Combined Norepinephrine and Dopamine Reuptake Inhibition for Long‐Term Memory Enhancement

Abstract

The psychostimulants amphetamine and methylphenidate are highly effective cognitive enhancers, particularly for their ability to enhance long‐term memory (LTM). While psychostimulants have been argued to exert their procognitive effects exclusively through norepinephrine transporter (NET) inhibition and their reinforcing effects exclusively through dopamine transporter (DAT) inhibition, there is increasing evidence that DAT also plays a critical role in learning and memory, including LTM enhancement. In the present study, we examined the effects of a drug combination of a potent NET inhibitor with a weak DAT inhibitor, using Pavlovian fear conditioning. While NET or DAT inhibition alone failed to enhance LTM across a wide range of doses (Carmack et al., 2014), we found that combined NET/DAT inhibition produced robust enhancements in immediate and long‐term fear memory acquisition. These findings support the theory that both NET and DAT inhibition are required for psychostimulant‐induced LTM enhancement. Additionally, we propose that a pharmaceutical combination of moderate NET inhibition and weak DAT inhibition could lead to the development of a non‐stimulating, non‐addictive, and non‐controlled, yet highly effective cognitive enhancer.Support or Funding InformationNIH grant DA020041 (SGA)