MeBib Suppressed Methamphetamine Self-Administration Response via Inhibition of BDNF/ERK/CREB Signal Pathway in the Hippocampus

Abstract

Methamphetamine (MA) is one of the most commonly abused drugs in the world by illegal drug users. Addiction to MA is a serious public health problem and effective therapies do not exist to date. It has also been reported that behavior induced by psychostimulants such as MA is related to histone deacetylase (HDAC). MeBib is an HDAC6 inhibitor derived from a benzimidazole scaffold. Many benzimidazole-containing compounds exhibit a wide range of pharmacological activity. In this study, we investigated whether HDAC6 inhibitor MeBib modulates the behavioral response in MA self-administered rats. Our results demonstrated that the number of active lever presses in MA self-administered rats was reduced by pretreatment with MeBib. In the hippocampus of rats, we also found MA administration promotes GluN2B, an NMDA receptor subunit, expression, which results in sequential activation of ERK/CREB/BDNF pathway, however, MeBib abrogated it. Collectively, we suggest that MeBib prevents the MA seeking response induced by MA administration and therefore, represents a potent candidate as an MA addiction inhibitor.

Epigenetic Regulatory Dynamics in Models of Methamphetamine-Use Disorder

“…A specific HDAC6i that is thiazolidinedione-based has been shown to normalize the abundance of acetylated α-tubulin and to reverse METH-induced morphological changes in a neuroblastoma cell line [72]. Moreover, Kim et al (2020) [73] used another HDAC6i, MeBib derived from a benzimidazole scaffold, and were able to reduce the METH SA by rats [73].…”

Epigenetic mechanisms involved in methamphetamine addiction

“…The number of active lever presses in METH self-administration rats was reduced by pretreatment with an inhibitor of HDAC6. METH administration increased GluN2B, an NMDA receptor subunit expression and sequential activation of extracellular regulated protein kinases (ERK)/cAMP-response element binding protein (CREB)/brain derived neurotrophic factor (BDNF) pathway which were abolished by an inhibitor of HDAC6 in the Hip, which suggests that HDAC6 inhibitor prevents METH self-administration in rats (Kim et al, 2020). Collectively, HDAC6-isoform selective inhibitor provided therapeutic potential with the treatment of METH addiction.…”

The Role of CaMKII and ERK Signaling in Addiction

“…Methamphetamine administration significantly increased the behavioral sensitization evaluated by the total distance in mice, and elevated ERK phosphorylation and ΔFosB levels in the mouse NAc [ 102 ]. Methamphetamine injection also elevated the expression of GluN2B, which in turn caused a significant increase in ERK, CREB phosphorylation, and BDNF levels [ 103 ]. Ethanol-induced enhancement of ethanol sensitization and ERK phosphorylation levels were observed in the mouse NAc shell, and these elevations were inhibited by pretreatment with MPEP, which is an mGluR5 antagonist [ 104 ].…”