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

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_2/3 receptors may be therapeutically beneficial. In contrast, recent investigations indicate heightened D₃ receptor levels in stimulant users prompting the view that D₃ antagonism may help prevent relapse. Here we tested whether a 'blunted' response to amphetamine in methamphetamine (MA) users extends to D₃-rich brain areas. Fourteen MA users and 15 healthy controls completed two positron emission tomographic scans with a D₃-preferring probe [¹¹C]-(+)-PHNO at baseline and after amphetamine (0.4 mg/kg). Relative to healthy controls, MA users had greater decreases in [¹¹C]-(+)-PHNO binding (increased dopamine release) after amphetamine in D₃-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 D₂-rich striatum; however, drug use severity was negatively associated with amphetamine-induced striatal changes in [¹¹C]-(+)-PHNO binding. Our study provides evidence that dopamine transmission in extrastriatal 'D₃-areas' is not blunted but rather increased in MA users. Together with our previous finding of elevated D₃ receptor level in MA users, the current observation suggests that greater dopaminergic transmission at the D₃ dopamine receptor may contribute to motivation to use drugs and argues in favor of D₃ antagonism as a possible therapeutic tool to reduce craving and relapse in MA addiction.