Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
Department of Psychiatry and Behavioral Sciences, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
Int J Mol Sci. 2021 Dec 14;22(24):13420. doi: 10.3390/ijms222413420.
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.
缺乏有效的治疗方法以及性别的差异导致了在精神兴奋剂成瘾和过量方面的治疗效果不佳，这使得我们有必要进一步研究安非他命类兴奋剂与滥用相关的作用机制。摄取转运体，如有机阳离子转运体 3（OCT3）和单胺转运体（PMAT），是研究较少的潜在兴奋剂药物作用靶点，它们在单胺能神经传递中发挥作用。我们的目标是使用药理学、Decynium-22（D22；0.1mg/kg，OCT3 和 PMAT 的阻断剂）和基因（组成型 OCT3 和 PMAT 敲除（-/-）小鼠）方法，在雄性和雌性中，研究 OCT3 和 PMAT 在介导安非他命（1mg/kg）诱导的条件性位置偏好（CPP）和对其运动刺激作用的敏化中的作用。我们的结果表明，OCT3 是雄性动物中 CPP 发展为安非他命所必需的，而在雌性动物中，PMAT 是 D22 预防 CPP 发展为安非他命所必需的。OCT3 和 PMAT 似乎都对雌性动物对安非他命的运动刺激作用的敏化以及雄性动物中 PMAT 的敏化作用很重要。综上所述，这些发现支持了 OCT3 和 PMAT 在安非他命的奖赏和运动刺激作用中的重要的、依赖于性别的作用。
