Clinical studies suggest an association between maternal smoking and a number of persisting neurobehavioral deficits. Several of these deficits are at least partially mediated by dopamine (DA) systems and are evident during adolescence, which is a critical period of development for limbic brain regions, including DA systems. While several animal studies have shown that gestational nicotine (GN) treatment induces changes in DA during adolescence, few studies correlate these findings with behavior. To test the hypothesis that GN treatment changes DA-mediated behaviors in adolescent animals, timed pregnant dams were implanted with osmotic minipumps containing saline or nicotine (3 mg/kg/day). Offspring were tested behaviorally on postnatal day 32, which is defined as early adolescence. GN males showed an increase in the threshold dose needed for cocaine self-administration. However, at higher doses these animals showed significantly greater cocaine intake and cocaine-induced c-fos mRNA expression in reward related brain regions. GN males also demonstrated changes in DA-mediated operant responding for sucrose pellets. Complex changes were observed in DA-mediated locomotor function. GN animals of both sexes exhibited reduced cocaine-induced stereotypy, resulting from a functional loss of postsynaptic DA D2 receptors. Unlike stereotypy, cocaine-induced locomotion did show sex differences, with the injection stress of pretreatment influencing the cocaine response in females. Whereas GS females exhibited more cocaine-induced locomotion than GN females when no pre-injection was given, saline pretreatment reversed this effect. Antagonist experiments showed that D2 receptors played a significant role in mediating cocaine-induced locomotion in GN females, but no GS. The tobacco smoke constituents, nicotine and monoamine oxidase inhibitors (MAOI), were evaluated for interactions during gestation. MAOI treatment during gestation increased exploratory behavior of the offspring. GN treatment enhanced the expression of cocaine-induced behavioral sensitization, but not when animals were also treated with MAOIs (GMN). GMN animals developed tolerance to cocaine-induced vertical activity and demonstrated contextual conditioning to the cocaine-paired environment. The current study suggests that tobacco smoke constituents, such as nicotine and MAOIs, can induce changes in DA-mediated behaviors by affecting the development of adolescent DA systems.
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