title: [Towards an understanding of the molecular mechanisms underlying the pharmacological treatments of attention deficit hyperactivity disorder].
abstract: Methylphenidate and the amphetamines are the most frequently used medications for treating attention-deficit/hyperactivity disorder (ADHD). These medications modulate both norepinephrine as well as dopamine. Methyl-phenidate is a pure blocker of the norepinephrine and dopamine transporters. The amphetamines also block reuptake of both catecholamines, but they also release all three monoamines, norepinephrine, dopamine, and serotonin, from presynaptic vesicles. Amphetamines are the most robust agents in increasing synaptic dopamine levels, since they do so regardless of the endogenous level of the relevant neurons. Stimulant-evoked synaptic increases of dopamine have been demonstrated in the striatum in humans, but pharmacologic effects are likely relevant to therapeutic action in other regions, particularly the prefrontal cortex. Blockade of noradrenergic reuptake in the prefrontal cortex may also indirectly increase prefrontal dopamine levels, but there is also evidence that noradrenergic effects are mediated by alpha-2a noradrenergic receptors. A recent study in non-human primates found that methylphenidate and atomoxetine both increased the efficiency of prefrontal pyramidal neurons, but via distinct mechanisms. Methylphenidate decreased non-specific signals, i.e., neuronal noise, via D1 receptors. By contrast, atomoxetine increased the strength of specific signals via activation of alpha-2 receptors. These findings, although in non-human primates, suggest that combinations of agents working on these complementary systems (D1 and alpha-2a) may be worth considering and evaluating rigorously in patients with ADHD with sub-optimal responses to monotherapy.
authors.affiliation: Phyllis Green and Randolph Cowen Institute for Pediatric Neuroscience, Child Study Center, NYU School of Medicine, 215 Lexington Ave., New York, NY 10016, USA. francisco.castellanos@nyumc.org
authors.forename: F Xavier
authors.initials: FX
authors.lastname: Castellanos
authors.forename: M Teresa
authors.initials: MT
authors.lastname: Acosta
mesh_terms: D000662:Amphetamines / Q000494:pharmacology / Q000627:therapeutic use; D000069445:Atomoxetine Hydrochloride; D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy* / Q000503:physiopathology; D000697:Central Nervous System Stimulants / Q000494:pharmacology / Q000627:therapeutic use*; D003342:Corpus Striatum / Q000187:drug effects / Q000502:physiology; D004298:Dopamine / Q000378:metabolism; D006801:Humans; D008774:Methylphenidate / Q000494:pharmacology / Q000627:therapeutic use; D009638:Norepinephrine / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects / Q000502:physiology; D011437:Propylamines / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000662:Amphetamines; D000697:Central Nervous System Stimulants; D011437:Propylamines; D008774:Methylphenidate; D000069445:Atomoxetine Hydrochloride; D004298:Dopamine; D009638:Norepinephrine