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Dopamine and its receptor binding sites appear in the brain early in the embryonic period raising the possibility that dopamine may influence brain development. We show that one component of dopamine’s role in brain development is its ability to influence proliferation and differentiation of progenitor cells in the neostriatum and the dorsomedial prefrontal cortex on embryonic day 15 in mice. Dopamine and a D₁-like receptor agonist reduce the relative proportion of progenitor cells incorporating the S phase marker bromodeoxyuridine. A D₂-like agonist produces the opposite effect. Both the effects are evident in the lateral ganglionic eminence, neuroepithelial precursor of the neostriatum and in the neuroepithelium of the dorsomedial prefrontal cortex. Neostriatal progenitor cells are more responsive than cortical progenitor cells to the effects of dopamine receptor activation. Furthermore, progenitor cells in the ventricular zone are more responsive to D₁-like agonists and progenitors in the subventricular zone more so to D₂-like agonists. Thus, dopamine’s developmental effects show regional and progenitor cell type specificity, presumably due to heterogeneity in the distribution of its receptor binding sites.

Use of tobacco products is injurious to health in men and women. However, tobacco use by pregnant women receives greater scrutiny because it can also compromise the health of future generations. More men smoke cigarettes than women. Yet the impact of nicotine use by men upon their descendants has not been as widely scrutinized. We exposed male C57BL/6 mice to nicotine (200 μg/mL in drinking water) for 12 wk and bred the mice with drug-naïve females to produce the F1 generation. Male and female F1 mice were bred with drug-naïve partners to produce the F2 generation. We analyzed spontaneous locomotor activity, working memory, attention, and reversal learning in male and female F1 and F2 mice. Both male and female F1 mice derived from the nicotine-exposed males showed significant increases in spontaneous locomotor activity and significant deficits in reversal learning. The male F1 mice also showed significant deficits in attention, brain monoamine content, and dopamine receptor mRNA expression. Examination of the F2 generation showed that male F2 mice derived from paternally nicotine-exposed female F1 mice had significant deficits in reversal learning. Analysis of epigenetic changes in the spermatozoa of the nicotine-exposed male founders (F0) showed significant changes in global DNA methylation and DNA methylation at promoter regions of the dopamine D2 receptor gene. Our findings show that nicotine exposure of male mice produces behavioral changes in multiple generations of descendants. Nicotine-induced changes in spermatozoal DNA methylation are a plausible mechanism for the transgenerational transmission of the phenotypes. These findings underscore the need to enlarge the current focus of research and public policy targeting nicotine exposure of pregnant mothers by a more equitable focus on nicotine exposure of the mother and the father.