Ezrin-radixin-moesin proteins are regulated by Akt-GSK3β signaling in the rat nucleus accumbens core

The ezrin-radixin-moesin (ERM) proteins are a family of membrane-associated proteins known to play roles in cell-shape determination as well as in signaling pathways. We have previously shown that amphetamine decreases phosphorylation levels of these proteins in the nucleus accumbens (NAcc), an important neuronal substrate mediating rewarding effects of drugs of abuse. In the present study, we further examined what molecular pathways may be involved in this process. By direct microinjection of LY294002, a PI3 kinase inhibitor, or of S9 peptide, a proposed GSK3β activator, into the NAcc core, we found that phosphorylation levels of ERM as well as of GSK3β in this site are simultaneously decreased. These results indicate that ERM proteins are under the regulation of Akt-GSK3β signaling pathway in the NAcc core. The present findings have a significant implication to a novel signal pathway possibly leading to structural plasticity in relation with drug addiction.

Repeated Exposure to beta-phenylethylamine Produces Locomotor Sensitization to Amphetamine, but Not Vice Versa, in the Rat

Repeated administration of amphetamine (AMPH) produces behavioral sensitization, a proposed model for the escalation of drug use characteristic of human addicts. beta-Phenylethylamine (PEA) is an endogenous trace amine found in mammalian brain and resembles AMPH both structurally and behaviorally. Previously, it has been reported that chronic PEA administration produces behavioral sensitization to the challenges of AMPH. However, these data were obtained with very high amount of PEA for a relatively long period of time. Further, the effect of PEA challenge on the expression of behavioral sensitization developed by AMPH pre-exposures has not been tested yet. Thus, we examined in the present experiment the expression of behavioral sensitization with AMPH challenge after a mild chronic PEA treatment. Rats were repeatedly administered with systemic injections of saline, beta-phenylethylamine (PEA) (10 or 50 mg/kg), or amphetamine (AMPH) (1.5 mg/kg). When challenged a week after the last pre-injection, rats pre-exposed to either PEA or AMPH showed behavioral sensitization to AMPH (1.0 mg/kg), while these effects were not observed to PEA (50 mg/kg) itself. These results demonstrate that repeated exposure to PEA produces behavioral sensitization to AMPH challenge, while PEA challenge has no effect on the expression of behavioral sensitization developed by AMPH pre-exposures, suggesting that PEA may play a role in the development of locomotor sensitization to AMPH, but not in the expression of it.