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.

Brain-Specific Inhibition of mTORC1 by a Dual Drug Strategy: A Novel Approach for the Treatment of Alcohol Use Disorder

“…Data obtained in rodents suggest that inhibition of mTORC1 in the brain dampens numerous adverse behaviors associated with alcohol use 10,17,21,24 . In contrast, inhibition of mTORC1 does not alter the consumption of natural rewarding substances 40 , suggesting that inhibition of mTORC1 does not affect reward per se . Furthermore, inhibition of mTORC1 is not aversive or rewarding, nor does it alter locomotion 40 .…”

“…In contrast, inhibition of mTORC1 does not alter the consumption of natural rewarding substances 40 , suggesting that inhibition of mTORC1 does not affect reward per se . Furthermore, inhibition of mTORC1 is not aversive or rewarding, nor does it alter locomotion 40 . Importantly, a single administration of Rapamycin or RapaLink-1 produces a long-lasting attenuation of excessive alcohol use and relapse 21,23 .…”

“…Furthermore, the approach described herein, enabling the separation between the desirable, CNS-mediated actions of a drug versus the undesirable periphery-mediated drug effects could be used for the development of other CNS-targeted therapeutic approaches. For instance, Fyn kinase has been implicated in mechanisms underlying Alzheimer’s disease 39 , AUD 40 and opiate addiction 41 , and small molecule inhibitors such as AZD0530 have been in development for the treatment of Alzheimer’s disease 39 . Protecting the activity of the kinase in the periphery will enable the reduction of potential side effects and increase the safety of the inhibitor.…”

Differential Correlation of Serum BDNF and microRNA Content in Rats with Rapid or Late Onset of Heavy Alcohol Use

“…Over more than a decade, we and others observed that the BDNF system interacts with alcohol in a unique way (Logrip et al, 2015;Ron and Berger, 2018). We found that moderate but not excessive intake of alcohol increases the expression of BDNF in the dorsal striatum and more specifically in the dorsolateral striatum (DLS) of rodents (Jeanblanc et al, 2009;Logrip et al, 2009;McGough et al, 2004) resulting in the activation of TrkB/ERK1/2 signaling (Jeanblanc et al, 2013;Logrip et al, 2009;McGough et al, 2004), and in the induction of the dopamine D3 receptor (Jeanblanc et al, 2006) and preprodynorphin (Logrip et al, 2008) gene expression, which in turn keeps alcohol drinking in moderation.…”

“…As disruption of normal BDNF signaling in the brain promotes the development of heavy alcohol use in rodents and possibly in humans (Ron and Berger, 2018), and as lowered serum BDNF levels are associated with AUD, we set out to determine if the same is true for the BDNF machinery in the peripheral blood serum of rats. We further determined whether the decrease in BDNF serum content is associated with alterations in the levels of microRNAs targeting BDNF.…”