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Alpha6 nicotinic receptors are extremely important in nicotine addiction. They are a subclass of the nicotinic receptor family, the receptors that are responsible for the effects of nicotine in the brain. The alpha6 subunit is important in nicotine addiction, and is expressed only in a limited number of brain regions. There is a high concentration of alpha6 nicotinic receptors the midbrain dopaminergic neurons, where reward processing takes place. Due to their importance in nicotine addiction and limited expression pattern, we chose to study whether modulation of alpha6 containing nicotinic receptors by lynx1 may be important in nicotine addiction. Previous studies have shown that lynx1, a three-fingered toxin with similarity to alpha-bungarotoxin, can modulate alpha4beta2 and alpha7 nicotinic receptors, the two most abundant nicotinic receptors. This study will focus on the effect of lynx1 on alpah6 nicotinic receptors. It will do so by using the alpha 6 L9’S mouse line, a mouse model that expresses hypersensitive alpha6 receptors. Recordings from midbrain dopaminergic neurons of the alpha6 L9’S mouse have demonstrated that the nicotinic receptors have larger responses. Additionally, these mice exhibit hyperactivity and an inability to habituate to novel environments. Recent studies have shown that these mice also develop conditioned place preference, a measurement of nicotine reinforcement, at lower doses of nicotine than wild-type mice. To study the effect of lynx1 on the alpha6 L9’S mice, the alpha6 L9’S mice were bred to lynx1 knockout mice (lynx1KO). The alpha6 L9’S mice can be considered to be a tool to understand alpha6 nicotinic receptor function, and they have bred them to the lynx1KO mice to test whether lynx1 has a role in modulating alpha6 containing receptors. The studies proposed in this application will determine whether the phenotypes of the alpha6 L9’S mice described above are altered when lynx1 is removed. If these phenotypes are disrupted when lynx1 is removed, this will demonstrate that lynx1 is involved in the normal function of alpha6 nicotinic receptors. Since these receptors are important in nicotine addiction, this suggests that lynx1 modulation of alpha6 nicotinic receptors may be important in nicotine addiction. |
