Inhibition of the norepinephrine transporter improves behavioral flexibility in rats and monkeys

Abstract

Rationale 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. Objectives 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. Materials and methods Adult male Long-Evans rats and vervet monkeys were trained, respectively, on a fourposition 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.

Heterogeneous organization of the locus coeruleus projections to prefrontal and motor cortices

“…This finding is in general agreement with observations that executive functions are impaired by manipulations that limit noradrenergic transmission in prefrontal cortex (9,10,25) and that symptoms of various psychiatric diseases are partially alleviated with drugs that promote NE actions within the synapse (9,(26)(27)(28)(29)(30). Methylphenidate is of particular interest in this context, as Berridge and coworkers have shown previously that doses of methylphenidate, which are effective in treating symptoms of attention deficit hyperactivity disorder (ADHD) without increasing locomotion, preferentially increase NE efflux and responsiveness of individual neurons in the PFC, but not within other cortical regions (31,32).…”

“…Many studies have provided evidence of a facilitating effect of NE or LC activation on the signal-processing capabilities of various networks in the mammalian brain, but the extent to which such actions are uniform and simultaneous across forebrain terminal fields has not been resolved. Heterogeneity among LC-prefrontal projection neurons opens the door for differential actions of LC output on specified prefrontal subregions as has been suggested by selective lesion and pharmacologic studies (9,10,30,38,39). Recent work using similar experimental strategies has revealed similar novel functional and organizational principles of dopamine projections to prefrontal versus limbic terminal fields (33), thus providing considerable new insights regarding the impact of dopaminergic inputs to those circuitries in health and disease.…”

Pupil Diameter Predicts Changes in the Exploration–Exploitation Trade-off: Evidence for the Adaptive Gain Theory

“…Furthermore, several pharmacological studies have shown that drug-induced activation of the LC-NE system increases cognitive flexibility and behavioral disengagement. For example, drugs that increase tonic NE levels (i.e., mimic the effects of elevated NE release that characterize the tonic LC mode) have been found to improve attentional-set shifting and reversal learning in rats and monkeys (Seu, Lang, Rivera, & Jentsch, 2008;Lapiz, Bondi, & Morilak, 2007;Lapiz & Morilak, 2006;Steere & Arnsten, 1997;Devauges & Sara, 1990; but see Chamberlain et al, 2006). In humans, increased NE levels induced by the selective NE reuptake inhibitor atomoxetine have been found to improve the ability to stop an ongoing motor response when cued to do so (Chamberlain et al, 2006).…”

Understanding the Effects of Stimulant Medications on Cognition in Individuals with Attention-Deficit Hyperactivity Disorder: A Decade of Progress

“…Imaging studies have also shown that MP and AMP, at clinically relevant doses, can significantly increase extracellular DA (Villemagne et al, 1999;Volkow et al, 1999bVolkow et al, , 2009a. Imaging studies in non-human primates have also shown significant blockade of the NE transporter at doses that are pharmacologically equivalent to those used in humans, which is interesting in light of the data indicating that enhanced extracellular catecholamine levels in cortical regions, secondary to NE reuptake inhibition, improves multiple aspects of inhibitory control over responding in rats and monkeys (Seu et al, 2009). Synaptic levels of DA and NE, under physiological conditions, act primarily as neuromodulators changing the efficacy of other transmitter signals (Keeler et al, 1989;Kiyatkin, 2002) as a function of ongoing neuronal activity (Seamans and Yang, 2004).…”