DRD2 genotype predicts prefrontal activity during working memory after stimulation of D2 receptors with bromocriptine

Franke, Barbara; Fazio, Leonardo; Selvaggi, Pierluigi; Giorgio, Annabella Di; Taurisano, Paolo; Quarto, Tiziana; Romano, Raffaella; Porcelli, Annamaria; Mancini, Marina; Masellis, Rita; Ursini, Gianluca; Simeis, Giuseppe De; Caforio, Grazia; Ferranti, Laura; Bianco, Luciana Lo; Rampino, Antonio; Todarello, Orlando; Popolizio, Teresa; Blasi, Giuseppe; Bertolino, Alessandro

doi:10.1007/s00213-013-3398-9

Cited by 14 publications

(21 citation statements)

References 54 publications

(94 reference statements)

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“…While these findings link to putative neurobiological targets of Rgs2, dysregulation of GPCR expression by itself may contribute to the observed phenotype of Rgs2 −/− mice. 5-HT 2A and 5-HT 2C receptors as well as D 2 receptors were previously implicated in memory processes (Bonasera et al 2015;Gelao et al 2014;Morici et al 2015;Rocchetti et al 2015;Saab et al 2009;Wang et al 2004;Zhang et al 2013), while the 2A receptor and the NPY 1 receptor were associated with increased anxiety (Bertocchi et al 2011;Karl et al 2006;Lahdesmaki et al 2002;Longo et al 2014;Schramm et al 2001). A dysregulation of 5-HT 1A and 5-HT 1B receptors in the raphe nuclei was previously reported by Lifschytz and coworkers, the same group also noted comparable expression level in cortex and hypothalamus in line with our results of selectively reduced 5-HT 1A expression levels in the amygdala.…”

Section: Discussionmentioning

confidence: 99%

Increased fear learning, spatial learning as well as neophobia in Rgs2^−/− mice

Raab

Popp

Lesch

et al. 2017

Genes Brain and Behavior

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Anxiety disorders result from a complex interplay of genetic and environmental factors such as stress. On the level of cellular signaling, regulator of G protein signaling 2 (Rgs2) has been implicated in human and rodent anxiety. However, there is limited knowledge about the role of Rgs2 in fear learning and reactivity to stress. In this study, Rgs2 mice showed increased fear learning, male mice displayed increased contextual and cued fear learning, while females showed selectively enhanced cued fear learning. Male Rgs2 mice displayed increased long-term-contextual fear memory, but increased cued fear extinction. Learning in spatial non-aversive paradigms was also increased in Rgs2 mice. Female, but not male mice show increased spatial learning in the Barnes maze, while male mice showed enhanced place preference in the IntelliCage, rendering enhanced cognitive function non-specific for aversive stimuli. Consistent with the previous results, Rgs2 deletion resulted in increased innate anxiety, including neophobic behavior expressed as hypolocomotion, in three different tests based on the approach-avoidance conflict. Acute electric foot shock stress provoked hypolocomotion in several exploration-based tests, suggesting fear generalization in both genotypes. Rgs2 deletion was associated with reduced monoaminergic neurotransmitter levels in the hippocampus and prefrontal cortex and disturbed corresponding GPCR expression of the adrenergic, serotonergic, dopaminergic and neuropeptide Y system. Taken together, Rgs2 deletion promotes improved cognitive function as well as increased anxiety-like behavior, but has no effect on acute stress reactivity. These effects may be related to the observed disruption of the monoaminergic systems.

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Section: Discussionmentioning

confidence: 99%

Increased fear learning, spatial learning as well as neophobia in Rgs2^−/− mice

Raab

Popp

Lesch

et al. 2017

Genes Brain and Behavior

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“…A more recent study has suggested that dopamine may mitigate cognitive impairment in AD at least in part through the interaction of dopaminergic and cholinergic systems [101]. However, although emerging evidence has highlighted the function of the dopaminergic system in the consolidation of memory [102, 103], the correlation between dopaminergic system deficits and AD cognitive impairment has not yet been comprehensively investigated.…”

Section: Synaptic Transmission Changes In Admentioning

confidence: 99%

Mitochondrial Dysfunction and Synaptic Transmission Failure in Alzheimer’s Disease

Guo

Tian

2017

JAD

137

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Alzheimer's disease (AD) is a chronic neurodegenerative disorder, in which multiple risk factors converge. Despite the complexity of the etiology of the disease, synaptic failure is the pathological basis of cognitive impairment, the cardinal sign of AD. Decreased synaptic density, compromised synaptic transmission, and defected synaptic plasticity are hallmark synaptic pathologies accompanying AD. However, the mechanisms by which synapses are injured in AD-related conditions have not been fully elucidated yet. Mitochondria are a critical organelle in neurons. The pivotal role of mitochondria in supporting synaptic function and the concomitant occurrence of mitochondrial dysfunction with synaptic stress in postmortem AD brains as well as AD animal models seem to lend the credibility to the hypothesis that mitochondrial defects underlie synaptic failure in AD. This concept is further strengthened by the protective effect of mitochondrial medicine on synaptic function against the toxicity of amyloid-β, a key player in the pathogenesis of AD. In this review, we focus on the association between mitochondrial dysfunction and synaptic transmission deficits in AD. Impaired mitochondrial energy production, deregulated mitochondrial calcium handling, excess mitochondrial reactive oxygen species generation, and release play a crucial role in mediating synaptic transmission deregulation in AD. The understanding of the role of mitochondrial dysfunction in synaptic stress may lead to novel therapeutic strategies for the treatment of AD through the protection of synaptic transmission by targeting to mitochondrial deficits.

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“…D2 receptor density has been shown to be increased in the brains of schizophrenic patients [Stelzel et al, ]. DRD2 genotypes have been reported to predict prefrontal activity during working memory after D2 receptor stimulation with bromocriptine [Gelao et al, ]. Within the dopamine system, D2 receptors appear to play a significant role in the expression of schizophrenia; consequently, the DRD2 gene has long been considered a promising candidate risk gene of this disease.…”

Section: Introductionmentioning

confidence: 99%

Association between DRD2 (rs1799732 and rs1801028) and ANKK1 (rs1800497) polymorphisms and schizophrenia: A meta‐analysis

Yao

Pan

Ding

et al. 2014

American J of Med Genetics Pt B

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The role of dopamine D2 receptor (DRD2) polymorphisms in schizophrenia remains controversial. We performed a meta-analysis to determine whether DRD2 polymorphisms influence the risk of schizophrenia and examined the relationship between rs1799732, rs1801028, and rs1800rs028 an23381d rs1800497 genetic variants and the etiology of schizophrenia. Relevant case-control studies were retrieved by database searches and selected according to established inclusion criteria. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the strength of the associations. Meta-regression, subgroup analysis, sensitivity analysis, and cumulative meta-analysis were performed. A total of 76 studies with 16096 cases and 18965 controls were included. Specifically, 24 studies with 6075 cases and 6643 controls involved rs1799732, 36 studies with 8043 cases and 10194 controls involved rs1801028 and 16 studies with 1978 cases and 2128 controls involved rs1800497. No significant associations were observed between rs1799732 and rs1800rs732 and rs1800497 and schizophrenia. The rs1801028 locus was associated with schizophrenia, with a pooled OR of 1.221 (95% CI = 1.037-1.438, P = 0.016). This meta-analysis indicates that the rs1801028 locus may be associated with schizophrenia. These data provide possible references for future case-control studies related to schizophrenia.

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DRD2 genotype predicts prefrontal activity during working memory after stimulation of D2 receptors with bromocriptine

Abstract: These results indicate that bromocriptine stimulation modulates prefrontal activity in terms of disengagement or of efficiency depending on DRD2 genotype and working memory load.

Cited by 14 publications

References 54 publications

Increased fear learning, spatial learning as well as neophobia in Rgs2^−/− mice

Increased fear learning, spatial learning as well as neophobia in Rgs2^−/− mice

Mitochondrial Dysfunction and Synaptic Transmission Failure in Alzheimer’s Disease

Association between DRD2 (rs1799732 and rs1801028) and ANKK1 (rs1800497) polymorphisms and schizophrenia: A meta‐analysis

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DRD2 genotype predicts prefrontal activity during working memory after stimulation of D2 receptors with bromocriptine

Abstract: These results indicate that bromocriptine stimulation modulates prefrontal activity in terms of disengagement or of efficiency depending on DRD2 genotype and working memory load.

Cited by 14 publications

References 54 publications

Increased fear learning, spatial learning as well as neophobia in Rgs2−/− mice

Increased fear learning, spatial learning as well as neophobia in Rgs2−/− mice

Mitochondrial Dysfunction and Synaptic Transmission Failure in Alzheimer’s Disease

Association between DRD2 (rs1799732 and rs1801028) and ANKK1 (rs1800497) polymorphisms and schizophrenia: A meta‐analysis

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Increased fear learning, spatial learning as well as neophobia in Rgs2^−/− mice

Increased fear learning, spatial learning as well as neophobia in Rgs2^−/− mice