Role of Organic Cation Transporter 3 and Plasma Membrane Monoamine Transporter in the Rewarding Properties and Locomotor Sensitizing Effects of Amphetamine in Male andFemale Mice.

Lynette C. Daws,Wouter Koek,Nikki J. Clauss

doi:10.3390/ijms222413420

Abstract

A lack of effective treatment and sex-based disparities in psychostimulant addiction and overdose warrant further investigation into mechanisms underlying the abuse-related effects of amphetamine-like stimulants. Uptake-2 transporters such as organic cation transporter 3 (OCT3) and plasma membrane monoamine transporter (PMAT), lesser studied potential targets for the actions of stimulant drugs, are known to play a role in monoaminergic neurotransmission. Our goal was to examine the roles of OCT3 and PMAT in mediating amphetamine (1 mg/kg)-induced conditioned place preference (CPP) and sensitization to its locomotor stimulant effects, in males and females, using pharmacological, decynium-22 (D22; 0.1 mg/kg, a blocker of OCT3 and PMAT) and genetic (constitutive OCT3 and PMAT knockout (−/−) mice) approaches. Our results show that OCT3 is necessary for the development of CPP to amphetamine in males, whereas in females, PMAT is necessary for the ability of D22 to prevent the development of CPP to amphetamine. Both OCT3 and PMAT appear to be important for development of sensitization to the locomotor stimulant effect of amphetamine in females, and PMAT in males. Taken together, these findings support an important, sex-dependent role of OCT3 and PMAT in the rewarding and locomotor stimulant effects of amphetamine.

Highlights

Amphetamine-like drugs are among the most commonly abused drugs worldwide, second only to cannabis [1]
Using a combination of pharmacological and genetic techniques, we provide evidence that organic cation transporter 3 (OCT3) and plasma membrane monoamine transporter (PMAT) are sex-dependently involved in the rewarding properties of 1 mg/kg amphetamine
This is the first assessment of a role for OCT3 in the rewarding properties of amphetamine in both males and females, as well as the first assessment of the role of PMAT in the rewarding properties of amphetamine

Summary

Introduction

Amphetamine-like drugs are among the most commonly abused drugs worldwide, second only to cannabis [1]. Abuse of amphetamine-like psychostimulants is on the rise in North America, Oceania, and Asia [2,3,4] Use of these drugs leads to a variety of adverse effects that place an undue burden on the public health system. Long-term use can lead to addiction, paranoia, mood disturbances, agitation, psychosis, cognitive impairment, and death [5,6]. The impact of these effects is more likely to fall on individuals from demographics in which the use of amphetamine-like drugs is disproportionately popular, such as women [7]. Between 2016 and 2017, deaths from psychostimulant overdose increased by 33% and impacted more women than men [11]

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