Increased alcohol consumption and development of tolerance to alcohol‐induced sedation in NBCn1 knockout mice

Abstract

The Na/HCO3 cotransporter NBCn1 plays a role in regulating synaptic pH. We recently reported that a human SLC4A7 gene polymorphism identified as a marker for polysubstance abuse is responsible for the production of a transporter variant that has a defect in function and expression. This finding prompted us to test whether NBCn1 is involved in alcoholism. Here, we examined alcohol‐drinking behaviors, as well as locomotor/anxiety and spatial learning behaviors, in NBCn1 knockout (KO) mice. In the open filed test, NBCn1 KO mice displayed decreased locomotor activity compared to wild type (WT) littermates. However, the activity in the elevated plus maze test was similar between WT and KO mice, indicating negligible change in anxiety. In the Morris water maze test, both groups of mice had learning behaviors improving each day with similar latency to escape in repeated trainings and distance traveled. The two groups learned the platform location with similar time spent in the trained quadrant during the probe trials. Thus, hippocampal‐based spatial learning was not altered in KO mice. Next, alcohol‐related behaviors were tested in a two‐bottle choice drinking experiment, in which mice were given to 3–15% ethanol with 3% increments at 4 days and alcohol consumption was measured. KO mice consumed more alcohol than WT mice with higher alcohol preference (p < 0.05). The consumption was also increased after repeated alcohol withdrawals. In the loss of righting reflex test following alcohol administration (3.5 g/kg alcohol; intraperitoneal), KO mice had a longer duration of sedation, but blood alcohol concentration did not differ. The duration became shorter when KO mice were pretreated with alcohol for 7 days, indicating the development of tolerance to the hypnotic effects of alcohol. Whole cell current clamp of hippocampal neurons showed that neurons from KO mice had a higher action potential threshold, no recurrent action potential, and a more depolarized membrane potential. These results indicate that abnormalities in NBCn1 alter alcohol consumption and alcohol‐related behaviors by changing neuronal excitability. Increased voluntary alcohol consumption in KO mice is probably driven by decreased rewarding value of alcohol. Neurons from KO mice are less excitable, which would lead to decreased neurotransmitter release. Thus, the rewarding value of alcohol is reduced, requiring more alcohol to achieve the same level of hedonic response.Support or Funding InformationNIH and Emory URCThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.