In Vivo Imaging of Cerebral Dopamine D3 Receptors in Alcoholism

Abstract

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.

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

“…Further work has investigated a selective D 3 -antagonist medication in an operant food self-administration paradigm and showed that a D 3 -antagonist attenuated lever presses and food intake in both lean and OB rats, providing preliminary evidence of D 3 R-related motivation to consume food (Thanos et al, 2008). This notion is consistent with clinical data implicating the D 3 R in populations abusing substances that influence nigrostriatal reward pathway function (Boileau et al, 2012;Erritzoe et al, 2014;Matuskey et al, 2014;Payer et al, 2014).…”

“…Our data suggest that D 2/3 Rs are higher in OB compared with NW individuals in regions densely populated with D 3 Rs, thus implicating the D 3 R as a potential pharmacologic target for the treatment of obesity. These data also implicate the same nigrostriatal pathway alterations in obesity that have been previously observed with [ 11 C](+)PHNO in cocaine (Matuskey et al, 2014;Payer et al, 2014), methamphetamine (Boileau et al, 2012), and alcohol (Erritzoe et al, 2014) abusers, indicating excessive food consumption might alter reward pathways in similar ways as do substances of abuse. The direct role of the D 3 R in addiction is not currently clear .…”

Imaging the D3 dopamine receptor across behavioral and drug addictions: Positron emission tomography studies with [11C]-(+)-PHNO

“…In a second study in primarily cocaine-abusing individuals (Payer et al, 2013), our group replicated the evidence for heightened [ 11 C]-(+ )-PHNO binding in substantia nigra ( + 24% higher binding) in cocaine dependence, a finding that was simultaneously reported by Matuskey et al (2014), who demonstrated that cocaine addiction was associated with an upregulation of D 3 receptors in the substantia nigra ( + 29%), as well as the hypothalamus (+ 28%) and amygdala ( + 35%) (Matuskey et al, 2014). Erritzoe et al (2014) have recently extended the finding of potential D 3 upregulation to alcohol use disorder (n= 16 males), reporting 17% greater [ 11 C]-( +)-PHNO binding in the hypothalamus (where D 3 fraction represents 100%). Further, conducting the study under conditions of blockade with the D 3 -selective antagonist compound GSK598809 (60 mg p.o.)…”

“…Furthermore, these regions are small and hard to define, and thus potentially sensitive to motion artefact and image misalignment. In areas of mixed D 3 /D 2 binding, it is possible to theoretically estimate the D 3 fraction based on published literature (Tziortzi et al, 2011), but selective pharmacologic blockade is necessary to adequately dissect and estimate the D 3 contribution (see for example Erritzoe et al, 2014). The globus pallidus presents another regional limitation, as it is hard to define on typical T1 and proton density magnetic resonance images because of low contrast due to the numerous striato-pallidonigral myelinated axons that traverse it.…”

Heightened Dopaminergic Response to Amphetamine at the D3 Dopamine Receptor in Methamphetamine Users

“…In contrast, a recent body of work suggests that, unlike other measured dopaminergic markers, the D 3 receptor might be upregulated in animal models (Le Foll et al, 2005;Neisewander et al, 2004) and in postmortem (Mash, 1997;Staley and Mash, 1996) and living brain of humans with stimulant (Boileau et al, 2012;Matuskey et al, 2014;Payer et al, 2014) and perhaps alcohol (Erritzoe et al, 2014) addiction (see (Boileau et al, 2015b) for a review). General interest in D 3 receptor has developed in large part because of preferential expression of D 3 in limbic brain areas associated with reward/motivation (eg, ventral striatum) and because animal models suggested that D 3 -selective antagonists decrease drug-seeking behavior.…”