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Elevation of brain neuroleptic/dopamine receptors in schizophrenia
... The dopamine hypothesis of schizophrenia theorizes that hyperactivity of dopamine 2 receptor (D2R) neurotransmission in subcortical and limbic regions of the brain may contribute to positive symptoms of schizophrenia, potentially in part due to an increase in D2R density [41][42][43][44][45]. Negative and cognitive symptoms of schizophrenia on the other hand are believed to be associated, at least in part, with cortical hypofunctionality of the dopamine 1 receptor [46,47]. ...
The increase in presynaptic striatal dopamine is the main dopaminergic abnormality in schizophrenia (SCZ). SCZ is primarily treated by modulating the activity of monoamine systems, with a focus on dopamine and serotonin receptors. Glial cell line-derived neurotrophic factor (GDNF) is a strong dopaminergic factor, that recently was shown to correlate with SCZ in human CSF and in striatal tissue. A 2-3-fold increase in GDNF in the brain was sufficient to induce SCZ-like dopaminergic and behavioural changes in mice. Here, we analysed the effect of acute, chronic, and embryonic methamphetamine, a drug known to enhance the risk of psychosis, on Gdnf and its receptors, Gfra1 and Ret, as well as on monoamine metabolism-related gene expression in the mouse brain. We found that acute methamphetamine application increases Gdnf expression in the striatum and chronic methamphetamine decreases the striatal expression of GDNF receptors Gfra1 and Ret. Both chronic and acute methamphetamine treatment upregulated the expression of genes related to dopamine and serotonin metabolism in the striatum, prefrontal cortex, and substantia nigra. Our results suggest a potential mechanism as to how methamphetamine elicits individual psychosis risk in young adults—variation in initial striatal GDNF induction and subsequent GFRα1 and RET downregulation may determine individual susceptibility to psychosis. Our results may guide future experiments and precision medicine development for methamphetamine-induced psychosis using GDNF/GFRa1/RET antagonists.
... The Seeman laboratory tested the numbers of D2 receptors in schizophrenia post mortem striatal tissue against the numbers in general population post mortem brain and found them to be significantly elevated (11) . The research team thought it had discovered a schizophrenia biomarker, but then discovered that the distribution of D2 receptors in the post mortem brain of individuals with schizophrenia was bimodal, meaning that some had higher D2 densities than controls and some did not (12) . ...
This brief article summarizes the contributions of Philip Seeman to the understanding of the role of dopamine receptors in the etiology of schizophrenia and in the mode of action of antipsychotic drugs.
... This is supported by the clinical potency of first-generation antipsychotics (and to some extent, second-generation "atypical" 31 ), whereby blockade of striatal dopamine D2 receptors correlates with therapeutic efficacy for psychotic symptoms 32,33 . In humans, these receptors are primarily expressed in the dorsal striatum [34][35][36] . Complementary work centered on the DA hypothesis implicates hippocampal, thalamic and focal ventral tegmental area (VTA) alterations as central in the formation of positive symptoms of SCZ 37,38 . ...
Distributed neural dysconnectivity is considered a hallmark feature of schizophrenia, yet a tension exists between studies pinpointing focal disruptions versus those implicating brain-wide disturbances. The cerebellum and the striatum communicate reciprocally with the thalamus and cortex through monosynaptic and polysynaptic connections, forming cortico-striatal-thalamic-cerebellar (CSTC) functional pathways that may be sensitive to brain-wide dysconnectivity in schizophrenia. It remains unknown if the same pattern of alterations persists across CSTC systems, or if specific alterations exist along key functional elements of these networks. We characterized connectivity along major functional CSTC subdivisions using resting-state functional magnetic resonance imaging in 159 chronic patients and 162 matched controls. Associative CSTC subdivisions revealed consistent brain-wide bi-directional alterations in patients, marked by hyper-connectivity with sensory-motor cortices and hypo-connectivity with association cortex. Focusing on the cerebellar and striatal components, we validate the effects using data-driven k -means clustering of voxel-wise dysconnectivity and support vector machine classifiers. We replicate these results in an independent sample of 202 controls and 145 patients, additionally demonstrating that these neural effects relate to cognitive performance across subjects. Taken together, these results from complementary approaches implicate a consistent motif of brain-wide alterations in CSTC systems in schizophrenia, calling into question accounts of exclusively focal functional disturbances.
... Molecular imaging studies have supported an association of increased subcortical dopamine transmission with the positive symptoms of schizophrenia, with the limitation that this finding is not pathognomonic [16]. Early post-mortem studies suggested that the neuropathological changes in schizophrenia included both an increase in striatal dopamine levels, and an increase in D2 receptor density [17]. Recent research has shown tyrosine hydroxylase, the rate-limiting enzyme involved in the synthesis of dopamine, is significantly increased in the substantia nigra of patients with schizophrenia compared to patients with depression and healthy controls [18]. ...
Introduction: Schizophrenia is one of the most serious and frightening of all mental illnesses. It affects almost 1% of the population worldwide. The main concept and treatment of schizophrenia are based on the dopaminergic hypothesis. However, accumulating evidence has shown that the core pathophysiology of schizophrenia might involve dysfunction in dopaminergic, glutamatergic, serotonergic, and gamma-aminobutyric acid signaling.The aim of the study: The purpose of this systemic review was to collect and analyse current and new information on the pathogenesis of schizophrenia.Material and method: Standard criteria were used to review the literature data. The search of articles in the PubMed database was carried out using the following keywords: schizophrenia, dopamine hypothesis, serotoninergic hypothesis, hypothesis of schizophrenia .Description of the state of knowledge: There are evidence that pathogenesis of schizophrenia include dysfunction in dopaminergic, serotoninergic, GABAergic, glutamatergic systems. The use of drugs that act on any of these systems reduces the symptoms of the disease. Nicotinic receptors may also be the target for drugs in treatment of schizophrenia. Studies about the role of nicotinic receptors in pathogenesis of schizophrenia show that it normalize many of the sensory processing deficits found in schizophrenia.Summary: Despite the fact that current concept and treatment are still based on the dopaminergic hypothesis of the disease, existing theories and each new theory, open up different ways for treating schizophrenia. Considering that schizophrenia is one of the most serious and frightening of all mental illnesses and has major public health implications, more research about pathogenesis and ways of treatment is needed.
... This is supported by the clinical potency of first-generation antipsychotics (and to some extent, second-generation "atypical" (Seeman 2002)), whereby blockade of striatal dopamine D2 receptors correlates with therapeutic efficacy for psychotic symptoms (Seeman and Lee 1975;. In humans, these receptors are primarily expressed in the dorsal striatum (Lee and Seeman 1980;Mackay et al. 1982;Howes et al. 2009). Complementary work centered on the DA hypothesis implicates hippocampal, thalamic and focal ventral tegmental area (VTA) alterations as central in the formation of positive symptoms of SCZ (Grace et al. 2007;Lodge and Grace 2011). ...
Distributed neural dysconnectivity is considered a hallmark feature of schizophrenia (SCZ), yet a tension exists between studies pinpointing focal disruptions versus those implicating brain-wide disturbances. The cerebellum and the striatum communicate reciprocally with the thalamus and cortex through monosynaptic and polysynaptic connections, forming cortico-striatal-thalamic-cerebellar (CSTC) functional pathways that may be sensitive to brain-wide dysconnectivity in SCZ. It remains unknown if the same pattern of alterations persists across CSTC systems, or if specific alterations exist along key functional elements of these networks. We characterized connectivity along major functional CSTC subdivisions using resting-state functional magnetic resonance imaging in 159 chronic patients and 162 matched controls. Associative CSTC subdivisions revealed consistent brain-wide bi-directional alterations in patients, marked by hyper-connectivity with sensory-motor cortices and hypo-connectivity with association cortex. Focusing on the cerebellar and striatal components, we validate the effects using data-driven k-means clustering of voxel-wise dysconnectivity and support vector machine classifiers. We replicate these results in an independent sample of 202 controls and 145 patients, additionally demonstrating that these neural effects relate to cognitive performance across subjects. Taken together, these results from complementary approaches implicate a consistent motif of brain-wide alterations in CSTC systems in SCZ, calling into question accounts of exclusively focal functional disturbances.
... Evidence supporting a role for mesolimbic hyperdopaminergia in psychosis has come from in vivo microdialysis studies in freely-moving rats showing a preferential increase of extracellular dopamine in the ventral striatum following administration of dopamine agonists (Carboni et al., 1989;Robinson et al., 1988). Both post-mortem and in vivo positron emission tomography (PET) studies have reported evidence of increased density of dopamine receptors, particularly D2 receptors, in the striatum of treatment-naive and medicated schizophrenia patients Lee and Seeman, 1980;Owen et al., 1978;Wong et al., 1986), although these increases may be partly driven by antipsychotic medication (for a discussion see (Howes et al., 2015)). ...
The dopamine hypothesis is the longest standing pathoetiologic theory of schizophrenia. Because it was initially based on indirect evidence and findings in patients with established schizophrenia, it was unclear what role dopamine played in the onset of the disorder. However, recent studies in people at risk of schizophrenia have found elevated striatal dopamine synthesis capacity and increased dopamine release to stress. Furthermore, striatal dopamine changes have been linked to altered cortical function during cognitive tasks, in line with preclinical evidence that a circuit involving cortical projections to the striatum and midbrain may underlie the striatal dopamine changes. Other studies have shown that a number of environmental risk factors for schizophrenia, such as social isolation and childhood trauma, also affect presynaptic dopaminergic function. Advances in preclinical work and genetics have begun to unravel the molecular architecture linking dopamine, psychosis, and psychosocial stress. Included among the many genes associated with risk of schizophrenia are the gene encoding the dopamine D2 receptor and those involved in the upstream regulation of dopaminergic synthesis, through glutamatergic and gamma-aminobutyric acidergic pathways. A number of these pathways are also linked to the stress response. We review these new lines of evidence and present a model of how genes and environmental factors may sensitize the dopamine system so that it is vulnerable to acute stress, leading to progressive dysregulation and the onset of psychosis. Finally, we consider the implications for rational drug development, in particular regionally selective dopaminergic modulation, and the potential of genetic factors to stratify patients.
Postmortem research historically provided the technical and evidential basis for in vivo receptor imaging. In vitro mapping of receptor distribution and density is an essential first step for novel tracer development in order to image brain receptors in a living human subject. The chapter reviews the technical distinctions between receptor estimation postmortem and in vivo. The advantages and disadvantages of each approach are also discussed with respect to psychiatric disorder in particular. The neuropharmacology of schizophrenia has been most studied with neuroreceptor imaging and is used as an instructive example of the contribution of both methodologies to understanding the role of dopamine in the disorder. These data include simple studies estimating dopamine D2 receptors in schizophrenia, dynamic in vivo challenges of the dopamine system, and examining the links between dopamine D2 receptor occupancy by antipsychotic drugs and their toxic and therapeutic effects. These studies reveal the necessity of bridging the gap between ante- and postmortem research in schizophrenia and other disorders.
Because of the structurally and functionally heterogeneous nature of the brain, it is necessary to measure changes in physiologic and biochemical parameters in the human brain on a regional basis. Such information is important in furthering our understanding of the normal function of the brain and the derangements that occur in various pathologic conditions. The development of the Kety-Schmidt technique for the quantitative measurement of cerebral blood flow in man, made it possible to determine the average rates of glucose and oxygen utilization and blood flow in the brain as a whole (1). Using these same principles a method to measure hemispheric changes in these parameters has been developed (2). Regional methods for the determination of cerebral blood flow using diffusable tracers have also been developed (3–5). These methods, however, do not provide 3-dimensional resolution by which it is possible to determine the physiologic and metabolic parameters in specific structural and functional subunits of the brain. With the development of the 18F-fluorodeoxyglucose technique it became possible to do this in terms of glucose metabolism in the human brain (6).
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