Threshold of adulthood for the onset of nicotine self-administration in male and female rats

Abstract

The great majority of tobacco addiction begins during adolescence. More heavily addicted smokers begin smoking earlier, but differentiating the neurobehavioral impact of nicotine self-administration during adolescence from self-selection bias (whereby people more prone to heavy addiction also begin earlier) cannot be ethically unconfounded in humans. The goals of this research were to determine the age threshold for the adult-like nicotine self-administration and determine sex differences. Male and female Sprague-Dawley rats were tested for nicotine self-administration starting at 4, 5, 6, 7, and 8 weeks of age in an operant FR1 schedule for IV nicotine (0.03 mg/kg/infusion) in 45-min sessions for 2 weeks, with 1 week of enforced abstinence and 1 week of resumed access. This study replicated our earlier work that nicotine self-administration was increased in adolescent vs. adult rats and that the effect was more pronounced in adolescent males, but the increased nicotine self-administration was more persistent in adolescent-onset females. The age threshold for adult-like behavior was 6-7 weeks of age. Adolescent-onset nicotine self-administration had persisting effects of eggaurated increases of nicotine self-administration when fixed-ratio requirements for self-administration were lowered. Female rats that had begun nicotine self-administration during adolescence showed exaggerated increases in nicotine self-administration after a switch back to FR1 from FR8, indicating a lessened control over their self-administration. Adolescent-onset nicotine self-administration was not found to potentiate cocaine self-administration. Adolescent-onset nicotine self-administration causes persistent increases in nicotine self-administration in female rats even after they reach adulthood and disrupts control over self-administration behavior.

Figure 1

The age-effect function of age of onset and nicotine self-administration averaged across sex, infusions (mean±sem) per 45-min. session for each of the four consecutive weeks of nicotine access as well as the week of nicotine access after one week of enforced abstinence. There was a significant Age-of-onset × Week-of-access interaction (p<0.05). Analysis of the simple main effects of age-of-onset during each week showed that during the first week of access the rats beginning access at four and five weeks of age self-administered significantly more nicotine than those beginning at seven or eight weeks of age (p<0.05-p<0.01). During the second week of access the rats beginning access at five weeks of age self-administered significantly more nicotine (p<0.05) than the rats that began access at eight weeks of age.

Figure 2

Sex differences in the age-effect function of age of onset and nicotine self-administration, infusions (mean±sem) per 45-min. session for each of the four consecutive weeks of nicotine access as well as the week of nicotine access after one week of enforced abstinence.

Figure 3

The age-effect function of age of the resumption of nicotine self-administration after a one-week period of enforced abstinence, infusions (mean±sem) per 45-min. session. The female rats that had begun nicotine access at 4 weeks of age self-administered significantly (p<0.05) more nicotine than the female rats that had begun nicotine access at eight weeks of age.

Figure 4

Individual animal data for the age-effect function of age of the resumption of nicotine self-administration after a one-week period of enforced abstinence, infusions per 45-min. session. X-axis: Weeks 1, 2, 3, 4 of nicotine access, resumption (R) of nicotine access after 1 week of enforced abstinence.

Figure 5

Six vs. eight-week old age of onset of nicotine self-administration initial training for nicotine self-administration fixed-ratio-1 (FR1), infusions (mean±sem) per 45-min. session in female rats. There was a significant (p<0.01) main effect of age of onset with the rats that had begun access at six weeks of age self-administering more nicotine than the rats that had begun access at eight weeks of age.

Figure 6

Six vs. eight-week old age of onset of nicotine self-administration fixed-ratio (FR) progression and reversal, infusions (mean±sem) per 45-min. session in female rats. There were significant main effects of age of onset (p<0.05) and FR (p<0.0001) with younger rats and lower FR resulting in higher levels of nicotine self-administration. There was also a significant age-of-onset × FR interaction (p<0.05) and analysis of the simple main effects at each FR condition showed that the rats that had onset of nicotine access at six weeks of age self-administered significantly more nicotine at FR4 (p<0.025) and the FR1-post conditions (p<0.001).

Figure 7

Six vs. eight-week old age of onset of nicotine self-administration effect on later cocaine self-administration to estrus phase, infusions (mean±sem) per 45-min. session in female rats. The rats that had begun nicotine access at six weeks self-administered significantly (p<0.05) more nicotine during the second week of access compared with rats that began nicotine access at eight weeks of age. No significant differences were seen with the subsequent switch to cocaine self-administration.

Figure 8

Six vs. eight-week old age of onset of nicotine self-administration effect on the relationship of later cocaine self-administration to estrus phase, infusions (mean±sem) per 45-min. session in female rats. The rats that had begun nicotine access at six weeks did not show any effect of estrus phase on subsequent cocaine self-administration. In contrast rats that had begun nicotine access at eight weeks of age did show a significantly (p<0.05-0.005) higher cocaine self-administration during the estrus phase than during the other phases of the cycle.