We observed an association of FKBP5 genotype and mRNA expression to subjective reports of “negative” drug effects during the human laboratory study. Genotype group differences were greatest during the saline condition and absent at the high nicotine condition. During the saline condition, the minor allele carriers reported less “negative” drug effects. In contrast, mRNA expression differences were absent during the saline condition and greatest during the high nicotine condition. Subjects with low FKBP5 expression reported less “negative” drug effects in response to nicotine relative to subjects with high FKBP5 expression. We also found that subjects with low FKBP5 mRNA expression had a blunted HR response to nicotine compared to subjects with high FKBP5 mRNA expression, but genotype was not associated with HR response. Stress hormones reduce the sensitivity of nicotinic receptors to nicotine,20, 21, 47 and they moderate the acute behavioral and HR response to nicotine in animal models.48, 49 Our findings regarding FKBP5 variation and the acute subjective and HR response to nicotine may reflect FKBP5-dependent stress hormone modulation of nicotinic receptor sensitivity in humans.
