Schizophrenia

Multifaceted aspects of dopamine dysfunction in schizophrenia

Dopamine dysfunction is a fundamental feature of schizophrenia. Now advances offered by neuroimaging-research are helping clinicians and scientists scrutinize the crucial changes and aberrations that could hold the clues to improved disease management. In this feature article, we report and summarize the opening plenary lecture at CINP 2016, given by Professor Anissa Abi-Dargham from New York, USA, on this hot topic.

Neuroimaging offers a powerful tool to dissect and potentially explain the functional and neurochemical processes at play in schizophrenia. Decades of research identify dopamine as a key player in the disease process, and now neuroimaging looks set to provide some new, much-needed, perspectives to fuel further research and potentially change approaches to patient care.

 

Shine a light

Why is neuroimaging so illuminating? According to Professor Anissa Abi-Dargham, the newly-appointed Professor of Psychiatry and Vice Chair for research in the Department of Psychiatry at Stony Brook University in New York, USA, it’s the ability of neuroimaging to tease out the multifaceted aspects of dopaminergic dysfunction at play as schizophrenia evolves, emerges and progresses as a clinical entity.

Professor Abi-Dargham provided an exhaustive review of decades of research that has been seated in the idea that dopaminergic dysfunction is a downstream effect of many other alterations in the brain. Dopaminergic pathways and processes in schizophrenia have been implicated ever since it was shown that the dopamine antagonist chlorpromazine had antipsychotic activity.

 

DA deficits as well as excesses

Professor Abi-Dargham urged delegates to consider the evidence that shows that - beyond excessive striatal presynaptic dopamine levels and excess D2 receptor stimulation - schizophrenia appears to involve profound deficits in dopamine in the cortex and other extra-striatal regions.

There appears to be more to the condition than hyperactivity of transmission mediated by D2 receptors in the limbic system.1

 

An interconnected and evolving process

She also reminded delegates that many excitatory and inhibitory processes in cortical circuits are tightly modulated by dopamine, and that key aspects of dopaminergic function in these regions arise as a result of events and processes at play in adolescence and maturation. 2-4

Professor Abi-Dargham explained that changes in cortical inhibitory circuits in the juvenile cortex during adolescence are implicated in the transition to schizophrenia. Initially D1 receptor stimulation predominates, with D2 receptor stimulation becoming more prominent during adulthood.

 

Sensitivities also affected

Imaging studies have allowed researchers to measure the number and density of synaptic (pre and post) D2 receptors and their occupancy, and the impact of schizophrenia on dopamine uptake, synthesis and storage. The availability of radiolabeled ligands with different binding affinities for dopamine receptors allows for comparison of dopaminergic activity across different brain regions.

In schizophrenia, while there is excess dopamine release in the striatum, it appears from imaging studies that specifically, it is changes in the rostral caudate, and stimulation of dopamine receptors in this brain region, that may be linked with psychosis. Excessive dopamine appears to affect brain plasticity within the striatum, weakening the rostral caudate connectivity with the rest of the brain.

 

Wide-ranging dopaminergic dysfunction

Professor Abi-Dargham said that it seems too little dopaminergic activity in the ventral striatum is linked with negative symptoms in schizophrenia, while too much activity might lead to psychosis. She said that dopamine appears to have less influence in the sensory motor striatum.

 

Not a level playing field

Imaging studies also suggest that some patients may not display the elevations in dopamine that are classically associated with the disorder – and as such may not respond as well as other patients to antipsychotic therapies that target and aim to block dopaminergic effects. Likewise, there may be some patients such as those with co-morbid substance abuse, who may have altered post-synaptic D2 receptor function, in the face of reduced dopamine release. 5,6

 

Dopamine and cognitive function

Professor Abi-Dargham described studies examining the neural correlates of working memory impairment in schizophrenia and their relation with dopaminergic dysfunction. 7-9

Research from her own group using PET fMRI suggests that there may be deficits in dopamine release within the dorsolateral prefrontal cortex (DLPFC) that are part of a widespread dopaminergic deficit affecting many cortical and extrastriatal regions, including the mid brain. 10,11  

 

Expanding the hypothesis on dopamine and schizophrenia

According to Professor Abi-Dargham, neuroimaging studies – preclinical and clinical – are helping to expand ideas on dopaminergic dysfunction in schizophrenia. 12 The striatum appears to be the only region of the brain with excessive dopamine release in schizophrenia, although it is not clear if this is due to a small subset or abnormally firing cells or linked with changes in local regulation of dopaminergic function.  Professor Abi-Dargham said that there is evidence for extrastriatal deficits and she described mid brain dopamine deficits as puzzling.

Future areas that Professor Abi-Dargham said are ripe for exploration using neuroimaging include study of the evolution of dopaminergic dysfunction in schizophrenia to establish what changes are already brewing as a result of genetic predisposition, study of dopaminergic plasticity including changes in dopamine turnover and receptor expression and activity, and more investigation of the effects of other neurotransmitter systems on dopaminergic function. She added that stem cell research might offer new ways to explore the cellular mechanisms and connectivity changes that determine the machinery and pathways of schizophrenia. Professor Abi-Dargham said that new insights will help inform and improve approaches to treatment of schizophrenia.

References
  1. Kegeles LS, et al. Increased synaptic dopamine function in associative regions of the striatum in schizophrenia. Arch Gen Psychiatry 2010;67(3):231-9.
  2. O’Donnell, P. Adolescent onset of cortical disinhibition in schizophrenia: insights from animal models. Schizophr Bull 2011;37 (3):484-92.
  3. Gerfen CR, Surmeier, DJ. Modulation of striatal projection systems by dopamine. Annu Rev Neurosci 2011;34:441-66.
  4. Howes OD, , et al. Dopamine synthesis capacity before onset of psychosis: a prospective [18F]-DOPA PET imaging study. Am J Psychiatry. 2011 Dec;168(12):1311-7
  5. Demjaha A, et al. Dopamine synthesis capacity in patients with treatment-resistant schizophrenia. Am J Psychiatry 2012;169(11):1203-10.
  6. Thompson, JL, et al. Striatal dopamine release in schizophrenia comorbid with substance dependence. Mol Psychiatry 2013;18(8):9090-15
  7. Van Snellenberg JX et al. Mechanisms of working memory impairment in schizophrenia. Biol Psychiatry 2016 Feb 23. pii: S0006-3223(16)00129-3. doi: 10.1016/j.biopsych.2016.02.017. [Epub ahead of print]
  8.  Kellendonk C et al. Modelling cognitive endophenotypes of schizophrenia in mice. Trends Neurosci 2009;32:347-58.
  9. Kellendonk C et al. Modelling excess striatal D2 receptors in mice. Prog Brain Res 2009;179:59-65.
  10. Slifstein M, et al. Deficits in prefrontal cortical and extrastriatal dopamine release in schizophrenia: a positron emission tomographic functional magnetic resonance imaging study. JAMA Psychiatry 2015;72:316-24.
  11. Cassidy CM, et al. Dynamic Connectivity between Brain Networks Supports Working Memory: Relationships to Dopamine Release and Schizophrenia. J Neurosci 2016;36:4377-88.
  12.  Cazorla M et al Dopamine D2 receptors regulate the anatomical and functional balance of basal ganglia activity. Neuron 2014;81:153-64.
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