Constitutive plasma membrane monoamine transporter (PMAT,<i>Slc29a4</i>) 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 ("uptake₁ ") 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 uptake₁ transporter function is reduced (e.g., antidepressant treatment). Pharmacologic or genetic reductions in uptake₁ 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.