Using a clinically relevant animal model, the applicants' studies have revealed that rats exposed to cocaine prenatally (IV) exhibit a selective impairment in two aspects of attentional function, whereas many other cognitive functions appear spared. The proposed studies are designed to test the hypothesis that: The type of attentional impairment seen following prenatal cocaine exposure results from alterations in catecholaminergic systems in prefrontal cortex (PFC) and/or anterior cingulate cortex (ACC), and that the targeting of these systems with potential therapeutic agents will ameliorate the attentional impairments. In the first set of studies, they will assess various attentional functions as well as the functional integrity of frontal dopaminergic (DA) and noradrenergic (NE) systems in the same animals. For the NE system, they will measure the density of alpha1 and alpha2 adrenoreceptors and NE transporter in PFC and ACC (and control regions). Similarly, the functional integrity of DA circuitry in ACC and PFC will be assessed by measures of D1, D2, and D3 receptor density, the DA transporter, and coupling of D1 and D2 receptors to their associated G proteins. In addition to providing new information about the effects of prenatal cocaine exposure on attentional function and on NE and DA systems in frontal cortex, these studies provide a unique opportunity to establish functional relationships between observed cognitive and neural changes. This is not possible with the more common approach of assessing behavioral and neural changes in separate groups of animals, often exposed to cocaine via different routes and doses, with very different handling and testing histories. In the second set of experiments, the efficacy of putative therapeutic agents will be examined. These studies will: (a) provide direct tests of putative links suggested by the first set of experiments and (b) identify drugs that are likely to be useful therapeutically. A final contribution of both sets of studies is to further elucidate the roles of the PFC and ACC and their catecholaminergic innervation in cognitive functioning. The use of tasks that specifically tap various attentional functions (including in-depth analyses of performance data), coupled with assessment of putative neural mechanisms in the same animals, should provide new information concerning the roles of these systems.
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