AUTHOR=Carreño Diana , Lotfipour Shahrdad 

TITLE=Sex- and genotype-dependent nicotine plus cue-primed reinstatement is enhanced in adolescent Sprague Dawley rats containing the human CHRNA6 3′-UTR polymorphism (rs2304297)

JOURNAL=Frontiers in Psychiatry

VOLUME=13

YEAR=2023

URL=https://www.frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2022.1064211

DOI=10.3389/fpsyt.2022.1064211

ISSN=1664-0640

ABSTRACT=<sec><title>Rationale</title><p>Large-scale human candidate gene studies have indicated that a genetic variant (rs2304297) in the alpha(α)6 nicotinic acetylcholine receptor (nAChR) subunit, encoded by the <italic>CHRNA</italic>6 gene, may play a key role in adolescent nicotine addictive behavior. We hypothesized that the polymorphism selectively enhances nicotine + cue-primed reinstatement, but not nicotine- or cue-reinstatement in α6<italic><sup>GG</sup></italic> (risk) vs. α6<italic><sup>CC</sup></italic> (non-risk) allele carriers, without having baseline effects on natural rewards.</p></sec><sec><title>Methods</title><p>Using CRISPR-Cas9 genomic engineering, we developed a humanized rat line with the human gene variant of the <italic>CHRNA</italic>6 3′-UTR<italic><sup>C</sup></italic><sup>123</sup><italic><sup>G</sup></italic> polymorphism in Sprague-Dawley rats. Genetically modified adolescent male and female rats were food trained under a fixed-ratio (FR)1 schedule of reinforcement and progressively increased to FR5. Animals were implanted with catheters and began nicotine self-administration (15 μg/kg/infusion) at FR5. Upon reaching stable responding, reinforced behavior was extinguished by removal of drug and cues. Reinstatement testing began for cue only, nicotine only, and nicotine + cue in a Latin Square Design. Animals were returned to extinction conditions for 2 days minimum between testing.</p></sec><sec><title>Results</title><p>For natural food rewards, nicotine self-administration, progressive ratio, and extinction, adolescent male and female (α6<italic><sup>GG</sup></italic> and α6<italic><sup>CC</sup></italic>) rats exhibited equivalent behaviors. Male α6<italic><sup>GG</sup></italic> rats show enhanced nicotine + cue-primed reinstatement when compared with male α6<italic><sup>CC</sup></italic> rats. This genotype effect on reinstatement was not seen in female rats.</p></sec><sec><title>Conclusion</title><p>Our findings support the <italic>in vivo</italic> functional role of the human <italic>CHRNA</italic>6 3′-UTR SNP genetic variant in sex-dependently enhancing nicotine seeking behavior in adolescent rats. Overall, the findings support clinical and preclinical data highlighting a role of α6 nAChRs mediating sex heterogeneity in substance use and related phenotypes.</p></sec>