We propose to evaluate the physiochemical and pharmacokinetic parameters of psychoactive drugs which influence their distribution to the fetus and the consequences of fetal drug exposure on development and aging of brain catecholamine neurons and neuroendocrine systems. We would conduct an extensive pharmacokinetic analysis of fetal disposition of the antidepressants desipramine, bupropion and its metabolite 2-hydroxy-bupropion to access the effects of lipid solubility of the drugs and maternal plasma protein binding on extent of exposure of the fetus to the maternally-administered drugs in the rat. These data will be correlated with our previous results for other antidepressants and barbiturates. In a second project, the """"""""subclinical"""""""" teratogenic effects of fetal drug exposure would be evaluated for each of these drugs and correlated with our data on other tricyclic antidepressants. We will evaluate a variety of parameters of development, reproductive function and brain catecholamine neurotransmission. In view of our observation that a common teratological consequence of in utero exposure to both antidepressants and barbiturates is a persistent hyperactivity of hypothalamic catecholaminergic neurons in adult progeny, we will evaluate the ontogeny of noradrenergic neurons and the number and affinity of noradrenergic receptors in drug-treated progeny. Finally, we have observed that the teratogenic effects of psychoactive drugs on several organ systems are similar to those which are normally observed during the aging process. Thus, we will evaluate the intriguing hypothesis that a consequence of in utero drug exposure is an acceleration in the rate of aging of organ system or of the organism itself. Thus, we would monitor a population of imipramine- (or phenobarbital-) exposed progeny for its life-long mortality rate, and the functional capacity of several systems for which normal age-related alterations are well defined. Collectively, the results of these experiments should allow us (i) to further define the relationships among drug lipid solubility, plasma protein binding, the extent of fetal drug exposure and the subclinical teratogenic effects, and (ii) hence to test the validity of using in vitro tests of lipid solubility and plasma protein-drug binding as predictors of fetal drug exposure and potential teratogenic effects. Finally, this project would allow us to evaluate our hypothesis that """"""""teratogenic aging"""""""" is a consequence of fetal exposure to some psychoactive drugs.
