Interference of norepinephrine transporter trafficking motif attenuates amphetamine-induced locomotor hyperactivity and conditioned place preference.
Interference of norepinephrine transporter trafficking motif attenuates amphetamine-induced locomotor hyperactivity and conditioned place preference.
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DOI：
10.1016/j.neuropharm.2017.10.005
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发表时间：
2018-01
影响因子：
4.7
通讯作者：
Jayanthi LD
中科院分区：
文献类型：
--
作者：
Mannangatti P;Ramamoorthy S;Jayanthi LD
安非他明（AMPH）介导的去甲肾上腺素转运蛋白（NET）下调需要NET-T258/S259运输基序。本研究利用细胞可渗透的NET-T258/S259基序干扰肽，它阻止AMPH诱导的NET下调，探讨这种形式的NET调节在AMPH介导的行为中的作用。在接受脑内微量注射包含NET-T258/S259基序的TAT缀合肽的大鼠中，急性全身性AMPH未能抑制注射TAT-NET-T258/S259野生型（WT）肽的半球中的NE转运，但在注射载体或乱序肽的半球中没有。与接受脑内载体或TAT-NET-T258 A/S259 A突变肽或相应的TAT缀合的乱序肽的大鼠相比，接受脑内TAT-NET-T258/S259 WT肽的大鼠中急性AMPH诱导的活动过度显著减少。基础运动活动没有改变肽输注单独。类似地，AMPH诱导的运动致敏在AMPH攻击之前接受脑内TAT-NETT 258/S259 WT肽的大鼠中显著降低，而在接受突变体或乱序肽的大鼠中没有。在条件性位置偏爱（CPP）实验中，在CPP实验前双侧延髓内注射TAT-NET-T258/S259 WT肽显著降低AMPH诱导的CPP表达。同样地，在药物激发前单次双侧小脑内微量注射TAT-NET-T258/S259 WT肽显著减弱AMPH引发的CPP恢复。另一方面，双侧小脑内微量注射乱序肽不影响AMPH诱导的CPP表达或恢复。这些数据证明了T258/S259依赖性NET调节在AMPH诱导的活动过度和致敏以及AMPH诱导的CPP表达和恢复中的作用。
Amphetamine (AMPH)-mediated norepinephrine transporter (NET) downregulation requires NET-T258/S259 trafficking motif. The present study utilizes cell permeable NET-T258/S259 motif interfering peptide, which blocks AMPH-induced NET downregulation, to explore the role of this form of NET regulation in AMPH-mediated behaviors. In rats receiving intra-accumbal microinjections of TAT-conjugated peptides encompassing NET-T258/S259 motif, acute systemic AMPH failed to inhibit NE transport in the TAT-NET-T258/S259 wild-type (WT) peptide injected hemisphere but not in the vehicle or scrambled peptide injected hemisphere. Acute AMPH-induced hyperactivity was significantly reduced in rats receiving intra-accumbal TAT-NET-T258/S259 WT peptide compared to those receiving intra-accumbal vehicle or TAT-NET-T258A/S259A mutant peptide or corresponding TAT-conjugated scrambled peptide. Basal locomotor activity was not altered by peptide infusions alone. Similarly AMPH-induced locomotor sensitization was significantly reduced in rats receiving intra-accumbal TAT-NETT258/S259 WT peptide prior to AMPH challenge and not in rats receiving the mutant or scrambled peptide. In conditioned place preference (CPP) paradigm, a single bilateral intra-accumbal microinjection of TAT-NET-T258/S259 WT peptide prior to CPP testing significantly reduced AMPH-induced CPP expression. Likewise, a single bilateral intra-accumbal microinjection of TAT-NET-T258/S259 WT peptide prior to drug-challenge significantly attenuated AMPH-primed CPP reinstatement. On the other hand, bilateral intra-accumbal microinjection of scrambled peptide did not affect AMPH-induced CPP expression or reinstatement. These data demonstrate a role for T258/S259-dependent NET regulation in AMPH-induced hyperactivity and sensitization as well as AMPH-induced CPP expression and reinstatement.
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影响因子：
5
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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