Abstract
ObjectiveBrain dopamine dysfunction in attention deficit/hyperactivity disorder (ADHD) could explain why stimulant medications, which increase dopamine signaling, are therapeutically beneficial. However while the acute increases in dopamine induced by stimulant medications have been associated with symptom improvement in ADHD the chronic effects have not been investigated.MethodWe used positron emission tomography and [11C]cocaine (dopamine transporter radioligand) to measure dopamine transporter availability in the brains of 18 never-medicated adult ADHD subjects prior to and after 12 months of treatment with methylphenidate and in 11 controls who were also scanned twice at 12 months interval but without stimulant medication. Dopamine transporter availability was quantified as non-displaceable binding potential using a kinetic model for reversible ligands.ResultsTwelve months of methylphenidate treatment increased striatal dopamine transporter availability in ADHD (caudate, putamen and ventral striatum: +24%, p<0.01); whereas there were no changes in control subjects retested at 12-month interval. Comparisons between controls and ADHD participants revealed no significant difference in dopamine transporter availability prior to treatment but showed higher dopamine transporter availability in ADHD participants than control after long-term treatment (caudate: p<0.007; putamen: p<0.005).ConclusionUpregulation of dopamine transporter availability during long-term treatment with methylphenidate may decrease treatment efficacy and exacerbate symptoms while not under the effects of the medication. Our findings also suggest that the discrepancies in the literature regarding dopamine transporter availability in ADHD participants (some studies reporting increases, other no changes and other decreases) may reflect, in part, differences in treatment histories.
Highlights
Attention deficit/hyperactivity disorder (ADHD) is considered to be the most prevalent psychiatric disorder of childhood and its increasingly being recognized in adults too
Twelve months of methylphenidate treatment increased striatal dopamine transporter availability in ADHD; whereas there were no changes in control subjects retested at 12month interval
Comparisons between controls and ADHD participants revealed no significant difference in dopamine transporter availability prior to treatment but showed higher dopamine transporter availability in ADHD participants than control after long-term treatment
Summary
Attention deficit/hyperactivity disorder (ADHD) is considered to be the most prevalent psychiatric disorder of childhood and its increasingly being recognized in adults too. The disorder is often chronic, with prominent symptoms (inattention, hyperactivity/ impulsivity and motivation deficits) and impairment frequently continuing into adulthood. Deficits in dopamine (DA) neurotransmission have been associated with the disorder [1]. As with youth, stimulant medications (methylphenidate (MPH) or amphetamine), which enhance DA signaling have been used for decades as a first line treatment option [2]. MPH acutely enhances DA signaling by blocking the dopamine transporter (DAT), which is the main mechanism by which DA signals are terminated [1]. While the acute DA enhancing effects of MPH have been associated with symptom improvement in children [3] and adults [4] with ADHD very little work has been done to evaluate its chronic effects in brain DA signaling. Inasmuch as DAT appear to adapt to the levels of synaptic DA (downregulating when DA is low and upregulating when DA is high), we hypothesized that chronic MPH treatment would result in upregulation of DAT
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