The BDFN-TrkB-KCC2 pathway as a potential treatment target for modulating alcohol consumption

Abstract ID 98214 Poster Board 111 Brain-derived neurotrophic factor (BDNF) is involved in various physiological processes. Its main receptor in the central nervous system is tyrosine receptor kinase B (TrkB), and the main ligand for TrkB in the central nervous system is BDNF. It has been shown previously that activating TrkB leads to downregulation of the chloride-exporting protein potassium chloride cotransporter 2 (KCC2). Downregulation of KCC2 results in a decreased chloride gradient and disrupted GABAA inhibitory neurotransmission. This BDNF-TrkB-KCC2 pathway is receiving increased attention in connection with substance use disorders (SUDs), leading to increasing potential to use this mechanism as a treatment target for SUDs. Here we investigate the BDNF-TrkB-KCC2 pathway in the context of alcohol exposure and voluntary alcohol consumption. We demonstrate that chronic intermittent ethanol (CIE) exposure leads to a significant increase in BDNF expression in the ventral tegmental area (VTA) and in the nucleus accumbens (NAc) following 24 hr of withdrawal, which persists for 7 days. Acute alcohol exposure does not elicit this same effect. Fluorescence microscopy in the VTA demonstrated KCC2 expression on neurons expressing the 67 kDa isoform of glutamic acid decarboxylase (GAD67), which labels GABA neurons, as well as on GAD67 negative neurons and non-neuronal cells, suggesting an expression pattern that is widely prevalent and not restricted to a single neuronal subpopulation. Using patch clamp electrophysiology in the cell-attached configuration, BDNF did not directly elicit changes in VTA GABA neuron firing rate when bath applied to alcohol-naïve brain slices, suggesting that BDNF's effects on cellular activity are more adaptive than acute. In a drinking in the dark (DiD) paradigm of voluntary alcohol consumption, we observe that blocking TrkB activity with intraperitoneal (IP) injection of the TrkB antagonist ANA-12 led to a decrease in alcohol consumption in alcohol-naïve animals but not in alcohol-dependent animals. In this same paradigm, increasing activation of TrkB with IP injection of the TrkB agonist 7,8-dihydroxyflavone (DHF) resulted in a non-significant trend toward increased alcohol consumption in alcohol-naïve but not in alcohol-dependent animals. These results support the BDNF-TrkB-KCC2 pathway as a potential avenue for modulating consumption of alcohol that merits additional investigation.