Receptor Tyrosine Kinases as Therapeutic Targets for Alcohol Use Disorder

Abstract

The receptor tyrosine kinases (RTKs) are a large family of proteins that transduce extracellular signals to the inside of the cell to ultimately affect important cellular functions such as cell proliferation, survival, apoptosis, differentiation, and migration. They are expressed in the nervous system and can regulate behavior through modulation of neuronal and glial function. As a result, RTKs are implicated in neurodegenerative and psychiatric disorders such as depression and addiction. Evidence has emerged that 5 RTKs (tropomyosin-related kinase B (TrkB), RET proto-oncogene (RET), anaplastic lymphoma kinase (ALK), fibroblast growth factor receptor (FGFR), and epidermal growth factor receptor (EGFR)) modulate alcohol drinking and other behaviors related to alcohol addiction. RTKs are considered highly "druggable" targets and small-molecule inhibitors of RTKs have been developed for the treatment of various conditions, particularly cancer. These kinases are therefore attractive targets for the development of new pharmacotherapies to treat alcohol use disorder (AUD). This review will examine the preclinical evidence describing TrkB, RET, ALK, FGFR, and EGFR modulation of alcohol drinking and other behaviors relevant to alcohol abuse.

New developments in the biology of fibroblast growth factors

“…FGF21 was shown to signal to neurons in the paraventricular nucleus to stimulate water consumption in response to alcohol (Song et al, 2018). These studies and others suggest that RTKs and FGFRs, in particular, may be viable drug targets to modify alcohol abuse behaviors (Hamada & Lasek, 2020).…”

Genetic inactivation of midkine, not pleiotrophin, facilitates extinction of alcohol-induced conditioned place preference

“…Pleiotrophin and MK inactivate the phosphatase activity of RPTPβ/ζ, increasing the phosphorylation levels of its substrates [12,18]. Some of these RPTPβ/ζ substrates such as ALK [19], also a proposed receptor for PTN and MK [14], and Fyn kinase [20] are known to be important regulators of alcohol behavioral effects [1,21]. Importantly, small-molecule blood-brain barrier (BBB)-permeable inhibitors of RPTPβ/ζ [22] have recently been shown to reduce alcohol-induced conditioned place preference (CPP) and alcohol consumption in mice [10,23], and to reduce alcohol consumption in an operant self-administration paradigm in rats [24].…”

Investigation of the Efficacy of Zonisamide in Alcohol Induced Hepatotoxicity

“…The pötential hepatöprötective effects öf zönisamide are drawing significant interest fröm the scientific and medical cömmunities 11 . A cömprehensive appröach, encömpassing everything fröm lifestyle mödificatiöns tö pharmacölögical interventiöns, is required tö prevent and treat alcöhöl-related liver injuries 12,13 . Understanding the röle öf zönisamide in this cöntext cöuld significantly aid in develöping effective treatment strategies and prövide new insights intö managing alcöhöl-induced liver cönditiöns 14 .…”