IN UTERO COCAINE-INDUCED 5-HT DYSFUCTION IN PROGENY

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The long term objective of this proposal is to understand how cocaine abuse during pregnancy can contribute to the development in offspring, of subsequent clinical disorders involving dysfunction of brain serotonin(5-HT) systems. Dysfunctional 5-HT systems have been implicated in anxiety, depression, suicidal behaviors and preference for alcohol. In adult animals, cocaine perturbs 5-HT neurons by decreasing their firing rate, inhibiting 5-HT synthesis and inhibiting 5-HT uptake. During gestation, 5-HT plays a critical trophic role in the maturation of 5-HT neurons and target cells receiving 5-HT projections. Our hypothesis is that in utero exposure to cocaine produces perturbations of fetal 5-HT systems that result in long-term deficits in the functional status and integrity of brain 5-HT systems in adult progeny. Our preliminary data support our hypothesis of long-term biochemical and functional deficits in progeny brain 5-HT systems following in utero exposure to cocaine. The goal of the present research is to establish the extent of cocaine-induced changes in adult progeny with respect to the following specific aims: (1) To Determine the Functional Status of Brain 5-HT Neurons by measuring (a) 5-HT/5-HIAA content in terminal and cell body regions and the corresponding number and affinity of 5-HT uptake sites in these regions, (b) the viability of 5-HT terminals by the ability of 5-HT releasers to stimulate ACTH and renin secretion, as well as, to reduce (deplete) brain 5-HT content; (2) To Determine the Functional Status of Postsynaptic 5-HT Receptors with respect to cocaine-induced changes in (a) the stimulation of ACTH and renin secretion by directly acting 5-HT1 and 5-HT2/1C serotonin agonists, and (b) the adaptational responsiveness of 5-HT receptors by investigating the dynamics of 5-HT1 and 5-HT2 receptor turnover following receptor inactivation; and (3) To Determine the Neuroanatomic Specificity of In Utero Cocaine-Induced Effects on 5-HT Pathways by measuring regional densities of 5-HT uptake sites, and 5-HT1 & 5-HT2 receptor subtypes using in vitro autoradiographic techniques. These studies should identify discrete brain regions where cocaine- induced receptor alterations may produce functional consequences. Methods: Pregnant rats will be treated b.i.d. from gestational day 13-20 and all progeny fostered at birth. Male and female progeny of pregnant rats from 3 Treatment Groups: (1) Saline-Injected Ad-Lib Fed; (2) Saline-Injected Pair-Fed; and (3) Cocaine-Injected (15 mg/kg) will be compared at a prepubescent time (PD30). Male progeny will also be investigated at postpubescent time (PD70). Significance: Since cocaine ("Crack") abuse among women of childbearing age is becoming increasingly prevalent, these studies will provide timely and important information regarding neurological deficits which may develop in offspring due to in utero cocaine-induced dysfunction of 5-HT systems. In this regard, changes in the stimulation of plasma hormones in response to 5-HT drugs may provide an important clinical marker for in utero cocaine-induced central 5-HT dysfunction in humans.