title: Age-related changes in prefrontal norepinephrine transporter density: The basis for improved cognitive flexibility after low doses of atomoxetine in adolescent rats.
abstract: Adolescence is a period of major behavioral and brain reorganization. As diagnoses and treatment of disorders like attention deficit hyperactivity disorder (ADHD) often occur during adolescence, it is important to understand how the prefrontal cortices change and how these changes may influence the response to drugs during development. The current study uses an adolescent rat model to study the effect of standard ADHD treatments, atomoxetine and methylphenidate on attentional set shifting and reversal learning. While both of these drugs act as norepinephrine reuptake inhibitors, higher doses of atomoxetine and all doses of methylphenidate also block dopamine transporters (DAT). Low doses of atomoxetine, were effective at remediating cognitive rigidity found in adolescents. In contrast, methylphenidate improved performance in rats unable to form an attentional set due to distractibility but was without effect in normal subjects. We also assessed the effects of GBR 12909, a selective DAT inhibitor, but found no effect of any dose on behavior. A second study in adolescent rats investigated changes in norepinephrine transporter (NET) and dopamine beta hydroxylase (DBH) density in five functionally distinct sub-regions of the prefrontal cortex: infralimbic, prelimbic, anterior cingulate, medial and lateral orbitofrontal cortices. These regions are implicated in impulsivity and distractibility. We found that NET, but not DBH, changed across adolescence in a regionally selective manner. The prelimbic cortex, which is critical to cognitive rigidity, and the lateral orbitofrontal cortex, critical to reversal learning and some forms of response inhibition, showed higher levels of NET at early than mid- to late adolescence. This article is part of a Special Issue entitled SI: Noradrenergic System.
authors.affiliation: Department of Psychology, University of New Hampshire, Durham, NH 03824, United States.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Bradshaw
authors.affiliation: Department of Neurobiology and Anatomy, Drexel College of Medicine, Philadelphia, PA 19129, United States.
authors.forename: Kara L
authors.initials: KL
authors.lastname: Agster
authors.affiliation: Department of Neurobiology and Anatomy, Drexel College of Medicine, Philadelphia, PA 19129, United States.
authors.forename: Barry D
authors.initials: BD
authors.lastname: Waterhouse
authors.affiliation: Department of Psychology, University of New Hampshire, Durham, NH 03824, United States. Electronic address: j.mcgaughy@unh.edu.
authors.forename: Jill A
authors.initials: JA
authors.lastname: McGaughy
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000818:Animals; D000069445:Atomoxetine Hydrochloride / Q000494:pharmacology*; D001288:Attention / Q000187:drug effects / Q000502:physiology; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D003071:Cognition / Q000187:drug effects / Q000502:physiology*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004299:Dopamine beta-Hydroxylase / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D056344:Executive Function / Q000187:drug effects / Q000502:physiology; D008297:Male; D008774:Methylphenidate / Q000494:pharmacology; D018697:Nootropic Agents / Q000494:pharmacology*; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000254:growth & development* / Q000378:metabolism; D011897:Random Allocation; D051381:Rats
chemical_list: D018759:Adrenergic Uptake Inhibitors; D000697:Central Nervous System Stimulants; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D018697:Nootropic Agents; D050484:Norepinephrine Plasma Membrane Transport Proteins; D010879:Piperazines; C493226:Slc6a2 protein, rat; D008774:Methylphenidate; D000069445:Atomoxetine Hydrochloride; C043425:vanoxerine; D004299:Dopamine beta-Hydroxylase
keywords: Anterior cingulate cortex; Dopamine beta hydroxylase; Lateral orbitofrontal cortex; Norepinephrine transporter; Prelimbic cortex