At least in the DLS, suppression of alcohol drinking by BDNF is mediated by activation of the MAPK/ERK pathway

At least in the DLS, suppression of alcohol drinking by BDNF is mediated by activation of the MAPK/ERK pathway. 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. gene, is the high-affinity binding receptor for brain-derived neurotrophic factor (BDNF), neurotrophin 4, and neurotrophin 3 (Fig. ?(Fig.1),1), which are members of the nerve growth factor family [8, 11, 12]. TrkB is expressed in neurons and glia and is found in both the peripheral and central nervous systems [13]. In the brain, it is enriched in the cortex, hippocampus, and specific nuclei of the brainstem. Although homozygous knockout mice survive to birth, they die as neonates due to an inability to feed because of defects in sensory and motor systems [14]. TrkB signaling is involved many processes such as synaptic plasticity, cell survival, and neurite outgrowth [9, 15] and aberrant TrkB signaling has been implicated in neurodegeneration, cancers, and neuropsychiatric disorders including AUD [9, 16]. Open in a separate window Fig. 1 Receptor tyrosine kinases (RTKs) and their corresponding ligands that have been investigated for alcohol drinking in animals. The domain structure of each RTK is illustrated. Ligands for each receptor are indicated above the receptor. Also indicated are the relevant downstream signaling pathways involved in alcohol drinking. Note that MAPK/ERK and JAK/STAT signaling are activated in response to ethanol in an ALK-dependent manner in cell lines, but it is not yet known if these pathways are responsible for altering drinking in response to ALK activation. MAM = meprin, A-5 protein, and receptor protein tyrosine phosphatase mu domain; L = receptor L domain; LDLa = low-density lipoprotein receptor domain class A; Ig = immunoglobulin domain; EGF = epidermal growth factor; TGF = transforming growth factor alpha; HB-EGF = heparin-binding EGF-like growth factor; EGFR = EGF receptor; RET = RET proto-oncogene; GDNF = glial-derived neurotrophic factor; GFR1 = GDNF family receptor alpha 1; PTN SB-505124 = pleiotrophin; MDK = midkine; ALK = anaplastic lymphoma kinase; BDNF = brain-derived neurotrophic factor; NT3 = neurotrophin 3; NT4 = neurotrophin 4; TrkB = tropomyosin-related kinase B; FGFs = fibroblast growth factors; FGF2 = fibroblast growth factor 2; FGFR = FGF receptor; MAPK/ERK = mitogen-activated protein kinase/extracellular signal-regulated kinase; JAK/STAT = Janus kinase/signal transducer and activator of transcription; PI3K/AKT = phosphoinositide 3-kinase/protein kinase B Inference that TrkB might be a therapeutic target for the treatment of AUD initially came from several studies on one of its ligands, BDNF. gene and protein expression are altered by alcohol exposure both and in various brain regions of rats and mice [17C30]. Of note, expression was increased in mouse dorsal striatum (DS) after voluntary ethanol intake and after a single binge ethanol drinking session and in rat DS after ethanol self-administration [19, 21, 28]. Direct manipulation of BDNF levels in the dorsolateral striatum (DLS) of rats bidirectionally altered ethanol self-administration, such that infusion of BDNF protein into the DLS reduced lever pressing for ethanol, whereas knockdown of expression in the DLS using a virally administered short hairpin (sh)RNA increased ethanol self-administration [28, 31]. The ability of BDNF in the DLS to suppress ethanol self-administration was SB-505124 dependent on MAPK/ERK signaling, because co-infusion of BDNF with the MAPK/ERK inhibitor SB-505124 U0126 blocked the ability of BDNF to suppress ethanol self-administration [31]. Heterozygous knockout mice consumed more ethanol than wild-type controls and exhibited enhanced ethanol conditioned place preference (CPP), which is a behavioral measure of the rewarding properties of ethanol [21, 32]. Conditional knockout of BDNF in mouse forebrain neurons increased intake of Bmpr2 a sweetened ethanol solution, and knockdown.