Chronic treatment with methylphenidate increases dopamine transporter density in patients with attention deficit hyperactive disorder

Objectives Brain dopamine (DA) dysfunction, particularly the dopamine transporters (DAT, main targets of stimulant medications), is implicated in attention deficit/hyperactivity disorder (ADHD). Here we assessed effect of long-term stimulant medication on DAT.

Methods DAT availability in 9 never-medicated ADHD subjects (30 ±10 yrs of age) was evaluated with PET and [¹¹C]cocaine prior to and after 12 months of treatment with oral methylphenidate (MP). In parallel, DAT were measured in 5 controls (NC) who were re-tested 12 months later without stimulant medication. DAT availability (Bmax/Kd) was analyzed with ROIs.

Results Prior to treatment DAT did not differ between ADHD (caudate-CA: 0.79±0.06, putamen-PU: 0.96±0.1, ventral striatum-VS: 0.75±0.15) and NC (CA: 0.74±0.12, PU: 0.87±0.1, VS: 0.8±0.1). MP treatment increased DAT in ADHD (CA: +20±25%, p<0.05; PU: +17±18%, p<0.02; VS: +37±32%, p<0.006); whereas there were no significant DAT changes in NC. Comparison of NC and ADHD after 12 month of treatment revealed higher DAT in ADHD than NC (CA: p<0.02; PU: p<0.001).

Conclusions This study reveals no significant difference in DAT availability in a comparison of stimulant-naive ADHD and NC. After long-term treatment of ADHD with stimulant medication, an increased DAT was observed, and a comparison of the two groups revealed significantly higher DAT density in ADHD than NC. Upregulation of DAT during chronic treatment with MP could underlie the decrease in MP’s efficacy with chronic treatment (tolerance).

Research Support NIMH/NIAAA/GCRC/DOE