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

Abstract

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.

Introduction

Environmental disturbances in perinatal life can produce long-lasting physiological changes that compromise the vitality of the developing organism. In humans, maternal stress during the second trimester of pregnancy places the unborn child at greater risk for mental and physical distress [1], [2]. Its most direct objective marker, low birth weight, has been linked with persistent irregularities in emotionality, sleep, cognition, and neuroendocrine functioning [1], [2]. Similar maladaptations are observed in rats born to mothers that were exposed to repeated episodes of stress across the comparable stage of offspring neural development (prenatal stress [PS]; [1], [2], [3], [4]). Thus, PS in rats may model an early-life factor that contributes to the onset of some diseases in humans.

In male rats, exposure to PS enhances the reinforcing and locomotor-sensitizing properties of amphetamine [5], [6] as well as the reinstatement of cocaine-seeking after extinction training [7]. PS also augments the rewarding properties of morphine [8] and ethanol [9], suggesting that early-life stress increases the abuse potential for a range of addictive drugs. Despite a well-established cross-species sex difference in sensitivity to drugs of abuse, addiction-relevant behaviors in PS models have been investigated almost exclusively with male rats (see [9] for an exception). As a result, it is unknown whether PS females are more vulnerable to psychostimulants than males, as is the case for rodents and humans without a history of early-life stress (see [10] for review).

One sex difference that has been identified in PS rats is in the ability to cope with later-life stress. Though PS males and females both exhibit a prolonged release of corticosterone (the primary glucocorticoid stress hormone) following the cessation of stress in adulthood [11], sex-specific features of corticosterone secretion have been identified both before (e.g., under basal conditions) and after acute and repeated stress regimens [12]. Because glucocorticoids modulate the behavioral and neurochemical-signaling effects of drugs (see [13] for review), and drugs are themselves stressors [14], [15], the sex-specific effects of PS were hypothesized to have important consequences for subsequent vulnerability to drugs of abuse.

Thus, the current report offers the first between-sex comparison of gestational stress effects on drug abuse liability. PS and control male and female rats were tested for the acquisition of cocaine self-administration or the development of psychomotor sensitization to repeated cocaine injections. Based on previous reports, we hypothesized that PS would enhance sensitivity to cocaine in both paradigms, and that the magnitude of PS effects would be sex-dependent.