Altered cocaine-induced behavioral sensitization in adult mice exposed to cocaine in utero

Abstract

Behavioral sensitization induced by psychostimulants is characterized by increased locomotion and stereotypy and may reflect aspects of neuronal adaptations underlying drug addiction in humans. To study the developmental contributions to addictive behaviors, we measured behavioral responses in adult offspring to a cocaine sensitization paradigm following prenatal cocaine exposure. Pregnant Swiss-Webster (SW) mice were injected twice daily from embryonic days 8 to 17 (E8-E17, inclusive) with cocaine (20 or 40 mg/kg/day; COC20 and COC40, respectively), or saline vehicle (SAL and SPF40) subcutaneously (s.c.). A nutritional control group of dams were ‘pair-fed’ with COC40 dams (SPF40). P120 male offspring from each prenatal treatment group were assigned to a behavioral sensitization group and injected with cocaine (15 mg/kg) or saline intraperitoneally (i.p.) every other day for seven doses. Locomotor activity and stereotypy were measured during habituation, cocaine initiation, and following a cocaine challenge 21 days after the last initiation injection. As expected, animals demonstrated significantly more locomotion and stereotypic behavior following acute and recurrent injection of cocaine compared to saline-injected animals. However, for each prenatal treatment group, cocaine-sensitized animals showed unique temporal profiles for the increase in locomotor sensitization and stereotypy over the course of the sensitization protocol. Two features that distinguished the altered behavioral progression of prenatally cocaine-exposed animals (COC40) from control (SAL) animals included blunted augmentation of locomotion and enhanced patterns of stereotypic behavior. These findings provide evidence that the behavioral activating effects of cocaine in adult animals are altered following exposure to cocaine in utero.

Introduction

Gestational exposure to cocaine and other drugs of abuse is the single largest preventable prenatal cause of developmental compromise in America today. The past two decades have seen a significant increase in cocaine use [48], at a time when fewer resources for detoxification of pregnant drug addicts are available [49]. According to the 1996 National Pregnancy and Health Survey, more than 40,000 infants born each year are exposed to cocaine prenatally [34]. Currently, 3.7% of pregnant women between 15 and 44 years of age report illicit drug use including 1% reporting crack cocaine use [33]; estimates suggest that the rate of licit drug use during pregnancy, such as tobacco and alcohol, may approach three to four times that rate.

Clinical studies have reported that exposure to cocaine in the womb may impair prenatal and postnatal brain growth, and adversely affect motor function, reactivity, language development, and attentional mechanisms [1], [8], [12], [31], [35]. Despite the complexity of confounding maternal factors, such as use of more than one drug during pregnancy, poor prenatal medical care, exposure to infectious diseases, and maternal malnutrition, further clinical studies have confirmed the independent role of cocaine in contributing to alterations in neurodevelopmental outcomes in some exposed offspring during infancy and childhood. These alterations may impact behaviors including the four “A's”: affect, attention, arousal, and action (see articles in Ref. [17]). The potential influence of gestational cocaine exposure in altering the rewarding properties of psychostimulants in these children, born in the early 1990's and now entering adolescence, has not been fully addressed. Presently, data suggests that following intrauterine exposure to tobacco [21] or alcohol [2], there is an increased liability for addiction to those same drugs that may be a direct consequence of prenatal exposure. As more infants born during the crack epidemic of the mid-1980's reach adolescence and young adulthood, immediate concerns abound regarding their vulnerability for a fifth “A”: addiction.

In the clinical setting identifying the specific role that prenatal drug exposure plays in contributing to adverse outcomes is confounded by genetic factors and environmental influences. Thus, utilizing animal models, in which the genetic background of each strain is uniform and control over environmental factors, can be achieved; the independent effect of prenatal exposure to cocaine in contributing to an increased liability for addiction can be isolated. A number of investigators [18], [23], [44] utilizing cocaine self-administration paradigms in adult rodents have identified that prenatal cocaine exposure enhances aspects of the reinforcing properties of psychostimulants. Such work is a developmental extension of studies investigating the consequences of recurrent amphetamine or cocaine administration in normal rodents.

It is well established that chronic psychostimulant administration results in long-term neuroadaptations, including increasing synaptic levels of dopamine (DA) in the brain which mediates aspects of their reinforcing effects [4], [32], [37]. Acute psychostimulant administration, characterized by augmented locomotor activity, is known to result in the activation of dopaminergic neurotransmission in the mesolimbic dopamine (DA) pathway projecting from the ventral tegmental area (VTA) of the midbrain to the nucleus accumbens (NAc), the major limbic component of the ventral striatum [4], [5], [13], [32], [36]. Psychostimulants also increase levels of dopamine in the mesostriatal DA pathway, which projects from the substantia nigra to the dorsolateral striatum, resulting in stereotypies characterized by compulsive, repetitive movements that are exaggerations of normal patterns of motor behavior [7], [10], [46]. Repeated drug exposure produces a sensitized behavioral response with progressively increasing locomotor activity paralleled by enhanced amphetamine and cocaine-induced increases in synaptic dopamine in the NAc [7], [10], [20], [40], [41], [42], [46], [50]. This behavioral sensitization in rodents is considered a useful model for the addictive behaviors of craving and relapse seen in human drug addicts [13], [14], [43].

We have utilized a cocaine-induced locomotor sensitization paradigm [11], [16] to further study the alterations in brain reward circuitry and behavior in our mouse model of prenatal cocaine exposure. Our data suggest that sensitization-induced changes in locomotion can be distinguished from stereotypic behaviors, and that both locomotion and stereotypy are altered in animals following prenatal cocaine exposure. These findings are consistent with previous work utilizing rodent models that demonstrate an altered rewarding efficacy of cocaine in adult offspring following intrauterine exposure to cocaine.