Dopamine, cognitive function, and gamma oscillations: role of D4 receptors

Furth, Katrina; Mastwal, Surjeet; Wang, Kuan Hong; Buonanno, Andrés; Vullhorst, Detlef

doi:10.3389/fncel.2013.00102

Cited by 72 publications

(47 citation statements)

References 243 publications

(334 reference statements)

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“…where they are thought to be involved in numerous cognitive functions (i.e., from working memory to executive functions and emotion) that are often found to be altered in mental pathologies, such as schizophrenia, attention and hyperactivity disorders, autism and so on (see [Furth et al, 2013] and references therein). Whether prefrontal D 4 receptors are involved in sexual effects of D 4 agonists and antagonists found in this study is unknown at present, although experimental evidence is available for a role of dopamine in this brain area in sexual arousal and motivation (see Melis and Argiolas, 2011]).…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Role of dopamine D4 receptors in copulatory behavior: Studies with selective D4 agonists and antagonists in male rats

Sanna

Contini

Melis

et al. 2015

Pharmacology Biochemistry and Behavior

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Section: Accepted Manuscriptmentioning

confidence: 99%

Role of dopamine D4 receptors in copulatory behavior: Studies with selective D4 agonists and antagonists in male rats

Sanna

Contini

Melis

et al. 2015

Pharmacology Biochemistry and Behavior

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“…Among dopamine receptors, D4 is mostly expressed in GABAergic neurons of the cerebral cortex, hippocampus, and substantia nigra [6]. Therefore, D4 receptor plays an important role in cognitive tasks and memory performance and is one of the major goals in treating schizophrenia [7]. Some efforts were based on synthesis of selective ligands against D4 receptor.…”

Section: Introductionmentioning

confidence: 99%

Homology modeling, molecular dynamic simulation, and docking based binding site analysis of human dopamine (D4) receptor

et al. 2015

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Human dopamine D4 receptor is a GPCR target in the treatment of neurological and psychiatric conditions such as schizophrenia and Parkinson's disease. The X-ray structure of this receptor has not been resolved so far. Therefore, a proper 3D structure of D4 could provide a good tool in order to design novel ligands against this target. In this study, homology modeling studies were performed to obtain a reasonable structure of the receptor using known templates. The obtained model was subjected to molecular dynamic simulation within a DPPC membrane system. Some structural features of the receptor such as a conserved disulfide bridge and ionic lock were considered in the modeling experiments. The resulted trajectories of simulation were clustered based on the root mean square deviation of the backbone. Some known ligands and decoys were accordingly docked into the representative frames of each cluster. The best final model was finally selected based on its ability to discriminate between active ligands and inactive decoys (ROC = 0.839). The presented model of human D4 receptor could be a promising starting point in future studies of drug design for the described target.

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“…Although hippocampal dysfunction contributes to cognitive impairment in schizophrenia (Gastambide et al, 2015), and dopamine receptors regulate inhibition in hippocampus (Gonzalez-Islas and Hablitz, 2001), haloperidol has not been found to be effective for treating the cognitive symptoms in schizophrenia (Furth et al, 2013). It is currently not known how haloperidol will affect hippocampal circuit function altered as a result of interneuron transcriptional dysregulation.…”

Section: Introductionmentioning

confidence: 99%

Transcriptional dysregulation causes altered modulation of inhibition by haloperidol

Brady

Bartley

et al. 2016

Neuropharmacology

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Many neuropsychiatric and neurodevelopmental disorders such as schizophrenia and autism involve interneuron transcriptional dysregulation. The transcriptional coactivator PGC-1α regulates gene expression in GABAergic interneurons, which are important for regulating hippocampal network activity. Genetic deletion of PGC-1α causes a decrease in parvalbumin expression, similar to what is observed in schizophrenia postmortem tissue. Our lab has previously shown that PGC-1α−/− mice have enhanced GABAergic inhibition onto CA1 pyramidal cells, which increases the inhibition/excitation (I/E) ratio, alters hippocampal circuit function, and impairs hippocampal dependent behavior. The typical antipsychotic haloperidol, a dopamine receptor antagonist with selectivity for D2-like receptors, has previously been shown to increase excitation in the CA1 region of hippocampus. We therefore tested whether haloperidol could normalize the I/E balance in CA1 of PGC-1α−/− mice, potentially improving circuit function and behavior. Surprisingly, we discovered instead that interneuron transcriptional dysregulation caused by loss of PGC-1α alters the effects of haloperidol on hippocampal synaptic transmission and circuit function. Acute administration of haloperidol causes disinhibition in CA1 and decreases the I/E ratio onto CA1 pyramidal cells in slices from PGC-1α+/+ mice, but not PGC-1α−/− mice. The spread of activity in CA1, assessed by voltage sensitive dye imaging, is increased by haloperidol in slices from PGC-1α+/+ mice; however haloperidol decreases the spread of activity in slices from PGC-1α−/− mice. Haloperidol increased the power of hippocampal gamma oscillation in slices from PGC-1α+/+ mice but reduced the power of gamma oscillations in slices from PGC-1α−/− mice. Nest construction, an innate hippocampal-dependent behavior, is inhibited by haloperidol in PGC-1α+/+ mice, but not in PGC-1α−/− mice, which already have impaired nest building. The effects of haloperidol are mimicked and occluded by a D2 receptor antagonist in slices from PGC-1α+/+ mice, and the effects of blocking D2 receptors are lost in slices from PGC-1α−/− mice, although there is no change in D2 receptor transcript levels. Together, our results show that hippocampal inhibitory synaptic transmission, CA1 circuit function, and hippocampal dependent behavior are modulated by the antipsychotic haloperidol, and that these effects of haloperidol are lost in PGC-1α−/− mice. These results have implications for the treatment of individuals with conditions involving PGC-1α deficiency.

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Dopamine, cognitive function, and gamma oscillations: role of D4 receptors

Cited by 72 publications

References 243 publications

Role of dopamine D4 receptors in copulatory behavior: Studies with selective D4 agonists and antagonists in male rats

Role of dopamine D4 receptors in copulatory behavior: Studies with selective D4 agonists and antagonists in male rats

Homology modeling, molecular dynamic simulation, and docking based binding site analysis of human dopamine (D4) receptor

Transcriptional dysregulation causes altered modulation of inhibition by haloperidol

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