Dopamine D2 Receptor Levels in Striatum, Thalamus, Substantia Nigra, Limbic Regions, and Cortex in Schizophrenic Subjects

Kessler, Robert; Woodward, Neil D.; Riccardi, Patrizia; Li, Rui; Ansari, M. Sib; Anderson, Sharlett; Dawant, Benoît M.; Zald, David H.; Meltzer, Herbert Y.

doi:10.1016/j.biopsych.2008.12.029

Cited by 121 publications

(87 citation statements)

References 85 publications

(111 reference statements)

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“…We found that D2R binding in the ventral striatum was one-third that of the dorsal striatum, consistent with previous reports in humans using PET (Okubo et al, 1999;Kessler et al, 2009) and postmortem epidepride binding (Joyce et al, 1991;Hall et al, 1996). Intriguingly, an in situ hybridization study in humans found higher levels of D 2 mRNA in the ventral striatum than the dorsal striatum (Meador-Woodruff et al, 1996), suggesting less D 2 message translation in the ventral striatum.…”

Section: Discussionsupporting

confidence: 92%

Relationship between Dose, Drug Levels, and D2 Receptor Occupancy for the Atypical Antipsychotics Risperidone and Paliperidone

Muly¹,

Votaw²,

Ritchie³

et al. 2012

J Pharmacol Exp Ther

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Blockade of D2 family dopamine receptors (D2Rs) is a fundamental property of antipsychotics, and the degree of striatal D2R occupancy has been related to antipsychotic and motor effects of these drugs. Recent studies suggest the D2R occupancy of antipsychotics may differ in extrastriatal regions compared with the dorsal striatum. We studied this issue in macaque monkeys by using a within-subjects design. [ 18 F]fallypride positron emission tomography scans were obtained on four different doses of risperidone and paliperidone (the 9-OH metabolite of risperidone) and compared with multiple off-drug scans in each animal. The half-life of the two drugs in these monkeys was determined to be between 3 and 4 h, and drug was administered by a constant infusion through an intragastric catheter. The D2R occupancy of antipsychotic was determined in the caudate, putamen, ventral striatum, and four prefrontal and temporal cortical regions and was related to serum and cerebrospinal fluid drug levels. Repeated 2-week treatment with risperidone or paliperidone did not produce lasting changes in D2R binding potential in any region examined. As expected, D2R binding potential was highest in the caudate and putamen and was approximately one-third that level in the ventral striatum and 2% of that level in the cortical regions. We found dose-dependent D2R occupancy for both risperidone and paliperidone in both basal ganglia and cortical regions of interest. We could not find evidence of regional variation in D2R occupancy of either drug. Comparison of D2R occupancy and serum drug levels supports a target of 40 to 80 ng/ml active drug for these two atypical antipsychotics.

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Section: Discussionsupporting

confidence: 92%

Relationship between Dose, Drug Levels, and D2 Receptor Occupancy for the Atypical Antipsychotics Risperidone and Paliperidone

Muly¹,

Votaw²,

Ritchie³

et al. 2012

J Pharmacol Exp Ther

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“…The diffuse projections of these subcortical structures may account for the wide range of cognitive findings and cortical damage exhibited across the C9ORF72 mutation cohort here. Involvement of thalamus and cerebellar connections could underpin the prominent neuropsychiatric features shown by these cases (Andreasen et al, 1996;Schmahmann, 2005;Goossens et al, 2007;Straube et al, 2007;Schmahmann and Pandya, 2008;Tedesco et al, 2011), as well as episodic memory deficits ( Van der Werf et al, 2003;de Jong et al, 2008) somatic complaints, hallucinations and delusions (Kessler et al, 2009;Tedesco et al, 2011). Although none of our cases had frank cerebellar ataxia, this has been described in previous cases of chromosome 9 linked FTLD (Pearson et al, 2011).…”

Section: Discussionsupporting

confidence: 68%

O1‐05‐01: Frontotemporal dementia with the C9ORF72 hexanucleotide repeat expansion: Clinical, neuroanatomical and neuropathological features

Mahoney¹,

Beck²,

Rohrer

et al. 2012

Alzheimer's & Dementia

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An expanded hexanucleotide repeat in the C9ORF72 gene has recently been identified as a major cause of familial frontotemporal lobar degeneration and motor neuron disease, including cases previously identified as linked to chromosome 9. Here we present a detailed retrospective clinical, neuroimaging and histopathological analysis of a C9ORF72 mutation case series in relation to other forms of genetically determined frontotemporal lobar degeneration ascertained at a specialist centre. Eighteen probands (19 cases in total) were identified, representing 35% of frontotemporal lobar degeneration cases with identified mutations, 36% of cases with clinical evidence of motor neuron disease and 7% of the entire cohort. Thirty-three per cent of these C9ORF72 cases had no identified relevant family history. Families showed wide variation in clinical onset (43-68 years) and duration (1.7-22 years). The most common presenting syndrome (comprising a half of cases) was behavioural variant frontotemporal dementia, however, there was substantial clinical heterogeneity across the C9ORF72 mutation cohort. Sixty per cent of cases developed clinical features consistent with motor neuron disease during the period of follow-up. Anxiety and agitation and memory impairment were prominent features (between a half to two-thirds of cases), and dominant parietal dysfunction was also frequent. Affected individuals showed variable magnetic resonance imaging findings; however, relative to healthy controls, the group as a whole showed extensive thinning of frontal, temporal and parietal cortices, subcortical grey matter atrophy including thalamus and cerebellum and involvement of long intrahemispheric, commissural and corticospinal tracts. The neuroimaging profile of the C9ORF72 expansion was significantly more symmetrical than progranulin mutations with significantly less temporal lobe involvement than microtubule-associated protein tau mutations. Neuropathological examination in six cases with C9ORF72 mutation from the frontotemporal lobar degeneration series identified histomorphological features consistent with either type A or B TAR DNA-binding protein-43 deposition; however, p62-positive (in excess of TAR DNA-binding protein-43 positive) neuronal cytoplasmic inclusions in hippocampus and cerebellum were a consistent feature of these cases, in contrast to the similar frequency of p62 and TAR DNA-binding protein-43 deposition in 53 control cases with frontotemporal lobar degeneration-TAR DNA-binding protein. These findings corroborate the clinical importance of the C9ORF72 mutation in frontotemporal lobar degeneration, delineate phenotypic and neuropathological features that could help to guide genetic testing, and suggest hypotheses for elucidating the neurobiology of a culprit subcortical network.

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“…Importantly, the current data are also consistent with that from previous studies using antagonist radioligands, which showed no difference in D 2 binding between healthy controls and patients with schizophrenia, 4,5,50 although in those studies, participants were scanned at rest. In contrast, several studies reported reduced D 2/3 in the thalamus in patients with schizophrenia, [51][52][53] whereas Kegeles and colleagues 54 observed increases in thalamic BP ND . Consistent with the results of Glenthoj and colleagues 55 and Talvik and colleagues, 56 we found no significant difference at the level of the whole thalamus.…”

Section: Discussionmentioning

confidence: 89%

Dopamine D2 and D3 binding in people at clinical high risk for schizophrenia, antipsychotic-naive patients and healthy controls while performing a cognitive task

Suridjan

Rusjan²,

Addington³

et al. 2013

J Psychiatry Neurosci

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Dopamine D2 Receptor Levels in Striatum, Thalamus, Substantia Nigra, Limbic Regions, and Cortex in Schizophrenic Subjects

Abstract: Background-Studies in schizophrenics have reported dopaminergic abnormalities in striatum, substantia nigra, thalamus, anterior cingulate, hippocampus and cortex which have been related to positive symptoms and cognitive impairments.

Cited by 121 publications

References 85 publications

Relationship between Dose, Drug Levels, and D2 Receptor Occupancy for the Atypical Antipsychotics Risperidone and Paliperidone

Relationship between Dose, Drug Levels, and D2 Receptor Occupancy for the Atypical Antipsychotics Risperidone and Paliperidone

O1‐05‐01: Frontotemporal dementia with the C9ORF72 hexanucleotide repeat expansion: Clinical, neuroanatomical and neuropathological features

Dopamine D2 and D3 binding in people at clinical high risk for schizophrenia, antipsychotic-naive patients and healthy controls while performing a cognitive task

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