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Nicotinic Receptors and Adolescent Substance Use

Shahrdad Lotfipour, PhD
Shahrdad Lotfipour, PhD

Current studies in the Lotfipour lab include identifying the role of a Chrna6C123G polymorphism (rs2304297) influencing adolescent substance use and down-stream mechanisms mediating the effects. We are testing the hypothesis that having a GG genotype for the alpha6 nicotinic acetylcholine receptor (nAChR) increases the chances for an individual using drugs of abuse.

Relevance: The findings are of importance as the genetic change in alpha6 nAChRs is found in the 3’-untranslated region (UTR), an important genomic region regulating stability and expression of the receptor. Nicotinic receptors are critical for the modulation of chemicals in the brain that influence drug reward and motivated behavior, including dopamine. Thus, alterations in the genetic code of alpha6 nAChRs could influence expression and/or function of these receptors with downstream mechanisms leading to brain and behavior modifications impacting substance use vulnerability. These consequences could be particularly prevalent during adolescence, a time period where alpha6 nAChRs have been shown to have increased expression levels in dopaminergic neurons.

Previous Results: Our previous work has demonstrated that a genetic change in the Chrna6 gene (encoding alpha6 nicotinic receptors) associate with drug use and increased striatum volume during human adolescence. In these studies, both alleles must be G to influence adolescent substance use and structural brain effects. If a C allele is inherited from one or both of the parents, adolescent substance use and brain structure are not altered.

Current Direction: To identify the mechanisms mediating the human results, our current studies have developed a 3’UTR humanized alpha6 nAChR mutant rat line. Using this line, we propose to assess the impact of this genetic polymorphism in substance use behavior.

Precision: The precision of the current studies is that alpha6 nAChR subunits are highly expressed in brain reward regions, including the ventral tegmental area dopaminergic neurons sending projections to dorsal and ventral striatum.

Innovation: Our studies are innovative as results would provide translational evidence for the relationships between brain, behavior and genetics influencing substance use. The research may discover novel mechanisms for distinct nicotinic receptors influencing substance use.

An infographic of the work can be viewed at: For more information about the Lotfipour lab, please visit: