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      Schizophrenia, Dopamine and the Striatum: From Biology to Symptoms

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          Abstract

          The mesolimbic hypothesis has been a central dogma of schizophrenia for decades, positing that aberrant functioning of midbrain dopamine projections to limbic regions causes psychotic symptoms. Recently, however, advances in neuroimaging techniques have led to the unanticipated finding that dopaminergic dysfunction in schizophrenia is greatest within nigrostriatal pathways, implicating the dorsal striatum in the pathophysiology and calling into question the mesolimbic theory. At the same time our knowledge of striatal anatomy and function has progressed, suggesting new mechanisms via which striatal dysfunction may contribute to the symptoms of schizophrenia. This Review draws together these developments, to explore what they mean for our understanding of the pathophysiology, clinical manifestations, and treatment of the disorder.

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          A mesoscale connectome of the mouse brain.

          Seung Wook Oh, Julie Harris, Lydia Ng … (2014)
          Comprehensive knowledge of the brain's wiring diagram is fundamental for understanding how the nervous system processes information at both local and global scales. However, with the singular exception of the C. elegans microscale connectome, there are no complete connectivity data sets in other species. Here we report a brain-wide, cellular-level, mesoscale connectome for the mouse. The Allen Mouse Brain Connectivity Atlas uses enhanced green fluorescent protein (EGFP)-expressing adeno-associated viral vectors to trace axonal projections from defined regions and cell types, and high-throughput serial two-photon tomography to image the EGFP-labelled axons throughout the brain. This systematic and standardized approach allows spatial registration of individual experiments into a common three dimensional (3D) reference space, resulting in a whole-brain connectivity matrix. A computational model yields insights into connectional strength distribution, symmetry and other network properties. Virtual tractography illustrates 3D topography among interconnected regions. Cortico-thalamic pathway analysis demonstrates segregation and integration of parallel pathways. The Allen Mouse Brain Connectivity Atlas is a freely available, foundational resource for structural and functional investigations into the neural circuits that support behavioural and cognitive processes in health and disease.
          Article 0 comments Cited 1029 times – based on 0 reviews     Review now
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            Psychosis as a state of aberrant salience: a framework linking biology, phenomenology, and pharmacology in schizophrenia.

            Shitij Kapur (2002)
            The clinical hallmark of schizophrenia is psychosis. The objective of this overview is to link the neurobiology (brain), the phenomenological experience (mind), and pharmacological aspects of psychosis-in-schizophrenia into a unitary framework. Current ideas regarding the neurobiology and phenomenology of psychosis and schizophrenia, the role of dopamine, and the mechanism of action of antipsychotic medication were integrated to develop this framework. A central role of dopamine is to mediate the "salience" of environmental events and internal representations. It is proposed that a dysregulated, hyperdopaminergic state, at a "brain" level of description and analysis, leads to an aberrant assignment of salience to the elements of one's experience, at a "mind" level. Delusions are a cognitive effort by the patient to make sense of these aberrantly salient experiences, whereas hallucinations reflect a direct experience of the aberrant salience of internal representations. Antipsychotics "dampen the salience" of these abnormal experiences and by doing so permit the resolution of symptoms. The antipsychotics do not erase the symptoms but provide the platform for a process of psychological resolution. However, if antipsychotic treatment is stopped, the dysregulated neurochemistry returns, the dormant ideas and experiences become reinvested with aberrant salience, and a relapse occurs. The article provides a heuristic framework for linking the psychological and biological in psychosis. Predictions of this hypothesis, particularly regarding the possibility of synergy between psychological and pharmacological therapies, are presented. The author describes how the hypothesis is complementary to other ideas about psychosis and also discusses its limitations.
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              Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats.

              G Di Chiara, A. Imperato (1988)
              The effect of various drugs on the extracellular concentration of dopamine in two terminal dopaminergic areas, the nucleus accumbens septi (a limbic area) and the dorsal caudate nucleus (a subcortical motor area), was studied in freely moving rats by using brain dialysis. Drugs abused by humans (e.g., opiates, ethanol, nicotine, amphetamine, and cocaine) increased extracellular dopamine concentrations in both areas, but especially in the accumbens, and elicited hypermotility at low doses. On the other hand, drugs with aversive properties (e.g., agonists of kappa opioid receptors, U-50,488, tifluadom, and bremazocine) reduced dopamine release in the accumbens and in the caudate and elicited hypomotility. Haloperidol, a neuroleptic drug, increased extracellular dopamine concentrations, but this effect was not preferential for the accumbens and was associated with hypomotility and sedation. Drugs not abused by humans [e.g., imipramine (an antidepressant), atropine (an antimuscarinic drug), and diphenhydramine (an antihistamine)] failed to modify synaptic dopamine concentrations. These results provide biochemical evidence for the hypothesis that stimulation of dopamine transmission in the limbic system might be a fundamental property of drugs that are abused.
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 7808616
                Journal ID (pubmed-jr-id): 7840
                Journal ID (nlm-ta): Trends Neurosci
                Journal ID (iso-abbrev): Trends Neurosci.
                Title: Trends in neurosciences
                ISSN (Print): 0166-2236
                ISSN (Electronic): 1878-108X
                Publication date Nihms-submitted: 28 February 2019
                Publication date (Electronic): 06 January 2019
                Publication date (Print): March 2019
                Publication date PMC-release: 15 March 2019
                Volume: 42
                Issue: 3
                Pages: 205-220
                Affiliations
                [1 ]Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, De Crespigny Park, London, SE5 8AF, UK
                [2 ]MRC London Institute of Medical Sciences, Hammersmith Hospital, London, W12 0NN, UK
                [3 ]Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, W12 0NN, UK
                [4 ]South London and Maudsley NHS Foundation Trust, London, SE5 8AF, UK
                [5 ]Department of Psychiatry, School of Medicine, Stony Brook University, New York, USA
                Author notes
                [* ]Correspondence: oliver.howes@ 123456kcl.ac.uk (O.D. Howes).
                Article
                Manuscript ID: EMS82043
                DOI: 10.1016/j.tins.2018.12.004
                PMC ID: 6401206
                PubMed ID: 30621912
                SO-VID: beacec9f-4a0c-4f8c-a42b-931759762b4e
                License:

                This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/).

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                ScienceOpen disciplines: Neurosciences
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                ScienceOpen disciplines: Neurosciences

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