Interference of norepinephrine transporter trafficking motif attenuates amphetamine-induced locomotor hyperactivity and conditioned place preference

NEUROPHARMACOLOGY

卷:128

Article

Mannangatti, Padmanabhan¹  Ramamoorthy, Sammanda¹  Jayanthi, Lankupalle Damodara¹ 

[1] Virginia Commonwealth Univ, Dept Pharmacol & Toxicol, R Blackwell Smith Bldg,Room 740,410 North,12th St, Richmond, VA 23298 USA

关键词: Norepinephrine;    Catecholamines;    Transporters;    Amphetamine;    Psychostimulants;    Behavior;   

DOI  :  10.1016/j.neuropharm.2017.10.005

来源: Elsevier

【 摘 要 】

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-NET-T258/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-1258/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. Published by Elsevier Ltd.

【 授权许可】

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