Consequences of paternal cocaine exposure in mice.

The present study examined the potential neuroteratological effects of paternal cocaine (COC) exposure using the novel mouse model of inhalational drug administration. In this model, mice were trained to self-administer COC in multi-hour daily inhalation sessions reminiscent of crack binges. The controls included males pair-fed with COC-inhaling animals as well as ad-lib-fed males. All males were bred with drug-naive females. The newborn pups sired by COC-inhaling males had a reduced biparietal head diameter, suggesting a decreased cerebral volume. When the pups reached adulthood, their sustained visuo-spatial attention and spatial working memory were tested using a 5-arm maze paradigm. During the attention tests, the percentage of correct trials at the shortest stimulus duration employed in the study (0.5 s) was significantly lower for the male offspring of COC-inhaling fathers as compared to the offspring of both pair-fed and ad-lib-fed controls. For the females sired by COC-inhaling fathers, the deficit was observed at light stimulus durations of 0.5 and 0.75 s. Also, during the working memory tests, the male offspring of COC-inhaling fathers required more sessions than the offspring of either pair-fed or ad-lib-fed fathers to reach the selected criterion at retention intervals of 16 min and longer. The impairment of working memory in female offspring of COC-inhaling fathers was even stronger, as the offspring needed more sessions to reach the criterion as compared to their control counterparts, even at retention intervals as short as 4 min. These findings suggest that paternal COC abuse prior to coitus may impact the development of the offspring, particularly if they are females. We further showed that chronic COC exposure in male mice does not result in substantial breakage of spermatozoal DNA, but significantly alters expression of DNA methyltransferases 1 and 3a in the germ cell-rich seminiferous tubules of the testis. Since these enzymes are essential for generating and maintaining parental gene imprinting in germ cells, our observations point to an intriguing possibility that COC may cause paternally induced neuroteratological effects by interfering with gene-imprinting patterns in male gametes.