Subcortical D3/D2 receptor binding in cocaine dependent humans

Objectives Evidence from animal model and postmortem human studies points to the importance of dopamine D3 in cocaine dependence (CD). This has yet to be verified via in vivo human studies. The objective of this study is to use the D3 preferred radioligand PHNO to compare healthy control (HC) with CD subjects in relevant subcortical regions.

Methods 10 medically healthy, non-treatment seeking CD subjects (mean age 42±7) were compared to 17 HC subjects (mean age 30±10) with no history of cocaine/illicit substance abuse. After an acclimatization period on an inpatient unit CD subjects received a MRI and then underwent PHNO acquisition using a High Resolution Research Tomograph (HRRT) for purposes of quantifying brain D3/D2 binding potential (BPND). Subjects received a bolus injection of 316±140 MBq of [11C] PHNO with a total injected mass of 0.028±0.004 µg/kg. The specific radioactivity was 63±29 MBq/nmol at the end of synthesis and 35±17 MBq/nmol at injection time. Parametric images were computed using the simplified reference tissue model (SRTM2) with the cerebellum as the reference region.

Results Subcortical regions rich in D2 and D3 were chosen for region of interest (ROI) analyses. No statistically significant changes were seen between HC and CD subjects in the caudate (-9%), pallidum (-7%), putamen (-7%), substantia nigra (22%), ventral striatum (-5%) and the thalamus (1%). Statistical significance differences were seen, however, in the amygdala (91%, P=.001) and when the ratio of D3 to D2 areas (SN/Striatum) were compared (30%, P=.02).

Conclusions The results suggest that that D2 rich regions (striatum and pallidum) are down-regulated and D3 rich areas (substantia nigra) are up-regulated in cocaine subjects. The statistically significant difference in the amygdala (an area where D3 binding is known to enforce the rewarding properties of cocaine in animals) and the SN/Striatum ratio further advocates a role of D3 in CD. Further studies are necessary to confirm these encouraging results.

Research Support NIDA 1R03DA027456-01 NARSAD M13201