INTRODUCTION: The World Health Organization (WHO) reported that smoking cessation rates among women have stagnated in the past decade, and estimates that hundreds of millions of women will be smokers in the next decade. Social, environmental, and biological conditions render women more susceptible to nicotine addiction, imposing additional challenges to quit smoking during gestation, which is likely why over 8% of pregnancies in Europe are associated with smoking. In epidemiological investigations, individuals born from gestational exposure to smoking exhibit a higher risk of development of attention-deficit/hyperactive disorder (ADHD) and liability to drug dependence. Among other teratogenic compounds present in tobacco smoke, nicotine actions during neuronal development could contribute to the observed outcomes, as nicotine misleads signaling among progenitor cells during brain development. Several experimental approaches have been developed to address the consequences of prenatal nicotine exposure (PNE) to the brain and behavior, but after four decades of studies, inconsistent data have been reported, and the lack of consensus in the field has compromised the hypothesis that gestational nicotine exposure participates in cognitive and emotional behavioral deficits.

AIMS: In this review, we discuss the most commonly used PNE models with focus on their advantages and disadvantages, their relative validity, and how the different technical approaches could play a role in the disparate outcomes.

RESULTS: We propose methodological considerations, which could improve the translational significance of the models.

CONCLUSIONS: Such alterations might be helpful in reconciling experimental findings, as well as leading to development of treatment targets for maladaptive behaviors in those prenatally exposed.

IMPLICATIONS: In this article, we have reviewed the advantages and disadvantages of different variables of the commonly-used experimental models of prenatal nicotine exposure (PNE). We discuss how variations in the nicotine administration methods, timing of nicotine exposure, and species employed could contribute to the disparate findings in outcomes for PNE offspring, both in behavior and neuronal changes. In addition, recent findings suggest consideration of epigenetic effects extending across generations. Finally, we have suggested improvements in the available PNE models that could contribute to enhancement of their validity, which could assist in reconciliation of experimental findings.