Within-Subject Comparison of [<sup>11</sup>C]-( + )-PHNO and [<sup>11</sup>C]raclopride Sensitivity to Acute Amphetamine Challenge in Healthy Humans

Self Cite

Animal studies support the role of the dopamine D3 receptor (DRD3) in alcohol reinforcement or liking. Sustained voluntary alcohol drinking in rats has been associated with an upregulation of striatal DRD3 gene expression and selective blockade of DRD3 reduces ethanol preference, consumption, and cue-induced reinstatement. In vivo measurement of DRD3 in the living human brain has not been possible until recently owing to a lack of suitable tools. In this study, DRD3 status was assessed for the first time in human alcohol addiction. Brain DRD3 availability was compared between 16 male abstinent alcohol-dependent patients and 13 healthy non-dependent age-matched males using the DRD3-preferring agonist positron emission tomography (PET) radioligand [ 11 C]PHNO with and without blockade with a selective DRD3 antagonist (GSK598809 60 mg p.o.). In striatal regions of interest, where the [ 11 C]PHNO PET signal represents primarily DRD2 binding, no differences were seen in [ 11 C]PHNO binding between the groups at baseline. However, baseline [ 11 C]PHNO binding was higher in alcohol-dependent patients in hypothalamus (V T : 16.5±4 vs 13.7±2.9, p ¼ 0.040), a region in which the [ 11 C]PHNO signal almost entirely reflects DRD3 availability. The reductions in regional receptor binding (V T ) following a single oral dose of GSK598809 (60 mg) were consistent with those observed in previous studies across all regions. There were no differences in regional changes in V T following DRD3 blockade between the two groups, indicating that the regional fractions of DRD3 are similar in the two groups, and the increased [ 11 C]PHNO binding in the hypothalamus in alcohol-dependent patients is explained by elevated DRD3 in this group. Although we found no difference between alcohol-dependent patients and controls in striatal DRD3 levels, increased DRD3 binding in the hypothalamus of alcohol-dependent patients was observed. This may be relevant to the development of future therapeutic strategies to treat alcohol abuse.

Section: D3 Receptors In Alcoholismmentioning

confidence: 65%

Section: D3 Receptors In Alcoholismmentioning

confidence: 96%

In Vivo Imaging of Cerebral Dopamine D3 Receptors in Alcoholism

Erritzoe

Tziortzi

Bargiela

et al. 2014

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“…Previous studies combining [ 11 C]raclopride PET and in vivo microdialysis in rhesus monkeys have shown that very large increases in synaptic DA concentrations were reflected in comparatively smaller changes in [ 11 C]raclopride binding (Breier et al, 1997;Endres et al, 1997). [ 11 C]-( þ )-PHNO is more sensitive to displacement by synaptic DA Narendran et al, 2006a;Shotbolt et al, 2012). However, the relationship between synaptic DA outflow and [ 11 C]-( þ )-PHNO binding is unknown.…”

Section: Resultsmentioning

confidence: 98%

Dopamine Response to Psychosocial Stress in Chronic Cannabis Users: A PET Study With [11C]-(+)-PHNO

Mizrahi

Suridjan

Kenk

et al. 2012

A number of addictions have been linked with decreased striatal dopamine (DA) receptor availability and DA release. Stress has a key role in cannabis craving, as well as in modulation of dopaminergic signaling. The present study aimed to assess DA release in response to a laboratory stress task with [ 11 C]-( þ )-PHNO positron emission tomography in cannabis users (CU). Thirteen healthy CU and 12 healthy volunteers (HV) were scanned during a sensorimotor control task (SMCT) and under a stress condition using the validated Montreal imaging stress task (MIST). The simplified reference tissue model (SRTM) was used to obtain binding potential (BP ND ) in striatal subdivisions: limbic striatum (LST), associative striatum (AST), and sensorimotor striatum (SMST). Stress-induced DA release (indexed as a percentage of reduction in , with no effect in any other brain region. In conclusion, despite an increase in striatal BP ND observed during the control task, chronic cannabis use is not associated with alterations in stress-induced DA release.

“…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). Prior work done with [ 11 C](+) PHNO has indicated that BMI correlated positively with D 2/3 R availability in the ventral striatum (VST) (Caravaggio et al, 2013), a region of mixed D 2 Rs and D 3 Rs (Tziortzi et al, 2011), in a cohort with a relatively narrow non-OB BMI range (range 18.6-27.8 kg/m 2 , mean 23.4 kg/m 2 ).…”

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

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.