Heightened Dopaminergic Response to Amphetamine at the D sub(3) Dopamine Receptor in Methamphetamine Users

• Published in: Neuropsychopharmacology (New York, N.Y.) N.Y.), 2016-12, Vol.41 (13), p.2994-3002
• Main Authors: Boileau, Isabelle, Payer, Doris, Rusjan, Pablo M, Houle, Sylvain, Tong, Junchao, McCluskey, Tina, Wilson, Alan A, Kish, Stephen J
• Format: Article
• Language: English
• ISSN: 0893-133X
• DOI: 10.1038/npp.2016.108

Neuroimaging studies in stimulant use (eg, cocaine, methamphetamine) disorders show that diminished dopamine release by dopamine-elevating drugs is a potential marker of relapse and suggest that increasing dopamine at the D sub(2/3) receptors may be therapeutically beneficial. In contrast, recent investigations indicate heightened D sub(3) receptor levels in stimulant users prompting the view that D sub(3) antagonism may help prevent relapse. Here we tested whether a 'blunted' response to amphetamine in methamphetamine (MA) users extends to D sub(3)-rich brain areas. Fourteen MA users and 15 healthy controls completed two positron emission tomographic scans with a D sub(3)-preferring probe [ super(11)C]-(+)-PHNO at baseline and after amphetamine (0.4 mg/kg). Relative to healthy controls, MA users had greater decreases in [ super(11)C]-(+)-PHNO binding (increased dopamine release) after amphetamine in D sub(3)-rich substantia nigra (36 vs 20%, p=0.03) and globus pallidus (30 vs 17%, p=0.06), which correlated with self-reported 'drug wanting'. We did not observe a 'blunted' dopamine response to amphetamine in D sub(2)-rich striatum; however, drug use severity was negatively associated with amphetamine-induced striatal changes in [ super(11)C]-(+)-PHNO binding. Our study provides evidence that dopamine transmission in extrastriatal 'D sub(3)-areas' is not blunted but rather increased in MA users. Together with our previous finding of elevated D sub(3) receptor level in MA users, the current observation suggests that greater dopaminergic transmission at the D sub(3) dopamine receptor may contribute to motivation to use drugs and argues in favor of D sub(3) antagonism as a possible therapeutic tool to reduce craving and relapse in MA addiction.