The dopamine transporter and attention-deficit/hyperactivity disorder.
The high incidence of attention-deficit/hyperactivity disorder (ADHD) and escalating use of ADHD medications present a compelling case for clarifying the pathophysiology of, and developing laboratory or radiologic tests for, ADHD. Currently, the majority of specific genes implicated in ADHD encode components of catecholamine signaling systems. Of these, the dopamine transporter (DAT) is a principal target of the most widely used antihyperactivity medications (amphetamine and methylphenidate); the DAT gene is associated with ADHD, and some studies have detected abnormal levels of the DAT in brain striatum of ADHD subjects. Medications for ADHD interfere with dopamine transport by brain-region- and drug-specific mechanisms, indirectly activating dopamine- and possibly norepinephrine-receptor subtypes that are implicated in enhancing attention and experiential salience. The most commonly used DAT-selective ADHD medications raise extracellular dopamine levels in DAT-rich brain regions. In brain regions expressing both the DAT and the norepinephrine transporter (NET), the relative contributions of dopamine and norepinephrine to ADHD pathophysiology and therapeutic response are obfuscated by the capacity of the NET to clear dopamine as well as norepinephrine. Thus, ADHD medications targeting DAT or NET might disperse dopamine widely and consign dopamine storage and release to regulation by noradrenergic, as well as dopaminergic neurons.
Madras
Bertha K
BK
Department of Psychiatry, Harvard Medical School, New England Primate Research Center, Southborough, MA 01772-9102, USA. bertha_madras@hms.harvard.edu
Miller
Gregory M
GM
Fischman
Alan J
AJ
D000222:Adaptation, Physiological; D000818:Animals; D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D000697:Central Nervous System Stimulants / Q000627:therapeutic use; D003952:Diagnostic Imaging; D050483:Dopamine Plasma Membrane Transport Proteins; D014644:Genetic Variation; D006801:Humans; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D050492:Vesicular Biogenic Amine Transport Proteins
D000697:Central Nervous System Stimulants; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; C493214:SLC6A3 protein, human; D050492:Vesicular Biogenic Amine Transport Proteins