Constitutive plasma membrane monoamine transporter (PMAT, Slc29a4) deficiency subtly affects anxiety‐like and coping behaviours

Abstract

Originally, uptake-mediated termination of monoamine (e.g., serotonin and dopamine) signalling was believed to only occur via high-affinity, low-capacity transporters ("uptake ") such as the serotonin or dopamine transporters, respectively. Now, the important contribution of a second low-affinity, high-capacity class of biogenic amine transporters has been recognised, particularly in circumstances when uptake transporter function is reduced (e.g., antidepressant treatment). Pharmacologic or genetic reductions in uptake function can change locomotor, anxiety-like or stress-coping behaviours. Comparable behavioural investigations into reduced low-affinity, high-capacity transporter function are lacking, in part, due to a current dearth of drugs that selectively target particular low-affinity, high-capacity transporters, such as the plasma membrane monoamine transporter. Therefore, the most direct approach involves constitutive genetic knockout of these transporters. Other groups have reported that knockout of the low-affinity, high-capacity organic cation transporters 2 or 3 alters anxiety-like and stress-coping behaviours, but none have assessed behaviours in plasma membrane monoamine transporter knockout mice. Here, we evaluated adult male and female plasma membrane monoamine transporter wild-type, heterozygous and knockout mice in locomotor, anxiety-like and stress-coping behavioural tests. A mild enhancement of anxiety-related behaviour was noted in heterozygous mice. Active-coping behaviour was modestly and selectively increased in female knockout mice. These subtle behavioural changes support a supplemental role of plasma membrane monoamine transporter in serotonin and dopamine uptake, and suggest sex differences in transporter function should be examined more closely in future investigations.

Serotonin Transporter and Plasma Membrane Monoamine Transporter Are Necessary for the Antidepressant-Like Effects of Ketamine in Mice

“…Regardless, our in vivo findings suggest that at the serotonin concentrations studied here, serotonin clearance is not different between PMAT+/+ and PMAT−/− mice, indicating that compensatory mechanisms for serotonin clearance might be at play in constitutive PMAT−/− mice. This idea is further supported by PMAT−/− mice displaying normal behavior in a battery of tests, with only subtle differences in anxiety-like and coping behaviors compared to PMAT+/+ mice reported [ 61 ].…”

Sex Differences in Blood–Brain Barrier Transport of Psychotropic Drugs

“…Plasma membrane monoamine transporter (PMAT/SLC29A4), a known transporter for cationic substances, is implicated in the efflux of amisulpride and haloperidol from the brain and is inhibited by nicotine ( Tega et al, 2018 ; Sekhar et al, 2019 ). Some evidence on sex differences exist for PMAT, as behavioral changes were noted only in female, but not male, PMAT knockout mice ( Gilman et al, 2018 ).…”

General Overview of Organic Cation Transporters in Brain

“…Gilman and coworkers compared locomotor activity, anxiety-like behavior, and stress coping behaviors between Pmat-KO mice and WT mice using various behavioral tests (Gilman et al 2018). With exception of a small gender independent increase of anxiety-related behavior in heterozygous Pmat-KO mice and a mild increase in active coping behavior in female homozygous KO mice, no significant effects of Pmat removal were observed.…”