Department of Psychological Sciences & Brain Health Research Institute, Kent State University, Kent, OH 44242, USA.
Cells. 2022 Jun 9;11(12):1874. doi: 10.3390/cells11121874.
Plasma membrane monoamine transporter (PMAT, Slc29a4) transports monoamine neurotransmitters, including dopamine and serotonin, faster than more studied monoamine transporters, e.g., dopamine transporter (DAT), or serotonin transporter (SERT), but with ~400-600-fold less affinity. A considerable challenge in understanding PMAT's monoamine clearance contributions is that no current drugs selectively inhibit PMAT. To advance knowledge about PMAT's monoamine uptake role, and to circumvent this present challenge, we investigated how drugs that selectively block DAT/SERT influence behavioral readouts in PMAT wildtype, heterozygote, and knockout mice of both sexes. Drugs typically used as antidepressants (escitalopram, bupropion) were administered acutely for readouts in tail suspension and locomotor tests. Drugs with psychostimulant properties (cocaine, D-amphetamine) were administered repeatedly to assess initial locomotor responses plus psychostimulant-induced locomotor sensitization. Though we hypothesized that PMAT-deficient mice would exhibit augmented responses to antidepressant and psychostimulant drugs due to constitutively attenuated monoamine uptake, we instead observed sex-selective responses to antidepressant drugs in opposing directions, and subtle sex-specific reductions in psychostimulant-induced locomotor sensitization. These results suggest that PMAT functions differently across sexes, and support hypotheses that PMAT's monoamine clearance contribution emerges when frontline transporters (e.g., DAT, SERT) are absent, saturated, and/or blocked. Thus, known human polymorphisms that reduce PMAT function could be worth investigating as contributors to varied antidepressant and psychostimulant responses.
血浆膜单胺转运体（PMAT，Slc29a4）比更受研究的单胺转运体（例如多巴胺转运体（DAT）或血清素转运体（SERT））更快地转运单胺神经递质，包括多巴胺和血清素，但亲和力低约 400-600 倍。理解 PMAT 清除单胺的贡献的一个相当大的挑战是，目前没有选择性抑制 PMAT 的药物。为了增进对 PMAT 单胺摄取作用的了解，并克服这一当前挑战，我们研究了选择性阻断 DAT/SERT 的药物如何影响 PMAT 野生型、杂合子和两性敲除小鼠的行为读数。通常用作抗抑郁药的药物（依地普仑、安非他酮）被急性给药，用于尾悬和运动测试中的读数。具有精神兴奋剂特性的药物（可卡因、D-苯丙胺）被反复给药，以评估初始运动反应以及精神兴奋剂诱导的运动敏感化。尽管我们假设 PMAT 缺陷型小鼠由于单胺摄取持续减弱，对抗抑郁药和精神兴奋剂药物的反应会增强，但我们反而观察到抗抑郁药在相反方向上的性别选择性反应，以及精神兴奋剂诱导的运动敏感化的微妙性别特异性降低。这些结果表明 PMAT 在两性之间的功能不同，并支持 PMAT 的单胺清除贡献在一线转运体（例如 DAT、SERT）缺失、饱和和/或阻断时出现的假说。因此，已知降低 PMAT 功能的人类多态性可能值得作为抗抑郁药和精神兴奋剂反应不同的原因进行研究。
