Deficits in Prefrontal Cortical and Extrastriatal Dopamine Release in Schizophrenia

Slifstein, Mark; Giessen, Elsmarieke van de; Snellenberg, Jared X. Van; Thompson, Judy; Narendran, Rajesh; Gil, Roberto; Hackett, Elizabeth; Girgis, Ragy R.; Ojeil, Najate; Moore, Holly; D’Souza, Deepak Cyril; Malison, Robert T.; Huang, Yiyun; Lim, Keunpoong; Nabulsi, Nabeel; Carson, Richard E.; Lieberman, Jeffrey A.; Abi‐Dargham, Anissa

doi:10.1001/jamapsychiatry.2014.2414

Cited by 309 publications

(159 citation statements)

References 50 publications

Supporting

Mentioning

144

Contrasting

Unclassified

Order By: Relevance

“…The finding of a decrease in activity in VTA, and not SN, DA projection neurons also seems to be consistent with recent findings in patients with schizophrenia. Using PET imaging, Slifstein et al (45) have measured a decrease in DA release in cortical and other extrastriatal regions in patients compared with healthy controls. This widespread blunting of DA release is in contrast to the increase in DA release found selectively in the associative striatum that has been well documented in patients with schizophrenia (10,46).…”

Section: Discussionmentioning

confidence: 99%

Increased dopamine D2 receptor activity in the striatum alters the firing pattern of dopamine neurons in the ventral tegmental area

Krabbe

Duda

Schiemann

et al. 2015

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

View full text Add to dashboard Cite

There is strong evidence that the core deficits of schizophrenia result from dysfunction of the dopamine (DA) system, but details of this dysfunction remain unclear. We previously reported a model of transgenic mice that selectively and reversibly overexpress DA D2 receptors (D2Rs) in the striatum (D2R-OE mice). D2R-OE mice display deficits in cognition and motivation that are strikingly similar to the deficits in cognition and motivation observed in patients with schizophrenia. Here, we show that in vivo, both the firing rate (tonic activity) and burst firing (phasic activity) of identified midbrain DA neurons are impaired in the ventral tegmental area (VTA), but not in the substantia nigra (SN), of D2R-OE mice. Normalizing striatal D2R activity by switching off the transgene in adulthood recovered the reduction in tonic activity of VTA DA neurons, which is concordant with the rescue in motivation that we previously reported in our model. On the other hand, the reduction in burst activity was not rescued, which may be reflected in the observed persistence of cognitive deficits in D2R-OE mice. We have identified a potential molecular mechanism for the altered activity of DA VTA neurons in D2R-OE mice: a reduction in the expression of distinct NMDA receptor subunits selectively in identified mesolimbic DA VTA, but not nigrostriatal DA SN, neurons. These results suggest that functional deficits relevant for schizophrenia symptoms may involve differential regulation of selective DA pathways.ventral tegmental area | dopamine D2 receptor | burst activity | NMDA receptor | schizophrenia D eficits in cognition and motivation are core features of schizophrenia (1, 2). These symptoms are listed in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition as a diagnostic criterion for schizophrenia spectrum disorder (3) and have a significant impact on patients' overall functioning and quality of life (4, 5). Currently, there are no effective treatments for these disabling aspects of the disease. Therefore, a high priority in the study of schizophrenia is to increase our understanding of the neurobiology of cognitive and motivational deficits. The midbrain dopamine (DA) system affects cognition and motivation in healthy subjects. It includes DA neurons of the ventral tegmental area (VTA), projecting to prefrontal cortex (PFC) and limbic areas (e.g., ventral striatum), and DA neurons of the substantia nigra (SN), projecting to the dorsal striatum (6). Involvement of the midbrain DA system is strongly implicated in both the cognitive and motivational deficits observed in schizophrenia (7,8). Moreover, it is well documented that the DA system is altered in patients with schizophrenia (reviewed in refs. 9, 10).To model the increase in striatal DA D2 receptor (D2R) activity observed in patients with schizophrenia, we previously generated transgenic mice that selectively and reversibly overexpress D2Rs in the striatum (D2R-OE mice) (11). In this model, expression of the transgenic D2Rs is restricted to the postsy...

show abstract

Section: Discussionmentioning

confidence: 99%

Increased dopamine D2 receptor activity in the striatum alters the firing pattern of dopamine neurons in the ventral tegmental area

Krabbe

Duda

Schiemann

et al. 2015

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

View full text Add to dashboard Cite

show abstract

“…A hypodopaminergic state underlying liability to schizophrenia is also supported by imaging studies showing that impairment in executive function and working memory correlate with lower dopamine availability in the prefrontal cortex, 32 and by evidence of heritability of striatal presynaptic dopamine function. 33 Unmedicated patients with schizophrenia who also had parkinsonism, performed worse on cognitive tests than those without parkinsonian impairment, independently of severity of psychopathology, sedation, akathisia, and dyskinesia 34 ; parkinsonism scores showed strong longitudinal associations with deficits in memory, executive functioning, and attention.…”

Section: Introductionmentioning

confidence: 89%

Prediction of Neurocognitive Deficits by Parkinsonian Motor Impairment in Schizophrenia: A Study in Neuroleptic-Naïve Subjects, Unaffected First-Degree Relatives and Healthy Controls From an Indigenous Population

Molina¹,

Alemán²,

Florenzano³

et al. 2016

SCHBUL

View full text Add to dashboard Cite

Background: Neurocognitive deficits are among the most debilitating and pervasive symptoms of schizophrenia, and are present also in unaffected first-degree relatives. Also, multiple reports reveal parkisonian motor deficits in untreated subjects with schizophrenia and in first-degree relatives of affected subjects. Yet, the relation between motor and cognitive impairment and its value as a classifier of endophenotypes has not been studied. Aims: To test the efficacy of midbrain hyperechogenicity (MHE) and parkinsonian motor impairment (PKM) as predictors of neurocognitive impairment in subjects with or at risk for schizophrenia, that could be used to segregate them from first-degree relatives and healthy controls. Method: Seventy-six subjects with chronic schizophrenia never exposed to antipsychotic medication, 106 unaffected first-degree relatives, and 62 healthy controls were blindly assessed for cognitive and motor function, and transcranial ultrasound. Results: Executive function, fluid intelligence, motor planning, and hand coordination showed group differences. PKM and MHE were significantly higher in untreated schizophrenia and unaffected relatives. Unaffected relatives showed milder impairment, but were different from controls. Conclusions: PKM and MHE predict cognitive impairment in neuroleptic-naive patients with schizophrenia and their unaffected first-degree relatives and may be used to segregate them from first-degree relatives and healthy controls.

show abstract

“…Several investigations of the dopamine system have studied the reward system with the use of a monetary incentive delay task and have demonstrated an in vivo coupling between the BOLD response and striatal dopaminergic neurotransmission with [ 11 C]raclopride 110,111 . Investigations of the D2 receptor system in patients have shown that schizophrenic patients show a deficit in the ability to release dopamine after amphetamine exposure, and that the amount of dopamine release correlates positively with BOLD signal changes due to a working memory task 56 . Together, these studies have provided in vivo insights about the neuromolecular pathways involved in the formation of brain functional processing in healthy humans and psychiatric disease.…”

Section: Multi-modal Imaging Of Receptor Functional Dynamics Witmentioning

confidence: 99%

News and views on in-vivo imaging of neurotransmission using PET and MRI

Sander

Hesse

2017

Q J Nucl Med Mol Imaging

View full text Add to dashboard Cite

Deficits in Prefrontal Cortical and Extrastriatal Dopamine Release in Schizophrenia

Cited by 309 publications

References 50 publications

Increased dopamine D2 receptor activity in the striatum alters the firing pattern of dopamine neurons in the ventral tegmental area

Increased dopamine D2 receptor activity in the striatum alters the firing pattern of dopamine neurons in the ventral tegmental area

Prediction of Neurocognitive Deficits by Parkinsonian Motor Impairment in Schizophrenia: A Study in Neuroleptic-Naïve Subjects, Unaffected First-Degree Relatives and Healthy Controls From an Indigenous Population

News and views on in-vivo imaging of neurotransmission using PET and MRI

Contact Info

Product

Resources

About