Effects of Sex and Prenatal Stress on Vulnerability to Drugs.

Abstract

The importance of neurodevelopmental events in utero is well established. When these processes are disrupted, the consequences are severe and long-lasting. Such is the case when prenatal growth overlaps with maternal stress (prenatal stress [PS]). Preclinical studies suggest that links between PS and emotional irregularities are a consequence of altered development of the limbic system. Because limbic circuitry also mediates reward processes, it is no surprise that PS facilitates rats’ susceptibility to drugs. Nevertheless, most of these studies have been performed with males. How PS affects the drug response of females, which is already greater than that of males, is largely unknown. Here we used cocaine to test both sexes, with the hope of better understanding whether PS alters the sexually-dimorphic risk of drug use escalating to problematic proportions. In our first study, we used in vivo microdialysis to determine if PS alters a sex difference in striatal functioning of rats that are drug naïve. In concordance with previous work, males without a history of PS expressed higher steady-state concentrations of dopamine than their female littermates. No sex difference was evident, however, in rats that did have a history of PS. PS lowered extracellular concentrations in males, but had no effect in females. Next we tested whether PS has sex-dependent effects on the response to cocaine, as predicted by results with microdialysis. Interestingly, PS facilitated the acquisition of drug taking exclusively in males, but augmented psychomotor sensitization selectively in females. Because self-administration and sensitization are both considered reliable indicators of drug susceptibility, it was unclear (in the context of addiction) whether PS was a greater risk factor for males or females. To resolve this uncertainty, we utilized a longer self-administration test regimen to more accurately model the extent of drug use observed in human addicts. After weeks of testing, we found that PS sex-dependently increased the number of addiction-like traits expressed by females. Although work at the clinical level is still needed for support, this suggests that PS places female drug users at increased risk of becoming addicted, perhaps by augmenting drug-associated neuroplasticity.