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Li W, Wu W, Zuo W, Fu R, Xie Z, Li G, Ye JH
Rutgers, New Jersey Medical School, Newark, USA
Alcohol use disorders are a serious problem worldwide. Interestingly, both the rewarding and aversive properties of ethanol are critical for its addiction. Whereas there is much evidence that links ethanol’s rewarding property with the mesolimbic dopamine system, originating from the ventral tegmental area (VTA), much less is known regarding ethanol-related aversion. The lateral habenular (LHb) is emerging as a brain region critically involved in processing aversive signals, including those related to ethanol. Glycine receptors (GlyRs), a major target of alcohol, are broadly expressed in the central nervous system, including the VTA and LHb, brain regions important for ethanol addiction. Here, I will review current knowledge on the roles of GlyRs in the activities of these brain regions and in alcohol-related behaviors of rats.
In the VTA, low concentration (EC50~1 uM) of glycine, probably via the activation of presynaptic GlyRs, reduced GABAergic transmission leading to the acceleration of action potential firing of VTA dopamine neurons. Intra-VTA infusion of 10 uM but not 50 uM glycine reduced ethanol drinking and seeking behaviors, an effect blocked by intra-VTA infusion of the GlyR antagonist strychnine. In neurons isolated from the LHb, glycine induced a current with an EC50 of 83 µM. In brain slices, application of strychnine induced a modest conductance (~15 pA) in many LHb neurons. In agreement, strychnine caused membrane depolarization, and increased the excitability of LHb neurons. Consistent with this, application of glycine induced membrane hyperpolarization and decreased LHb excitability. These findings identify extrasynaptic GlyRs as a critical regulator of LHb activity.
Importantly, intra-LHb infusion of glycine (100 uM, but not 10 uM) substantially mitigated mechanical allodynia and thermal hyperalgesia in rats during withdrawal from chronic ethanol consumption. In parallel, LHb infusion of 100 uM glycine reduced ethanol intake and preference, without altering either sucrose intake or general locomotor activity. Furthermore, these effects of glycine were blocked by LHb infusion of strychnine, indicating that they are mediated by strychnine-sensitive GlyRs. Thus, the LHb represent a cellular target for aversive experience during ethanol withdrawal. In addition, its reversal by glycine may provide a novel therapeutic approach to alleviate symptoms of ethanol withdrawal.