Sex- and age-dependent differences in nicotine susceptibility evoked by developmental exposure to tobacco smoke and/or ethanol in mice.

Either tobacco smoking or alcohol consumption during pregnancy sex-selectively increases susceptibility to drugs of abuse later in life. Considering that pregnant smoking women are frequently intermittent consumers of alcoholic beverages, here, we investigated whether a short-term ethanol exposure restricted to the brain growth spurt period when combined with chronic developmental exposure to tobacco smoke aggravates susceptibility to nicotine in adolescent and adult mice. Swiss male and female mice were exposed to tobacco smoke (SMK; research cigarettes 3R4F, whole-body exposure, 8 h/daily) or ambient air during the gestational period and until the tenth postnatal day (PN). Ethanol (ETOH, 2 g/Kg, 25%, i.p.) or saline was injected in the pups every other day from PN2 to PN10. There were no significant differences in cotinine (nicotine metabolite) and ethanol serum levels among SMK, ETOH and SMK + ETOH groups. During adolescence (PN30) and adulthood (PN90), nicotine (NIC, 0.5 mg/Kg) susceptibility was evaluated in the conditioned place preference and open field tests. NIC impact was more evident in females: SMK, ETOH and SMK + ETOH adolescent females were equally more susceptible to nicotine-induced place preference than control animals. At adulthood, SMK and SMK + ETOH adult females exhibited a nicotine-evoked hyperlocomotor profile in the open field, with a stronger effect in the SMK + ETOH group. Our results indicate that ethanol exposure during the brain growth spurt, when combined to developmental exposure to tobacco smoke, increases nicotine susceptibility with stronger effects in adult females. This result represents a worsened outcome from the early developmental dual exposure and may predispose nicotine use/abuse later in life.

Lifelong exposure to caffeine increases anxiety-like behavior in adult mice exposed to tobacco smoke during adolescence.

Caffeine and tobacco smoke are among the most frequently self-administered licit psychoactive drugs in the world. Both drugs affect anxiety levels, however, little is known on the impact of the dual exposure in the adolescent brain, the period during which smoking begins. Considering that anxiety is a relevant factor for smoking maintenance and relapse, we investigated the effects of lifelong exposure to caffeine on anxiety levels of Swiss mice exposed to tobacco smoke during adolescence. Caffeine was administrated during all prenatal and postnatal life (CAF, 0.1 g/l to drink). From postnatal day 30-45, animals were exposed to tobacco smoke (SMK, whole body exposure, 8 h/day) generated from research cigarettes type 3R4F (nicotine = 0.73 mg/per cigarette). Four groups were analyzed: (1) CAF + SMK exposure; (2) SMK exposure; (3) CAF exposure; (4) Control. Anxiety levels were assessed in the elevated plus maze at the end of smoke exposure (PN45), at short- (PN55) and long-term (PN75) withdrawal. Caffeine exposure reduced decision making time (time in center of maze) during adolescence (PN45 and PN55). In addition, caffeine increased anxiety-like behavior during long-term tobacco smoke withdrawal. The present study provides experimental evidence that caffeine and tobacco smoke during adolescence interact resulting in emotional dysregulation during tobacco smoke withdrawal. Particularly, increased anxiety-like behavior during long-term withdrawal in CAF + SMK animals demonstrates late-emergent effects. In this sense, our data suggest that lifelong caffeine exposure may be an important factor in tobacco relapse.