Methamphetamine induces dynamic changes of histone deacetylases in different phases of behavioral sensitization.

In recent years, abuse of amphetamine-type stimulants (ATS) has become a severe problem to the whole world, and methamphetamine (METH) has accounted for the majority percent of global ATS seizures. It has been confirmed that the changes of histone acetylation involve in the regulation of METH addiction [1]; however, the effects of METH on histone deacetylase (HDAC) are poorly understood. Behavioral sensitization is an important animal model to reflect the neurological changes in drug addiction [2]. It has been confirmed that the prefrontal cortex (PFC) is related with the circuitry of sensitization [3]. The development of sensitization may involve excitatory amino acids projections originating in the PFC [3], and the expression of sensitization to systemic cocaine was blocked after the PFC lesion [4]. This study aimed to investigate the activity and expression changes of HDACs in the PFC of rats with METH-induced behavioral sensitization. The model of behavioral sensitization was established by 7 days’ METH (5 mg/kg, s.c., once daily) administration followed by 7 days’ withdrawal, and challenged by single METH (1 mg/kg, s.c.) on the 15th day (Figure 1A). When challenged by METH, rats in METH–METH group showed significantly higher locomotor activity than the NS-METH group (F2,12 = 4.859, P < 0.01, Figure 1B), indicating the enhanced locomotor response of sensitization. This study found that the expressions of both HDAC1 and HDAC2, two isoforms of Class I HDACs, decreased after acute METH treatment (P < 0.05, Figure 2A), while the total HDACs activity did not change. Kennedy et al. [5] reported that HDAC1 knockdown inhibited the development of cocaine-induced behavioral sensitization, which suggested that HDAC1 played an important role in the induction of behavioral sensitization, and our data further proved the hypothesis. Long-term treatment with METH produced histone hyperacetylation [1], but it is not clear that the relationship between HDACs (A)