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

FIGURE 1. Experimental paradigm. Male and female CHRNA6 3′-UTR SNP knock-in rats underwent food self-administration, catheter implantation, nicotine self-administration, progressive ratio, extinction, and cue-, nicotine-, and nicotine + cue-induced reinstatement.

FIGURE 2. The human CHRNA6 3′-UTR SNP knock-in does not impact food self-administration. Female (A) and male (B), α6CC and α6GG, mean daily 30 min responses ± SEM for food self-administration at Fixed Ratio (FR)1 Time out (TO)1, FR2TO10, FR2TO20, FR5TO20 schedules of reinforcement. ***p = 0.0001 Reinforced (Rein) vs. Non-Reinforced (Non-reinf) responses. N = 8–14/group. Circles represent females and squares represents males.

FIGURE 3. The human CHRNA6 3′-UTR SNP knock-in does not impact nicotine self-administration, progressive ratio, and nicotine intake. Female (A) and male (B), α6CC and α6GG, mean daily 1-h responses ± SEM for nicotine self-administration at FR5TO20 schedule of reinforcement. No genotype or sex differences were observed for nicotine intake (C) or breakpoint values (D). ***p < 0.001. N = 8–14/group. Circles represent females and squares represent males.

FIGURE 4. The human CHRNA6 3′-UTR SNP does not influence extinction. After completion of nicotine self-administration, female (A) and male (B), α6CC and α6GG, were allowed to respond on the reinforced and non-reinforced lever without schedule consequence (e.g., infusion of nicotine, cue light and tone). Data are presented as a mean ± SEM percent of the last day of nicotine self-administration responding. No genotype or sex differences were observed for days to meet extinction criteria (C). ***p < 0.001 vs. Last FR5. N = 8–14/group. Circles represent females and squares represent males.

FIGURE 5. Sex and genotype dependent effects of reinstatement of nicotine in humanized CHRNA6 3′-UTR SNP rats. α6 3′ UTR SNP genotype- and sex-dependently influences nicotine + cue primed reinstatement, with males more impacted than females based on genotype (A,B). ***p < 0.001, **p < 0.01, *p < 0.05 vs. Extinction; #p < 0.05, ##p < 0.01, ###p < 0.001 vs. Nicotine + Cue; + +p = 0.01 Male α6GG compared with α6CC. N = 8–14/group. Circles represent females and squares represent males.