Prenatal cocaine exposure increases anxiety, impairs cognitive function and increases dendritic spine density in adult rats: influence of sex

Abstract

Cocaine exposure during pregnancy can impact brain development and have long-term behavioral consequences. The present study examined the lasting consequences of prenatal cocaine (PN-COC) exposure on the performance of cognitive tasks and dendritic spine density in adult male and female rats. From gestational day 8 to 20, dams were treated daily with 30 mg/kg (ip) of cocaine HCl or saline. At 62 days of age, offspring were tested consecutively for anxiety, locomotion, visual memory and spatial memory. PN-COC exposure significantly increased anxiety in both sexes. Object recognition (OR) and placement (OP) tasks were used to assess cognitive function. Behavioral tests consisted of an exploration trial (T1) and a recognition trial (T2) that were separated by an inter-trial delay of varying lengths. Male PN-COC subjects displayed significantly less time investigating new objects or object locations during T2 in both OR and OP tasks. By contrast, female PN-COC subjects exhibited impairments only in OR and only at the longest inter-trial delay interval. In addition, gestational cocaine increased dendritic spine density in the prefrontal cortex and nucleus accumbens in both genders, but only females had increased spine density in the CA1 region of the hippocampus. These data reveal that in-utero exposure to cocaine results in enduring alterations in anxiety, cognitive function and spine density in adulthood. Moreover, cognitive deficits were more profound in males than in females.

Figure 1. Prenatal cocaine increased anxiety-related behaviors in an elevated plus maze and open field task

(A) Female rats were significantly less anxious than males as determined in the ratio of time spent in the open arms (open/closed + open time) and PN-COC subjects were significantly more anxious than controls. (B) In an open field, females were less anxious than males and PN-COC animals also showed increased anxiety by visiting the inner sectors of the field significantly less often than control subjects. Asterisks denote a significant difference (p < 0.05) between cocaine exposed subjects and control subjects or between male and female subjects.

Figure 2. Prenatal cocaine significantly increased the mean exploration time during the exploratory phase of both memory tasks

On average, PN-COC subjects spent more time exploring the objects in both the (A) object recognition and (B) placement tasks. In addition, females explored the objects significantly more than male subjects in both the (A) object recognition and (B) placement tasks. Asterisks denote a significant difference (p < 0.05) between cocaine exposed subjects and control subjects or between male and female subjects.

Figure 3. Prenatal cocaine exposure results in sex-specific memory deficits

(A) In the object recognition task, three-way repeated measures ANOVA revealed a significant three way interaction. M PN-COC display visual memory deficits at two- and four- hr intertrial delay times while F PN-COC only displayed memory deficits at a 4-hr intertrial delay. (B) In the object placement task, three-way repeated measures ANOVA revealed a significant interaction between sex and treatment. PN-COC exposure impairs spatial memory only in males at both two- and four-hour intertrial delay times, while females remain unaffected. Asterisks highlight male and female subjects, independent of treatment, which performed well on both visual and spatial memory tasks (p< 0.05).

Figure 4. Prenatal cocaine exposure increased the spine density in CA1, PFC and NAC of adult subjects

ANOVAs for CA1 region of the dorsal hippocampus revealed a significant sex by treatment interaction on spine density in both apical and basal dendrites of the CA1 region in the hippocampus. PN-COC females had significantly higher spine density in both apical and basal dendrites of the CA1 region of the hippocampus. PN-COC significantly increased spine density on basal dendrites in the PFC and in the dendrites of the NAC. Asterisks highlight treatment groups that showed a significant increase in spine density (p < 0.05).

Figure 5. Golgi impregnated neurons in the PFC

Photomicrograph illustrating the cocaine-induced increase in dendritic spines on layer III pyramidal cells. The dendrites of (B) PN-COC subjects have greater spine density than (A) control subject. Scale bar = 10μm.