Inhibition of the norepinephrine transporter improves behavioral flexibility in rats and monkeys.
BACKGROUND
Poor cognitive control, including reversal learning deficits, has been reported in children with attention deficit hyperactivity disorder, in stimulant-dependent humans, and in animal models of these disorders; these conditions have each been associated with abnormal catecholaminergic function within the prefrontal cortex.


OBJECTIVE
In the current studies, we sought to explore how elevations in extracellular catecholamine levels, produced by pharmacological inhibition of catecholamine reuptake proteins, affect behavioral flexibility in rats and monkeys.


METHODS
Adult male Long-Evans rats and vervet monkeys were trained, respectively, on a four-position discrimination task or a three-choice visual discrimination task. Following systemic administration of pharmacological inhibitors of the dopamine and/or norepinephrine membrane transporters, rats and monkeys were exposed to retention or reversal of acquired discriminations.


RESULTS
In accordance with our a priori hypothesis, we found that drugs that inhibit norepinephrine transporters, such as methylphenidate, atomoxetine, and desipramine, improved reversal performance in rats and monkeys; this was mainly due to a decrease in the number of perseverative errors. Interestingly, the mixed dopamine and norepinephrine transporters inhibitor methylphenidate, if anything, impaired performance during retention in both rats and monkeys, while administration of the selective dopamine transporter inhibitor GBR-12909 increased premature responses but did not alter reversal learning performance.


CONCLUSIONS
Our results suggest that pharmacological inhibition of the membrane norepinephrine, but not membrane dopamine, transporter is associated with enhanced behavioral flexibility. These data, combined with earlier reports, may indicate that enhanced extracellular catecholamine levels in cortical regions, secondary to norepinephrine reuptake inhibition, improves multiple aspects of inhibitory control over responding in rats and monkeys.
Seu
Emanuele
E
Department of Psychology, University of California Los Angeles, P.O. Box 951563, Los Angeles, CA 90095-1563, USA. jentsch@psych.ucla.edu
Lang
Andrew
A
Rivera
Ronald J
RJ
Jentsch
J David
JD
D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000818:Animals; D000069445:Atomoxetine Hydrochloride; D001522:Behavior, Animal / Q000187:drug effects*; D002522:Chlorocebus aethiops; D002755:Choice Behavior / Q000187:drug effects; D003891:Desipramine / Q000494:pharmacology; D004192:Discrimination, Psychological / Q000187:drug effects; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D008297:Male; D008568:Memory / Q000187:drug effects; D008774:Methylphenidate / Q000494:pharmacology; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D010879:Piperazines / Q000494:pharmacology; D011437:Propylamines / Q000494:pharmacology; D011597:Psychomotor Performance / Q000187:drug effects; D051381:Rats; D020318:Rats, Long-Evans; D012193:Reversal Learning / Q000187:drug effects; D013028:Space Perception / Q000187:drug effects
D018759:Adrenergic Uptake Inhibitors; D018765:Dopamine Uptake Inhibitors; D050484:Norepinephrine Plasma Membrane Transport Proteins; D010879:Piperazines; D011437:Propylamines; D008774:Methylphenidate; D000069445:Atomoxetine Hydrochloride; C043425:vanoxerine; D003891:Desipramine