Brain region binding of the D2/3 agonist [11C]‐(+)‐PHNO and the D2/3 antagonist [11C]raclopride in healthy humans

Graff‐Guerrero, Ariel; Willeit, Matthäus; Ginovart, Nathalie; Mamo, David C.; Mizrahi, Romina; Rusjan, Pablo; Vitcu, Irina; Seeman, Philip; Wilson, Alan A.; Kapur, Shitij

doi:10.1002/hbm.20392

Cited by 94 publications

(94 citation statements)

References 62 publications

(60 reference statements)

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“…Significant post hoc pair-wise comparisons with Bonferroni correction (po0.05) are indicated: a vs controls; b vs UHR. Glutamate in the striatum of prodrome and acute psychosis C de la Fuente-Sandoval et al antipsychotics (Farde et al, 1988;Graff-Guerrero et al, 2008). In addition, the associative striatum establishes major connections with the frontal lobe (Lehericy et al, 2004).…”

Section: Summary Of Main Resultsmentioning

confidence: 99%

Higher Levels of Glutamate in the Associative-Striatum of Subjects with Prodromal Symptoms of Schizophrenia and Patients with First-Episode Psychosis

Fuente‐Sandoval

León-Ortíz

Favila

et al. 2011

Neuropsychopharmacol

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The glutamatergic and dopaminergic systems are thought to be involved in the pathophysiology of schizophrenia. Their interaction has been widely documented and may have a role in the neurobiological basis of the disease. The aim of this study was to compare, using proton magnetic resonance spectroscopy ( 1 H-MRS), glutamate levels in the precommissural dorsal-caudate (a dopamine-rich region) and the cerebellar cortex (negligible for dopamine) in the following: (1) 18 antipsychotic-naïve subjects with prodromal symptoms and considered to be at ultra high-risk for schizophrenia (UHR), (2) 18 antipsychotic-naïve first-episode psychosis patients (FEP), and (3) 40 age-and sex-matched healthy controls. All subjects underwent a 1 H-MRS study using a 3Tesla scanner. Glutamate levels were quantified and corrected for the proportion of cerebrospinal fluid and percentage of gray matter in the voxel. The UHR and FEP groups showed higher levels of glutamate than controls, without differences between UHR and FEP. In the cerebellum, no differences were seen between the three groups. The higher glutamate level in the precommissural dorsal-caudate and not in the cerebellum of UHR and FEP suggests that a high glutamate level (a) precedes the onset of schizophrenia, and (b) is present in a dopamine-rich region previously implicated in the pathophysiology of schizophrenia.

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Section: Summary Of Main Resultsmentioning

confidence: 99%

Higher Levels of Glutamate in the Associative-Striatum of Subjects with Prodromal Symptoms of Schizophrenia and Patients with First-Episode Psychosis

Fuente‐Sandoval

León-Ortíz

Favila

et al. 2011

Neuropsychopharmacol

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208

157

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“…As previously mentioned, [ 11 C](+)PHNO is a D 2/3 R agonist tracer that has demonstrated higher binding in D 3 R-predominant extrastriatal regions compared with D 2 R-predominant dorsal striatal regions (Graff-Guerrero et al, 2008;Narendran et al, 2006;Searle et al, 2010;Tziortzi et al, 2011). Such a preference might explain why the current study demonstrated higher tracer binding in regions densely populated with D 3 Rs (ie, the SN/VTA and the pallidum) and in the mixed D 2/3 R area of the VST when compared with studies that utilized D 2/3 R antagonist tracers that predominantly estimate D 2 Rs.…”

Section: Discussionmentioning

confidence: 99%

“…The D 3 -preferring D 2/3 R agonist PET tracer, [ 11 C](+) PHNO, has been found to be especially reliable (due to an excellent specific-to-nonspecific binding ratio) at quantifying extrastriatal midbrain reward regions particularly essential for the synthesis and production of dopamine such as the SN/VTA, where D 3 Rs are predominant (Graff-Guerrero et al, 2008;Narendran et al, 2006;Searle et al, 2010;Tziortzi et al, 2011). In addition, [ 11 C](+)PHNO has also been shown to bind to high-affinity, presumably 'active', G-protein coupled forms of the D 2 R within the striatum (Shotbolt et al, 2012;Willeit et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Elevated Dopamine D2/3 Receptor Availability in Obese Individuals: A PET Imaging Study with [11C](+)PHNO

Gaiser

Gallezot

Worhunsky

et al. 2016

Neuropsychopharmacol

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Most prior work with positron emission tomography (PET) dopamine subtype 2/3 receptor (D 2/3 R) non-selective antagonist tracers suggests that obese (OB) individuals exhibit lower D 2/3 Rs when compared with normal weight (NW) individuals. A D 3 -preferring D 2/3 R agonist tracer, [ 11 C](+)PHNO, has demonstrated that body mass index (BMI) was positively associated with D 2/3 R availability within striatal reward regions. To date, OB individuals have not been studied with [ 11 C](+)PHNO. We assessed D 2/3 R availability in striatal and extrastriatal reward regions in 14 OB and 14 age-and gender-matched NW individuals with [ 11 C](+)PHNO PET utilizing a high-resolution research tomograph. Additionally, in regions where group D 2/3 R differences were observed, secondary analyses of 42 individuals that constituted an overweight cohort was done to study the linear association between BMI and D 2/3 R availability in those respective regions. A group-by-brain region interaction effect (F 7, 182 = 2.08, p= 0.047) was observed. Post hoc analyses revealed that OB individuals exhibited higher tracer binding in D 3 -rich regions: the substantia nigra/ventral tegmental area (SN/VTA) (+20%; p = 0.02), ventral striatum (VST) (+14%; po0.01), and pallidum (+11%; p = 0.02). BMI was also positively associated with D 2/3 R availability in the SN/VTA (r = 0.34, p = 0.03), VST (r = 0.36, p = 0.02), and pallidum (r = 0.30, p = 0.05) across all subjects. These data suggest that individuals who are obese have higher D 2/3 R availability in brain reward regions densely populated with D 3 Rs, potentially identifying a novel pharmacologic target for the treatment of obesity.

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“…It is also worth mentioning that the human and non-human primate studies were performed in vivo and thus the apparent decrease in binding could be due to an increase in endogenous dopamine, which would interfere with ligand binding. Whatever the case, it will clearly be important to conduct studies in addicts using ligands being developed to quantify the D2 High receptor (Graff-Guerrero, et al, 2007, Willeit, et al, 2008 to determine if the reported decrease in D2 receptors in addicts is more apparent than real.…”

Section: Discussionmentioning

confidence: 99%

Cocaine self-administration produces a persistent increase in dopamine D2High receptors

Briand

Flagel

Seeman

et al. 2008

European Neuropsychopharmacology

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Cocaine addicts are reported to have decreased numbers of striatal dopamine D2 receptors. However, in rodents, repeated cocaine administration consistently produces hypersensitivity to the psychomotor activating effects of both indirect dopamine agonists, such as cocaine itself, and importantly, to direct-acting D2 receptor agonists. The current study reports a possible resolution to this long-standing paradox. The dopamine D2 receptor exists in both a low and a high affinity state, and dopamine exerts its effects via the more functionally relevant high-affinity D2 receptor (D2 High ). We report here that cocaine self-administration experience produces a large (approximately 150%) increase in the proportion of D2 High receptors in the striatum with no change in the total number of D2 receptors, and this effect is evident both 3 and 30 days after the discontinuation of cocaine self-administration. Changes in D2 High receptors would not be evident with the probes used in human (and non-human primate) imaging studies. We suggest, therefore, that cocaine addicts and animals previously treated with cocaine may be hyper-responsive to dopaminergic drugs in part because an increase in D2 High receptors results in dopamine supersensitivity. This may also help explain why stimuli that increase dopamine neurotransmission, including drugs themselves, are so effective in producing relapse in individuals with a history of exposure to cocaine.

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Brain region binding of the D_2/3 agonist [¹¹C]‐(+)‐PHNO and the D_2/3 antagonist [¹¹C]raclopride in healthy humans

Cited by 94 publications

References 62 publications

Higher Levels of Glutamate in the Associative-Striatum of Subjects with Prodromal Symptoms of Schizophrenia and Patients with First-Episode Psychosis

Higher Levels of Glutamate in the Associative-Striatum of Subjects with Prodromal Symptoms of Schizophrenia and Patients with First-Episode Psychosis

Elevated Dopamine D2/3 Receptor Availability in Obese Individuals: A PET Imaging Study with [11C](+)PHNO

Cocaine self-administration produces a persistent increase in dopamine D2High receptors

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