Regulation of miR-128 in the nucleus accumbens affects methamphetamine-induced behavioral sensitization by modulating proteins involved in neuroplasticity.

Abstract

Methamphetamine (METH) -induced behavioral sensitization depends on long-term neuroplasticity in the mesolimbic dopamine system, especially in the nucleus accumbens (NAc). miR-128, a brain enriched miRNA, was found to have abilities in regulating neuronal excitability and formation of fear-extinction memory. Here, we aim to identify the role of miR-128 on METH-induced locomotor sensitization of male mice. We identified a significant increase of miR-128 in the NAc of mice upon repeated-intermittent METH exposure but not acute METH administration. Microinjection of adeno-associated virus (AAV)-miR-128 over-expression and inhibition constructs into the NAc of mice resulted in enhanced METH-induced locomotor sensitization and attenuated effects of METH respectively. Isobaric tags for relative and absolute quantification (iTRAQ) technology and ingenuity pathway analysis (IPA) were carried out to uncover the potential molecular mechanisms underlying miR-128-regulated METH sensitization. Differentially expressed proteins, including 25 potential targets for miR-128 were annotated in regulatory pathways that modulate dendritic spines, synaptic transmission and neuritogenesis. Of which, Arf6, Cpeb3 and Nlgn1, were found to be participating in miR-128-regulated METH sensitization. Consistently, METH-induced abnormal changes of Arf6, Cpeb3 and Nlgn1 in the NAc of mice were also detected by qPCR and validated by western blot analysis. Thus, miR-128 may contribute to METH sensitization through controlling neuroplasticity. Our study suggested miR-128 was an important regulator of METH- induced sensitization and also provided the potential molecular networks of miR-128 in regulating METH-induced sensitization.