Prenatal morphine exposure differentially alters learning and memory in male and female rats

Abstract

The present study tested the hypothesis that exposure to morphine on prenatal days 11–18 impairs performance on tasks requiring learning and memory in adult male and female rats. In Experiment 1, a symmetrical maze was used to measure learning. In Experiment 2, an eight-arm radial maze was used to assess working spatial memory. The results of Experiment 1 demonstrated that prenatal morphine exposure reduces the time needed to complete the trials, but does not affect the accuracy of performance in male rats. In contrast, prenatal drug treatment had no effects on either the time or the accuracy of performance in female rats. In Experiment 2, both male and female morphine-exposed rats needed more time to complete regular trials (no delay) than controls; however, morphine exposure in male rats did not affect performance on tasks requiring memory, measured with delay trials, but hindered it in ovariohysterectomized (OVX) female rats. In OVX females, replacement injections of both estrogen and progesterone restored the impairment of performance on delay trials produced by prenatal morphine exposure. Thus, the present study demonstrates that prenatal morphine exposure differentially alters performance of adult male and female rats on tasks requiring learning and spatial memory.

Introduction

Some human studies describe adverse effects of prenatal drug exposure on cognitive and neurobehavioral development [8], [15]. For example, studies show hyperactive behavior during the neonatal period; high activity, impulsivity, poor self-control, and poor performance on cognitive tests during childhood; and school adjustment and delinquency behavioral problems during adolescence [8], [15]. However, there are no studies available on how prenatal morphine exposure alters human behaviors and cognitive function in adulthood.

Animal studies show that opiates modify learning and memory [3], [4], [13], [29]. Learning and memory can be impaired by acute administration of opiates, such as morphine [3], [29]. The opiate antagonist, naloxone, enhances working memory-based performance in the radial-arm maze [4]. Pretreatment with naloxone antagonizes the disruptive effect of opiates on working memory [3], and opiate antagonists improve spatial memory in both young and adult rats [13]. We and others [11], [24], [25], [33], [37], [42] have shown that prenatal morphine exposure alters the opiate system in adult offspring, which may result in an altered capacity for learning and memory in prenatally morphine-exposed rats.

In addition, there is evidence demonstrating that learning and memory in animals differ between the sexes and are affected by gonadal hormones [10], [14], [17], [31], [39], [41]. In maze tasks, male rats perform better than female rats [1], [6]. Doses of estrogen in diestrus levels enhance spatial memory in the radial-arm maze [5], [18] and in the water maze [22], while high levels of estrogen impede performance on maze tasks [12], [40]. Although many studies have examined the effects of estrogen [5], [18], [22] on spatial cognition, little is known regarding the effects of progesterone. Our previous work demonstrates that both estrogen and progesterone, but not either alone, are necessary to elicit the receptive and proceptive components of sexual behavior [32]. Further, the replacement of both female gonadal hormones is necessary to demonstrate differences in the density of δ-opioid receptors [37] and in seizure susceptibilities [38] between prenatally saline- and morphine-exposed, adult females. Therefore, we hypothesized that there would be differences in spatial working memory between estrogen and estrogen plus progesterone replacement of adult, ovariohysterectomized (OVX) females exposed prenatally to morphine.

Based on the above, it seems that both opiates and gonadal hormones can affect learning and memory. Additionally, prenatal morphine exposure has long-lasting effects on the opiate system and on gonadal hormone-regulated behaviors. However, it is unknown whether prenatal morphine exposure affects learning and memory in adulthood. Therefore, the present study tested the hypothesis that exposure to morphine on prenatal days 11–18 differentially alters learning and memory in adult male and female rats.

Two types of maze were utilized to assess hippocampal-dependent tasks [2], [9], [19], [20]. Experiment 1 tested learning behavior using visual and nonvisual cues in a modified symmetrical maze of Davenport et al. [6]. This type of maze had been used successfully to assess differences in models of developmental drug exposure [6], [7], [23], [27]. Experiment 2 tested working spatial memory using two types of testing trials in the eight-arm radial maze: (a) regular trials (without a delay period), and (b) delay trials (with a 1- or 3-h delay period). Because Luine et al. [18] demonstrated that estrogen replacement alters working spatial memory tested in delay trials, but does not affect performance of adult females in regular trials, the present study examined the effects of female gonadal hormones on delay trials in an eight-arm radial maze. To avoid the possible confound of long-term hormone removal, females were gonadally intact during the acquisition phase of learning.