Testing environment shape differentially modulates baseline and nicotine-induced changes in behavior: Sex differences, hypoactivity, and behavioral sensitization

Abstract

In those who use nicotine, the likelihood of dependence, negative health consequences, and failed treatment outcomes differ as a function of gender. Women may be more sensitive to learning processes driven by repeated nicotine exposure that influence conditioned approach and craving. Sex differences in nicotine's influence over overt behaviors (i.e. hypoactivity or behavioral sensitization) can be examined using passive drug administration models in male and female rats. Following repeated intravenous (IV) nicotine injections, behavioral sensitization is enhanced in female rats compared to males. Nonetheless, characteristics of the testing environment also mediate rodent behavior following drug administration. The current experiment used a within-subjects design to determine if nicotine-induced changes in horizontal activity, center entries, and rearing displayed by male and female rats is detected when behavior was recorded in round vs. square chambers. Behaviors were recorded from each group (males-round: n=19; males-square: n=18; females-square: n=19; and females-round: n=19) immediately following IV injection of saline, acute nicotine, and repeated nicotine (0.05mg/kg/injection). Prior to nicotine treatment, sex differences were apparent only in round chambers. Following nicotine administration, the order of magnitude for the chamber that provided enhanced detection of hypoactivity or sensitization was contingent upon both the dependent measure under examination and the animal's biological sex. As such, round and square testing chambers provide different, and sometimes contradictory, accounts of how male and female rats respond to nicotine treatment. It is possible that a central mechanism such as stress or cue sensitivity is impacted by both drug exposure and environment to drive the sex differences observed in the current experiment. Until these complex relations are better understood, experiments considering sex differences in drug responses should balance characteristics of the testing environment to provide a complete interpretation of drug-induced changes to behavior.

Sex-specific nicotine sensitization and imprinting of self-administration in rats inform GWAS findings on human addiction phenotypes

“…1D, E ) as levels of locomotion were far from maximal throughout the test. While levels of gonadal hormones during the estrous cycle have been suggested to contribute to stimulant SST in outbred females [ 40 , 41 ], it is unlikely that estrous phase contributed in the F1 females in the present experiments as they did not show SST and did not show more variability than males in locomotor activity [ 42 ]. Thus, F344/BN F1 rats are responsive to NIC exposure, which has a long-lasting effect that leads to male-specific NIC SST.…”

“…First and foremost, the greater acute responding to NIC, but the lack of SST to NIC, in the F1 females in the present experiments may be a specific attribute of these rat strains. This is because gonadal hormones during the estrous cycle have been suggested to contribute to greater stimulant [ 41 ] and NIC [ 40 ] induced locomotion and locomotor SST in outbred females relative to males. We have initially chosen to study F344/BN F1 rats, because we aimed to explore the molecular mechanism of any observed imprinting effect on animal behaviors by examining AIE, in which the allelic imbalance analysis would benefit from phenotypic differences between two parental lines and in this case F344 is known to have the lowest sensitivity to NIC among six tested strains including BN [ 67 ].…”