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We have developed a rabbit model of in utero exposure to intravenous injections of cocaine given twice daily to dams from gestational days 8-29. At the doses employed (4 mg/kg, injected twice daily), no differences were found in the body weight gain of dams, time to delivery, litter size, and body weight or other physical characteristics of the offspring. However, cocaine-exposed pups displayed an abnormal structural and neurochemical development of the anterior cingulate cortex which persisted into adulthood. In agreement with the known functions of the anterior cingulate cortex, we found that adult, sexually mature rabbits, exposed to cocaine prenatally, demonstrate impairments in motor function, alterations in associative learning and severe impairments in discrimination learning. Moreover, the alterations in discrimination learning were interpreted to be due to deficits in attentional processes. Specifically, cocaine progeny preferentially attend to more salient stimuli even when these are not relevant to the task. Consequently they have difficulty in attending to less salient but relevant stimuli when more salient but irrelevant stimuli occur in the same context. We concluded that the learning deficits are a reflection of the morphologic and neurochemical abnormalities of the anterior cingulate cortex. Alterations in dopamine function of the caudate nucleus may also contribute to the deficits in motor performance.

The nictitating membrane (NM) reflex was assessed in adult Dutch-belted rabbits exposed to cocaine in utero. The intensity threshold for eliciting the reflex was increased in cocaine progeny and the amplitude of the reflex was decreased at the lower stimulus intensities. However, cocaine and saline progeny showed equivalent rates of habituation of the NM reflex when tested with a suprathreshold eliciting stimulus. Reliable modification of the NM reflex was obtained when the reflex-eliciting stimulus was preceded by an auditory stimulus at intervals of 100-800 ms. Cocaine and saline progeny exhibited an increase in the peak amplitude of the reflex, a shortening of the latency of the reflex, and a shortening of the latency to achieve peak amplitude of the reflex as a function of increases in the interstimulus interval. Furthermore, cocaine progeny showed significantly longer response latencies than saline progeny across all interstimulus intervals, although neither the peak amplitude nor the latency to achieve peak amplitude was affected. Thus, prenatal exposure to cocaine affected elicitation of the defensive NM reflex to an aversive stimulus but did not affect the sensorimotor integration necessary for modification of the reflex by antecedent stimulation.

Previous studies had demonstrated that in utero exposure to cocaine produces structural changes in the development of the rabbit's anterior cingulate cortex. Because the anterior cingulate cortex has been proposed to subserve a variety of cognitive processes including associative learning, we investigated the effects of intrauterine exposure to cocaine on the acquisition of the rabbit's classically conditioned nictitating membrane response. Adult, sexually mature rabbits born of dams that had received intravenous injections of either saline or cocaine (4 mg/kg, twice a day) from day 8 to day 29 of gestation were classically conditioned by pairing tone and light CSs with an airpuff US. Rabbits that had been exposed to cocaine in utero demonstrated a more rapid acquisition of CRs to a tone CS but not to a light CS as compared with saline controls. Control experiments indicated that the accelerated learning to the tone CS was not due to sensitization, pseudoconditioning, altered baseline rate of responding, an increased responsiveness to the airpuff US, or to a change in the intensity threshold of the tone CS for elicitation of CRs. We conclude that in utero exposure to cocaine alters the processing of auditory stimuli and this leads to an abnormally rapid acquisition of CRs. It is suggested that this functional consequence of prenatal exposure to cocaine is due to structural abnormalities in anterior cingulate cortex.

The rabbit has been used to model the potential effects of in utero exposure to cocaine on fetal and postnatal development. Special advantages of this animal model include the fact that cocaine can be easily administered intravenously, thus mimicking crack cocaine use by pregnant women. Results indicate that at the dosage used (8 mg/kg of body weight, given intravenously daily) gross teratologic defects do not develop. Cocaine-exposed pregnant does not differ from controls in weight gain or in the number of live kits delivered. Cocaine-exposed kits do not differ from controls in survival or in postnatal weight gain. The importance of this rabbit model is that offspring that have been exposed to these doses of cocaine in utero have a variety of abnormalities in structure and function of the central nervous system in the absence of any major teratologic defects.