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-minute sessions for two weeks, with one week of enforced abstinence and one 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.

Adolescent alcohol exposure: Are there separable vulnerable periods within adolescence?

“…Rats exposed to experimenter-administered nicotine during early adolescence (P28-31) were found to subsequently exhibit increased cocaine self-administration, an effect not evident with exposure later in adolescence (P38-41) or in adulthood (P86-89)(Dao et al, 2011). In contrast, adolescent-onset nicotine self-administration was not observed to alter later cocaine self-administration, although females allowed to self-administer nicotine from 4-8 weeks of age self-administered more nicotine after a week of abstinence than females given the opportunity to self-administer nicotine from 8-12 weeks of age; this effect was not evident in males (Levin et al, 2011). In mice, nicotine exposure during early adolescence (P24-35) was reported to increase later oral self-administration and stimulant effects of nicotine relative to control animals, whereas mid- and late-adolescent exposures (P37-48; P50-61) did not (Adriani et al, 2002).…”

Emergence of sex differences in the development of substance use and abuse during adolescence

“…Studies of sex differences in drug-self administration in rodents are more abundant and consistent in the finding that females acquire self-administration faster, escalate use more during extended access and will work harder under a progressive ratio to obtain psychostimulants, nicotine, opioids and tetrahydrocannabinol (Anker & Carroll, 2011; Becker & Hu, 2008; Carroll & Anker, 2010; Carroll et al, 2004; Fattore et al, 2008; Fattore et al, 2009; Feltenstein, Ghee, & See, 2012; Levin et al, 2011; Lynch, 2006; Lynch et al, 2002). Most rodent studies have detected robust sex differences in alcohol consumption (females consume more, especially in mice) although the greater fluid consumption by females must be considered in evaluating reported results.…”

Impact of Tobacco Regulation on Animal Research: New Perspectives and Opportunities

“…Research on the differential effects of nicotine in adolescents compared with adults is mixed. Several studies suggest that adolescent rats self-administer more nicotine (30 µg/kg) and acquire stable behavior faster than adults Levin, Rezvani, Montoya, Rose, & Swartzwelder, 2003;Levin et al, 2011). However, relatively little attention has been given to acquisition of self-administration at low doses.…”

“…These data are limited, however, both in terms of the age of initiation and the exclusive focus on males. Several studies have reported sex differences in the acquisition of nicotine self-administration during adolescence Levin et al, 2011), including a greater likelihood of females acquiring at a low dose (5 µg/kg; Lynch, 2009). Likewise, other work has suggested that adolescents may be more sensitive to the potentiating effects of acetaldehyde (a tobacco constituent discussed in the Could Other Constituents of Tobacco Impact the Threshold for Self-administration?…”