The consequences of prenatal cocaine exposure are of growing concern as a public health issue. Using a well established animal model of prenatal cocaine exposure in rabbits (3 mg/kg cocaine IV, b.i.d. from gestation day 8 (G8) to G29), we will investigate the seizure susceptibility of the offspring in response to IV cocaine administration. The advantage of this model is the ease with which we can perform IV administration, which is more similar to the pharmacokinetics of common patterns of human cocaine use than IP or SC models. Since we have collected a large body of data using this model which demonstrate molecular and neuroanatomical alterations in the GABAergic system as a consequence of prenatal cocaine exposure, we will investigate whether the function of the GABAergic system is altered in terms of its seizure-related responses. To do so, we will measure the seizure susceptibility of the offspring in response to the GABA receptor antagonist bicuculline. In addition, we will compare the seizure- related effects cocaine and bicuculline to determine if these behaviors are produced through a common output pathway. We will attempt to prevent the production of cocaine-elicited seizures with muscimol, a GABA receptor agonist. We will examine the time course of the development of tolerance to both cocaine and bicuculline-elicited seizures, and we will determine whether there is any degree of cross- tolerance between them. Results will be informative concerning the degree of dysfunction of the GABAergic system following prenatal cocaine exposure and will be potentially useful in evaluating the effects of anticonvulsant medications.
