Sex differences in prenatal stress effects on cocaine pursuit in rats.

Disruption of early-life ontogeny has severe and persistent consequences for the health of the developing organism. Both clinical and preclinical findings indicate that such interference can be caused by maternal stress during the gestation period (prenatal stress [PS]). In rats, PS facilitates the rewarding and neurochemical-stimulating effects of drugs, suggesting that PS may represent a risk factor for drug abuse in humans. Very little, however, is known about its effects in females, even though sex differences in drug susceptibility have been well documented in no PS (NPS) controls. Thus, we tested for independent effects and interactions between maternal restraint stress during the last week of gestation and sex on drug use with an extended regimen of drug self-administration. Male and female rats were provided daily access to a large but controlled amount of cocaine for seven weeks. Drug pursuit during the final week was used to indicate susceptibility to developing an addiction-like phenotype, based on reports that drug use becomes increasingly compulsive-like after weeks of testing. Overall, females satisfied more addiction-like criteria than males, and the same was true for PS rats when compared to NPS controls. In addition, sex and PS interacted to disproportionately promote drug pursuit of females with a history of PS. These results indicate that sex differences in drug susceptibility persist with continued drug exposure, and that PS widens this difference by more severely affecting females. In all, PS may be a risk factor for drug addiction in humans, and to a greater extent in women vs. men.

Sex-specific susceptibility to cocaine in rats with a history of prenatal stress.

Across species, maternal stress during prenatal life (prenatal stress [PS]) increases the expression of health complications in the developing offspring. While numerous reports indicate that male rats with a history of PS are vulnerable to psychiatric disease-like symptoms and drugs of abuse, comparable studies with females have been more limited. Here, the effects of PS in male and female rats were compared with the use of two well-validated tests of drug abuse susceptibility--the acquisition of cocaine self-administration and the expression of sensitization to the drug's psychomotor-activating properties. When a low dose (0.2 mg/kg/infusion) was available for self-administration across 15 1-hour test sessions, drug-taking behaviors were unaffected by an individual's early-life stress history. On an escalating-doses regimen (0.3-0.5 mg/kg/infusion) of self-administration, however, exposure to PS selectively facilitated the rate of acquisition and overall drug intake of males. Conversely, cocaine-induced psychomotor sensitization was augmented by PS in females, but not males. We conclude that exposure to PS enhances the reinforcing and psychomotor-sensitizing properties of cocaine male and female rats, respectively, later in life. Thus, these results suggest that gestational stress is a sex-specific risk factor for different aspects of substance abuse.