Perinatal Caffeine, Acting on Maternal Adenosine A1 Receptors, Causes Long-Lasting Behavioral Changes in Mouse Offspring

Background: There are lingering concerns about caffeine consumption during pregnancy or the early postnatal period, partly because there may be long-lasting behavioral changes after caffeine exposure early in life. Methodology/Principal Findings: We show that pregnant wild type (WT) mice given modest doses of caffeine (0.3 g/l in drinking water) gave birth to offspring that as adults exhibited increased locomotor activity in an open field. The offspring also responded to cocaine challenge with greater locomotor activity than mice not perinatally exposed to caffeine. We performed the same behavioral experiments on mice heterozygous for adenosine A(1) receptor gene (A(1)RHz). In these mice signaling via adenosine A(1) receptors is reduced to about the same degree as after modest consumption of caffeine. A(1)RHz mice had a behavioral profile similar to WT mice perinatally exposed to caffeine. Furthermore, it appeared that the mother's genotype, not offspring's, was critical for behavioral changes in adult offspring. Thus, if the mother partially lacked A(1) receptors the offspring displayed more hyperactivity and responded more strongly to cocaine stimulation as adults than did mice of a WT mother, regardless of their genotype. This indicates that long-term behavioral alterations in the offspring result from the maternal effect of caffeine, and not a direct effect on fetus. WT offspring from WT mother but having a A(1)R Hz grandmother preserved higher locomotor response to cocaine. Conclusions/Significance: We suggest that perinatal caffeine, by acting on adenosine A(1) receptors in the mother, causes long-lasting behavioral changes in the offspring that even manifest themselves in the second generation.