The Synergistic Effect of Dopamine and Norepinephrine Transporter Inhibition on Cognitive Enhancement

Psychostimulants such as amphetamine and methylphenidate are highly effective cognitive enhancing medications, yet have a high potential for abuse and addiction. Evidence suggests that both norepinephrine transporter (NET) and dopamine transporter (DAT) inhibition is required for the procognitive effects of psychostimulants. Although DAT inhibition is also responsible for the addictive potential of psychostimulants, drugs with low activity at DAT may not produce addiction. In the present study, we examined the cognitive and reinforcing effects of various DAT inhibitors (e.g., bupropion, GBR-12909, GBR-12935) and NET inhibitors (e.g., atomoxetine, nisoxetine) alone and in combination, using Pavlovian fear conditioning and conditioned place preference. We found that certain dose combinations of these DAT and NET inhibitors produced enhancements in immediate and/or long-term fear memory acquisition, but did not produce reinforcement or behavioral sensitization. We propose that a pharmaceutical combination of DAT and NET inhibition could lead to the development of a non-stimulating, non-addictive, and non-controlled, yet highly effective cognitive enhancer. Support or Funding Information NIH DA020041 (SGA) This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.