Dopamine D3 receptor alterations in cocaine-dependent humans imaged with [11C](+)PHNO

Abstract

Background Evidence from animal models and postmortem human studies points to the importance of the dopamine D3 receptor (D3R) in cocaine dependence (CD). The objective of this pilot study was to use the D3R-preferring radioligand [11C](+)PHNO to compare receptor availability in groups with and without CD. Methods Ten medically healthy, non-treatment seeking CD subjects (mean age 41±8) in early abstinence were compared to 10 healthy control (HC) subjects (mean age 41±6) with no history of cocaine or illicit substance abuse. Binding potential (BPND), a measure of available receptors, was determined with parametric images, computed using the simplified reference tissue model (SRTM2) with the cerebellum as the reference region. Results BPND in CD subjects was higher in D3R-rich areas including the substantia nigra ((SN) 29%; P=0.03), hypothalamus (28%; P=0.02) and amygdala (35%, P=0.03). No between-group differences were observed in the striatum or pallidum. BPND values in the SN (r = + 0.83; p =0.008) and pallidum (r = + 0.67; p = 0.03) correlated with years of cocaine use. Conclusions Between-group differences suggest an important role for dopaminergic transmission in the SN, hypothalamus and amygdala in CD. Such findings also highlight the potential relevance of D3R as a medication development target in CD.

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 .…”

“…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. These distinctions suggest that the D 3 R subtype and the D 2 R subtype may be regulated differently with respect to obesity, a finding also observed in the stimulant-use-disorders literature (Boileau et al, 2012;Lee et al, 2009;Martinez et al, 2004;Matuskey et al, 2014;Payer et al, 2014;Volkow et al, 1990Volkow et al, , 2001. Further, the D 3 R has been implicated to be positively associated with behavioral impulsiveness and risky decision making, thus our findings of higher D 3 R availability in OB may be explained by underlying trait impulsivity (Payer et al, 2014).…”

“…Parametric images of non-displaceable tracer binding potentials (BP ND ), which are linearly proportional to the density of available D 2/3 Rs, were computed using a simplified reference tissue model (2-parameter version: SRTM2). This method has been previously validated for [ 11 C](+)PHNO (Gallezot et al, 2014b;Wu and Carson, 2002) and utilized to optimize the statistical quality of the SRTM applied in prior studies by reducing noise of the functional images (Matuskey et al, 2014(Matuskey et al, , 2015. Unbound concentration in tissue was estimated as the radioligand mass concentration in the cerebellum at 60-90 min post injection.…”

“…PET data were used to construct a time-activity curve for the cerebellum, a region of minimal D 2/3 R binding, which was used as the reference region as in previous studies (Boileau et al, 2012;Ginovart et al, 2007;Matuskey et al, 2014Matuskey et al, , 2015Matuskey et al, , 2016Mizrahi et al, 2011;Payer et al, 2014;Searle et al, 2010). A summed image (0-10 min after injection) was created from the motion-corrected PET data and registered to the participant's MR image, which was nonlinearly registered to an MR template in Montreal Neurological Institute (MNI) space.…”