This is a proposal to examine the long-term behavioral consequences of fetal exposure to cocaine. Four interrelated subprojects are proposed in Aims l to 4. Projects l and 2 found structural abnormalities in the cingulate cortex of adult rabbits that had been exposed prenatally to cocaine. Associative learning, reaction to noxious stimuli and attentional processes depend on the normal functioning of the cingulate cortex and all three of these functions were impaired in adult cocaine progeny.
Aim l will now determine whether the cognitive deficits in cocaine progeny are due to abnormal training-dependent alterations in the neural activity of the cingulate cortex and related structures. Dopamine (DA) D1 receptor-mediated signal transduction is impaired in anterior cingulate and in striatum (Project 5). The D1 receptor has been implicated in attentional processes. Thus, Aim 2 (in conjunction with Aim 4) will determine whether these cognitive deficits are related to differences between cocaine progeny and controls in the training-induced release of DA within cingulate cortex and whether DA agonists might ameliorate the cognitive deficits.
Aim 3 demonstrated that the deficits in D1 coupling (Project 5) are associated with deficits in d- amphetamine-induced motor responses that rely upon D1-signalling in the striatum. Proposed studies (Aim 3) will: use DA agonists and antagonists to define precisely the impairments in motor function produced by prenatal cocaine exposure, assess the vulnerability of cocaine progeny to behavioral sensitization by chronic cocaine, and test drug therapies to repair D1/G protein coupling or by-pass the deficit in signal transduction in order to normalize motor function.
Aim 4 will use microdialysis in vivo and ligand binding in vitro to analyze neurochemical mechanisms for the behavioral effects of drugs in Aim 3. These experiments will link behavioral abnormalities in cocaine progeny with abnormal functioning in specific brain regions and may offer therapeutic approaches for restoring brain function.
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