Distinct roles for primate caudate dopamine D1 and D2 receptors in visual discrimination learning revealed using shRNA knockdown
Masafumi TakajiAtsushi TakemotoChihiro YokoyamaAkiya WatakabeHiroaki MizukamiKeiya OzawaHirotaka OnoeKatsuki NakamuraTetsuo Yamamori
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Abstract The striatum plays important motor, associative and cognitive roles in brain functions. However, the rodent dorsolateral (the primate putamen) and dorsomedial (the primate caudate nucleus) striatum are not anatomically separated, making it difficult to distinguish their functions. By contrast, anatomical separation exists between the caudate nucleus and putamen in primates. Here, we successfully decreased dopamine D1 receptor (D1R) or D2R mRNA expression levels selectively in the marmoset caudate using shRNA knockdown techniques, as determined using positron emission tomography imaging with specific D1R and D2R ligands and postmortem in situ hybridization analysis. We then conducted a voxel-based correlation analysis between binding potential values of PET imaging and visual discrimination learning task performance in these genetically modified marmosets to find a critical role for the caudate D2R but no apparent role for the caudate D1R. This latter finding challenges the current understanding of the mechanisms underlying D1R activation in the caudate.Keywords:
Caudate nucleus
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The involvement of dopamine in multiple aspects of brain function has produced a great interest in dopaminergic pharmacology, and a large number of dopamine receptor ligands have been developed and tested. Dopamine receptors were initially divided into D1 and D2* subtypes on the basis of pharmacological and biochemical criteria (1). D1 receptors mediate stimulation, and D2 receptors inhibition, of adenylate cyclase by dopamine, and certain compounds interact selectively with the two types of receptor (2). In recent years, molecular cloning studies have demonstrated the presence of at least five genetically different dopamine receptor subtypes in the mammalian nervous system (3, 4). Since the cloned D 1 and D5 receptors are highly homologous and pharmacologically similar, they can be viewed as members of the D1 subfamily. In parallel, the cloned D2, D3, and D4 subtypes belong to the D2 subfamily. The pharmacologically characterized D1 and D2 receptors may involve different members of these two subfamilies. In functional studies, such as those reviewed here, the relative lack of selective compounds necessitates the continued use of the conservative D1/D2 classification, where D1 and D2 refer to the entire subfamily and not the cloned subtype. The only exception is the section on expression systems, where genetically characterized subtypes have been studied in isolation. Still, the expanded knowledge of dopamine receptor structures calls for a re-evaluation of previous concepts and an enhanced understanding of the five (or more) subtypes, which will stimulate the development of even more selective pharmacological tools and clinically useful drugs.KeywordsDopamine ReceptorAdenylate CyclaseChromaffin CellCalcium CurrentStriatal NeuronThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
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Dopamine antagonist
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Dopamine exerts its action through membrane receptors that belong to the seven transmembrane domains (7TM) G protein-coupled receptor family. The dopamine receptor family is composed of five members, which have been divided into two subgroups: the D1-like family, which contains the D1 receptor (D1R) and D5R, and the D2-like family containing D2R, D3R, and D4R. This subdivision is based on pharmacological, biochemical, and structural properties. Nevertheless, the close pharmacological properties together with the common anatomical site of expression of these receptors have induced the interest for generating animal models with which to assess the function of each individual dopamine receptor in vivo. To date, there exist mutants for all five receptors, in particular using the knockout technology each dopamine receptor has been independently knocked out. In this chapter we will summarize major findings related to the contribution of each dopamine receptor in the control of physiological functions regulated by dopamine. Analyses of these mutants clearly show a preponderant role for dopamine D1R and D2R receptors in most dopamine-mediated effects. At the same time these mutants are also revealing more hidden functions for D3R, D4R, and D5R very likely in the modulation of D1R- and D2R-mediated signaling.
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Aberrant dopaminergic signaling is a critical determinant in multiple psychiatric disorders, and in many disease states, dopamine receptor number is altered. Here we identify a molecular mechanism that selectively targets D2 receptors for degradation after their activation by dopamine. The degradative fate of D2 receptors is determined by an interaction with G protein coupled receptor-associated sorting protein (GASP). As a consequence of this GASP interaction, D2 responses in rat brain fail to resensitize after agonist treatment. Disruption of the D2-GASP interaction facilitates recovery of D2 responses, suggesting that modulation of the D2-GASP interaction is important for the functional down-regulation of D2 receptors.
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Specific binding of 3H-domperidone was detected in a homogenate of human caudate nucleus tissue obtained from mentally healthy people and schizophrenic patients postmortem. Analysis of Scatchard's graph revealed only one type of binding sites with a dissociation constant of about 17 nM and the maximal number of binding sites about 87 pmol/g of the initial tissue. According to the current concepts, 3H-domperidone is a selective ligand of D2 dopamine receptors mediating the psychotropic effect of neuroleptics. The use of human brain for the investigation of these receptors may contribute to the elucidation of the mechanism of action of psychotropic drugs.
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[Objective]To explore the effect of retinal pigment epithelium on the development of myopia, through the observation of changes of dopamine D2 receptor in retinal pigment epithelial cells. [Methods]Retinal pigment epithelial cells were cultured in vitro. They were divided into three groups. Group A was for normal control. Group B was treated with dopamine(1 μg/mL). Group C was treated with dopamine(10 μg/mL).[Results]There are expression of dopamine D2 receptor in all groups, which is mainly expressed in the cytolymph of RPE cells. There are more dopamine D2 receptor in group B and C. And there are significantly statistical differences comparing with group A (P 0.05).[Conclusion]The inhibitive effect of dopamine upon myopia might be the result of regulation of dopamine D2 receptor in retinal pigment epithelium.
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Rats were treated for 21 d with the selective D1 dopamine receptor antagonist SCH23390, the selective D2 dopamine receptor antagonist spiperone, the nonselective dopamine receptor antagonist cis- flupentixol, or a combination of SCH23390 and spiperone. In addition, a group of rats received L-prolyl-L-leucyl-glycinamide (PLG) for 5 d after the 21 d chronic spiperone treatment. Chronic treatment with SCH23390 resulted in a significant increase in D1 dopamine receptor density with no change in the D2 dopamine receptor density. Conversely, spiperone treatment resulted in a significant increase in D2 dopamine receptors and no change in D1 dopamine receptor density. PLG treatment had no effect. SCH23390 plus spiperone treatment resulted in a significant increase in both D1 and D2 dopamine receptor densities. However, although in vitro cis-flupentixol has an equal affinity for D1 and D2 dopamine receptors, only the D2 dopamine receptor density increased after chronic treatment with cis-flupentixol. In vivo treatment with the protein-modifying reagent N-ethoxycarbonyl-2-ethoxy- 1,2-dihydroquinoline (EEDQ), which irreversibly inactivates D1 and D2 dopamine receptors, was used to investigate the paradoxical, selective D2 dopamine receptor up-regulation induced by cis-flupentixol treatment. In vivo treatment with cis-flupentixol before EEDQ administration prevented the D1 and D2 dopamine receptor reductions induced by EEDQ. However, cis-flupentixol protected, in a dose- dependent manner, a greater percentage of D2 dopamine receptors than of D1 dopamine receptors from EEDQ-induced modification. These data indicate that, in vivo, cis-flupentixol preferentially interacts with D2 dopamine receptors and could explain why only D2 dopamine receptors were up-regulated following chronic treatment with cis-flupentixol. Rats were tested for their cataleptic response to the administered drug over the course of the chronic drug treatment. Catalepsy scores of rats receiving spiperone decreased over the course of treatment, with a significant reduction in catalepsy occurring by treatment day 5. The profound catalepsy observed in rats receiving SCH23390 did not change over the 21 d of treatment. Rats receiving cis-flupentixol demonstrated tolerance to its cataleptogenic effects, with a significant reduction in catalepsy observed by treatment day 7. During the 3 week treatment, the time between drug injection and a full cataleptic response to cis- flupentixol increased from 20 to 60 min, suggesting a tolerance to the D2, but not D1, dopamine receptor antagonism by cis- flupentixol.(ABSTRACT TRUNCATED AT 400 WORDS)
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