Dopamine D2 receptor occupancy levels of acute sulpiride challenges that produce working memory and learning impairments in healthy volunteers

Mehta, Mitul A.; Montgomery, Andrew J.; Kitamura, Yuri; Grasby, Paul M.

doi:10.1007/s00213-007-0947-0

Cited by 60 publications

(49 citation statements)

References 46 publications

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“…However, it is likely that too small a dose of sulpiride was used, resulting in the absence of any observable effect on brain activity. Although previous studies that used a 400 mg dose found subtle effects of neurocognitive testing (Mehta et al, 1999), a recent PET study by Mehta et al (2007) found that a single 400 mg dose of sulpiride (the same dose as used in the present study because of ethical constraints in testing higher doses) leads to only 28% occupancy of dopamine D 2 receptors in the striatum. In contrast, 60 mg of methylphenidate (the same dose as used in the present study) has been shown to lead to a much higher percentage occupancy (74%) of the dopamine transporter (Volkow et al, 1998).…”

Section: Discussionmentioning

confidence: 56%

Methylphenidate Has Differential Effects on Blood Oxygenation Level-Dependent Signal Related to Cognitive Subprocesses of Reversal Learning

Dodds

Müller²,

Clark³

et al. 2008

Journal of Neuroscience

111

103

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Complete understanding of the neural mechanisms by which stimulants such as methylphenidate ameliorate attention deficit hyperactivity disorder is lacking. Theories of catecholamine function predict that the neural effects of stimulant drugs will vary according to task requirements. We used event-related, pharmacological functional magnetic resonance imaging to investigate the effects of 60 mg of methylphenidate, alone and in combination with 400 mg of sulpiride, on blood oxygenation level-dependent (BOLD) signal in a group of 20 healthy participants during probabilistic reversal learning, in a placebo-controlled design. In a whole-brain analysis, methylphenidate attenuated BOLD signal in the ventral striatum during response switching after negative feedback but modulated activity in the prefrontal cortex when subjects maintained their current response set. The results show that the precise neural site of modulation by methylphenidate depends on the nature of the cognitive subprocess recruited.

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Section: Discussionmentioning

confidence: 56%

Methylphenidate Has Differential Effects on Blood Oxygenation Level-Dependent Signal Related to Cognitive Subprocesses of Reversal Learning

Dodds

Müller²,

Clark³

et al. 2008

Journal of Neuroscience

111

103

View full text Add to dashboard Cite

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“…Second, previous reports have suggested association between psychosis and relatively greater D2 density in striatum, even though change is moderate (2). Third, clinical symptoms and cognitive deficits have been associated with abnormal D2 signaling (3)(4)(5)(6)(7)(8)(9)(10)(11)(12). The relationship between D2 receptors and cognitive deficits in schizophrenia is also supported by previous models postulating that relatively excessive D2 signaling may lead to lower cortical signal-to-noise ratio and reduced filtering of information, as well as blocking of distracting inputs (10)(11)(12).…”

mentioning

confidence: 83%

DRD2/AKT1interaction on D2 c-AMP independent signaling, attentional processing, and response to olanzapine treatment in schizophrenia

Blasi

Napolitano

Ursini

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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The D2/AKT1/GSK-3β signaling pathway has been involved in the downstream intracellular effects of dopamine, in the pathophysiology of cognitive deficits and related brain activity in schizophrenia, as well as in response to treatment with antipsychotics. Polymorphisms in the D2 (DRD2 rs1076560) and AKT1 (AKT1 rs1130233) genes have been associated with their respective protein expression and with higher-order cognition and brain function, including attention. Given the strong potential for their relationship, we investigated the interaction of these polymorphisms on multiple molecular and in vivo phenotypes associated with this signaling pathway. We measured AKT1 and GSK-3β proteins and phosphorylation in human peripheral blood mononuclear cells, functional MRI cingulate response during attentional control, behavioral accuracy during sustained attention, and response to 8 wk of treatment with olanzapine in a total of 190 healthy subjects and 66 patients with schizophrenia. In healthy subjects, we found that the interaction between the T allele of DRD2 rs1076560 and the A allele of AKT1 rs1130233 was associated with reduced AKT1 protein levels and reduced phosphorylation of GSK-3β, as well as with altered cingulate response and reduced behavioral accuracy during attentional processing. On the other hand, interaction of these two alleles was associated with greater improvement of Positive and Negative Syndrome Scale scores in patients with schizophrenia after treatment with olanzapine. The present results indicate that these functional polymorphisms are epistatically associated with multiple phenotypes of relevance to schizophrenia. Our results also lend support to further investigation of this downstream molecular pathway in the etiology and treatment of this disorder.A large series of experimental data indicate that dopamine D2 receptors and schizophrenia are tightly related. First, these receptors are privileged targets of antipsychotic drugs, which antagonize their activity (1). Second, previous reports have suggested association between psychosis and relatively greater D2 density in striatum, even though change is moderate (2). Third, clinical symptoms and cognitive deficits have been associated with abnormal D2 signaling (3-12). The relationship between D2 receptors and cognitive deficits in schizophrenia is also supported by previous models postulating that relatively excessive D2 signaling may lead to lower cortical signal-to-noise ratio and reduced filtering of information, as well as blocking of distracting inputs (10-12). These brain processes contribute to different higherorder cognitive functions and are strongly involved in top-down modulation of attention (13,14). Consistent with these models, previous data have suggested that attentional behavior is affected by D2 genetic variation (15). Furthermore, deficits in attentional processing are centrally implicated in schizophrenia (16,17). In fact, patients with schizophrenia performing attentional tasks have abnormal activity in the cingulate cortex, a ...

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“…Striatal D 2 R activity is important for effective working memory as shown in animals and humans (e.g., Kellendonk et al 2006;Mehta et al 2008). Inactivation of striatal A 2A Rs might potentiate striatal dopaminergic signaling via D 2 Rs to produce the working memory enhancement, given the well-documented antagonistic A 2A R-D 2 R interaction in striatopallidal MSNs of the "indirect" pathway (Ferre et al 1997;Fredholm et al 2007).…”

Section: Selective Inactivation Of Striatal Neuronal a 2a Rs Is Suffimentioning

confidence: 99%

Selective inactivation of adenosine A_2A receptors in striatal neurons enhances working memory and reversal learning

Wei¹,

Singer²,

Coelho³

et al. 2011

Learn. Mem.

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The adenosine A 2A receptor (A 2A R) is highly enriched in the striatum where it is uniquely positioned to integrate dopaminergic, glutamatergic, and other signals to modulate cognition. Although previous studies support the hypothesis that A 2A R inactivation can be pro-cognitive, analyses of A 2A R's effects on cognitive functions have been restricted to a small subset of cognitive domains. Furthermore, the relative contribution of A 2A Rs in distinct brain regions remains largely unknown. Here, we studied the regulation of multiple memory processes by brain region-specific populations of A 2A Rs. Specifically, we evaluated the cognitive impacts of conditional A 2A R deletion restricted to either the entire forebrain (i.e., cerebral cortex, hippocampus, and striatum, fb-A 2A R KO) or to striatum alone (st-A 2A R KO) in recognition memory, working memory, reference memory, and reversal learning. This comprehensive, comparative analysis showed for the first time that depletion of A 2A R-dependent signaling in either the entire forebrain or striatum alone is associated with two specific phenotypes indicative of cognitive flexibility-enhanced working memory and enhanced reversal learning. These selective pro-cognitive phenotypes seemed largely attributed to inactivation of striatal A 2A Rs as they were captured by A 2A R deletion restricted to striatal neurons. Neither spatial reference memory acquisition nor spatial recognition memory were grossly affected, and no evidence for compensatory changes in striatal or cortical D 1 , D 2 , or A 1 receptor expression was found. This study provides the first direct demonstration that targeting striatal A 2A Rs may be an effective, novel strategy to facilitate cognitive flexibility under normal and pathologic conditions.

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Dopamine D2 receptor occupancy levels of acute sulpiride challenges that produce working memory and learning impairments in healthy volunteers

Cited by 60 publications

References 46 publications

Methylphenidate Has Differential Effects on Blood Oxygenation Level-Dependent Signal Related to Cognitive Subprocesses of Reversal Learning

Methylphenidate Has Differential Effects on Blood Oxygenation Level-Dependent Signal Related to Cognitive Subprocesses of Reversal Learning

DRD2/AKT1interaction on D2 c-AMP independent signaling, attentional processing, and response to olanzapine treatment in schizophrenia

Selective inactivation of adenosine A_2A receptors in striatal neurons enhances working memory and reversal learning

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Dopamine D2 receptor occupancy levels of acute sulpiride challenges that produce working memory and learning impairments in healthy volunteers

Cited by 60 publications

References 46 publications

Methylphenidate Has Differential Effects on Blood Oxygenation Level-Dependent Signal Related to Cognitive Subprocesses of Reversal Learning

Methylphenidate Has Differential Effects on Blood Oxygenation Level-Dependent Signal Related to Cognitive Subprocesses of Reversal Learning

DRD2/AKT1interaction on D2 c-AMP independent signaling, attentional processing, and response to olanzapine treatment in schizophrenia

Selective inactivation of adenosine A2A receptors in striatal neurons enhances working memory and reversal learning

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Selective inactivation of adenosine A_2A receptors in striatal neurons enhances working memory and reversal learning