Targeting the intracellular signaling "STOP" and "GO" pathways for the treatment of alcohol use disorders

Abstract

In recent years, research has identified the molecular and neural substrates underlying the transition of moderate "social" consumption of alcohol to the characteristic alcohol use disorder (AUD) phenotypes including excessive and compulsive alcohol use which we define in the review as the GO signaling pathways. In addition, growing evidence points to the existence of molecular mechanisms that keep alcohol consumption in check and that confer resilience for the development of AUD which we define herein as the STOP signaling pathways. In this review, we focus on examples of the GO and the STOP intracellular signaling pathways and discuss our current knowledge of how manipulations of these pathways may be used for the treatment of AUD.

Keywords: Addiction; Alcohol; BDNF; Fyn; GDNF; Medication Development; Signaling; Translation; mTOR.

Fig. 1

The STOP and GO intracellular signaling pathways control alcohol-drinking behaviors. Moderate and/or limited consumption of alcohol results in the activation of signaling cascades within the STOP pathways. STOP signaling pathways which center around genes such as BDNF and GDNF are described herein. Activation of the STOP signaling cascades limits the amount of consumed alcohol and keeps alcohol intake in check (right panel). Prolonged consumption of large quantities of alcohol activates the GO pathways. Activation of GO signaling cascades are driven in part, by the activation of Fyn and mTOR to produce neuroadaptations that contribute to the escalation and maintenance of excessive uncontrolled alcohol intake. The GO pathways are also the molecular underpinnings of other adverse phenotypes such as alcohol craving, seeking, and relapse (left panel)

Fig. 2

Drug candidates for the treatment of AUD. Preclinical animal models suggest that targeting GO and STOP signaling reduce alcohol-drinking behaviors as well as other behaviors associated with alcohol use. These include inhibitors of GO signaling and activators of STOP signaling. Specifically, cabergoline and ibogaine are inducers of GDNF expression. Memantine is an inducer of BDNF expression. LM22A-4 is an activator of the BDNF receptor TrkB, and LM11A31 is an inhibitor of the low affinity neurotrophin receptor, p75NTR. Saracatinib is a Fyn kinase inhibitor, and rapamycin and rapalink are mTORC1 inhibitors. Finally, lacosamide inhibits the function of CRMP2