonstrarem uma disfunção dopaminérgica na esquizofrenia, uma série de evidências indica que outros sistemas neuroreceptores estão envolvidos na fisiopatologia do transtorno.2,3 Pesquisas recentes têm sugerido que os receptores glutamatérgicos tipo N-methyl-D-aspartato (NMDA) estão envolvidos na fisiopatologia da esquizofrenia e podem ser alvo para tratamentos psicofarmacológicos. O sistema glutamatérgico é o maior sistema excitatório do sistema nervo...

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Dopamine D2 Receptor Blockade by Haloperidol 3H-Raclopride Reveals Much Higher Occupancy than EEDQ

Cited by 22 publications

References 9 publications

Double Dissociation of the Effects of Haloperidol and the Dopamine D3 Receptor Antagonist ABT-127 on Acquisition vs. Expression of Cocaine-Conditioned Activity in Rats

Double Dissociation of the Effects of Haloperidol and the Dopamine D3 Receptor Antagonist ABT-127 on Acquisition vs. Expression of Cocaine-Conditioned Activity in Rats

α1,6-Fucosyltransferase-deficient Mice Exhibit Multiple Behavioral Abnormalities Associated with a Schizophrenia-like Phenotype

Hipótese glutamatérgica da esquizofrenia

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