Heightened D3 dopamine receptor levels in cocaine dependence and contributions to the addiction behavioral phenotype: a positron emission tomography study with [11C]-+-PHNO.
The dopamine system is a primary treatment target for cocaine dependence (CD), but research on dopaminergic abnormalities (eg, D2 receptor system deficiencies) has so far failed to translate into effective treatment strategies. The D3 receptor system has recently attracted considerable clinical interest, and D3 antagonism is now under investigation as a novel avenue for addiction treatment. The objective here was to evaluate the status and behavioral relevance of the D3 receptor system in CD, using the positron emission tomography (PET) radiotracer [(11)C]-(+)-PHNO. Fifteen CD subjects (many actively using, but all abstinent 7-240 days on scan day) and fifteen matched healthy control (HC) subjects completed two PET scans: one with [(11)C]-(+)-PHNO to assess D3 receptor binding (BPND; calculated regionally using the simplified reference tissue model), and for comparison, a second scan with [(11)C]raclopride to assess D2/3 binding. CD subjects also completed a behavioral battery to characterize the addiction behavioral phenotype. CD subjects showed higher [(11)C]-(+)-PHNO BPND than HC in the substantia nigra, which correlated with behavioral impulsiveness and risky decision making. In contrast, [(11)C]raclopride BPND was lower across the striatum in CD, consistent with previous literature in 2 week abstinence. The data suggest that in contrast to a D2 deficiency, CD individuals may have heightened D3 receptor levels, which could contribute to addiction-relevant traits. D3 upregulation is emerging as a biomarker in preclinical models of addiction, and human PET studies of this receptor system can help guide novel pharmacological strategies for treatment.
1] Addiction Imaging Research Group, Centre for Addiction and Mental Health, Toronto, ON, Canada [2] Research Imaging Centre and Vivian M Rakoff PET Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada.
Doris E
DE
Payer
1] Addiction Imaging Research Group, Centre for Addiction and Mental Health, Toronto, ON, Canada [2] Research Imaging Centre and Vivian M Rakoff PET Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada.
Arian
A
Behzadi
1] Addiction Imaging Research Group, Centre for Addiction and Mental Health, Toronto, ON, Canada [2] Research Imaging Centre and Vivian M Rakoff PET Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada [3] Human Brain Laboratory, Centre for Addiction and Mental Health, Toronto, ON, Canada [4] Department of Pharmacology, University of Toronto, Toronto, ON, Canada [5] Campbell Family Mental Health Research Institute, Toronto, ON, Canada.
Stephen J
SJ
Kish
1] Research Imaging Centre and Vivian M Rakoff PET Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada [2] Human Brain Laboratory, Centre for Addiction and Mental Health, Toronto, ON, Canada [3] Department of Pharmacology, University of Toronto, Toronto, ON, Canada [4] Campbell Family Mental Health Research Institute, Toronto, ON, Canada [5] Division of Addictions, Centre for Addiction and Mental Health, Toronto, ON, Canada [6] Division of Schizophrenia, Centre for Addiction and Mental Health, Toronto, ON, Canada [7] Division of Brain and Therapeutics, Department of Psychiatry, University of Toronto, Toronto, ON, Canada [8] Department of Family and Community Medicine, University of Toronto, Toronto, ON, Canada.
Sylvain
S
Houle
1] Research Imaging Centre and Vivian M Rakoff PET Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada [2] Campbell Family Mental Health Research Institute, Toronto, ON, Canada [3] Division of Addictions, Centre for Addiction and Mental Health, Toronto, ON, Canada.
Alan A
AA
Wilson
1] Research Imaging Centre and Vivian M Rakoff PET Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada [2] Campbell Family Mental Health Research Institute, Toronto, ON, Canada.
Pablo M
PM
Rusjan
1] Addiction Imaging Research Group, Centre for Addiction and Mental Health, Toronto, ON, Canada [2] Research Imaging Centre and Vivian M Rakoff PET Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada [3] Human Brain Laboratory, Centre for Addiction and Mental Health, Toronto, ON, Canada [4] Campbell Family Mental Health Research Institute, Toronto, ON, Canada [5] Division of Addictions, Centre for Addiction and Mental Health, Toronto, ON, Canada.
Junchao
J
Tong
1] Campbell Family Mental Health Research Institute, Toronto, ON, Canada [2] Division of Schizophrenia, Centre for Addiction and Mental Health, Toronto, ON, Canada [3] Division of Brain and Therapeutics, Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
Peter
P
Selby
1] Division of Addictions, Centre for Addiction and Mental Health, Toronto, ON, Canada [2] Division of Schizophrenia, Centre for Addiction and Mental Health, Toronto, ON, Canada.
Tony P
TP
George
1] Addiction Imaging Research Group, Centre for Addiction and Mental Health, Toronto, ON, Canada [2] Research Imaging Centre and Vivian M Rakoff PET Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada [3] Human Brain Laboratory, Centre for Addiction and Mental Health, Toronto, ON, Canada.
Tina
T
McCluskey
1] Addiction Imaging Research Group, Centre for Addiction and Mental Health, Toronto, ON, Canada [2] Research Imaging Centre and Vivian M Rakoff PET Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada [3] Human Brain Laboratory, Centre for Addiction and Mental Health, Toronto, ON, Canada [4] Campbell Family Mental Health Research Institute, Toronto, ON, Canada [5] Division of Addictions, Centre for Addiction and Mental Health, Toronto, ON, Canada [6] Division of Schizophrenia, Centre for Addiction and Mental Health, Toronto, ON, Canada.
Isabelle
I
Boileau
D000328:Adult; D016739:Behavior, Addictive / Q000000981:diagnostic imaging* / Q000378:metabolism; D002250:Carbon Radioisotopes; D019970:Cocaine-Related Disorders / Q000000981:diagnostic imaging* / Q000378:metabolism; D018492:Dopamine Antagonists; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D049268:Positron-Emission Tomography / Q000379:methods; D050637:Receptors, Dopamine D3 / Q000037:antagonists & inhibitors* / Q000378:metabolism
D002250:Carbon Radioisotopes; D018492:Dopamine Antagonists; D050637:Receptors, Dopamine D3