Different Hypothalamic Nicotinic α7 Receptor Expression and Response to Low Nicotine Dose in Alcohol‐Preferring and Alcohol‐Avoiding Rats

The aim of this study was to examine possible differences in nicotinic acetylcholine receptors and responses in rats with genetic preference or avoidance for alcohol. This was done by using 2 rat lines with high alcohol preference (Alko Alcohol [AA]) or alcohol avoidance (Alko Non‐Alcohol [ANA]). Locomotor activity was measured following nicotine and histamine H3 receptor (H3R) antagonist treatment. In situ hybridization and receptor ligand binding experiments were used in drug‐naïve animals to examine the expression of different αnicotinic receptor subunits. The AArats were found to be more sensitive to the stimulatory effect of a low dose of nicotine than ANArats, which were not significantly activated. Combination of histamine H3R antagonist, JNJ‐39220675, and nicotine resulted to similar locomotor activation as nicotine alone. To further understand the mechanism underlying the difference in nicotine response in AAand ANArats, we studied the expression of α5, α6, and α7 nicotinic receptor subunits in specific brain areas of AAand ANArats. We found no differences in the expression of α5 nicotinic receptor subunits in the medial habenula and hippocampus or in α6 subunit in the ventral tegmental area and substantia nigra. However, the level of α7 nicotinic receptor subunit mRNAwas significantly lower in the tuberomamillary nucleus of posterior hypothalamus of alcohol‐preferring AArats than in alcohol‐avoiding ANArats. Also the hypothalamic [125]I‐α‐bungarotoxin binding was lower in AArats indicating lower levels of α7 nicotinic receptors. The lower expression and receptor binding of α7 nicotinic receptors in the tuberomamillary nucleus of AArats suggest a difference in the regulation of brain histamine neurons between the rat lines since the α7 nicotinic receptors are located in histaminergic neurons. Stronger nicotine‐induced locomotor response, mediated partially via α7 receptors, and previously described high alcohol consumption in AArats could be explained by the found difference in tuberomamillary α7 receptor levels. Alcohol preferring and alcohol avoiding rats display different expression and receptor binding levels of nicotinic receptor subtype alpha7. The alpha7 receptor expression is located specifically on histaminergic neurons suggesting that regulation of brain histaminergic system might differ between the rat lines and explain the difference in alcohol consumption and nicotine responses in these animals.