SSRI TREATMENT OF PRENATAL COCAINE-INDUCED 5HT DEFICITS

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DESCRIPTION (applicant's abstract): Various mood disorders are being increasingly diagnosed in offspring exposed to cocaine in utero. In humans, impairments in serotonin (5-HT) function are associated with disorders such as anxiety, depression and increased impulsivity and aggression. During the initial funding period, we identified long-term neurochemical and functional impairments in brain 5-HT systems in rat offspring exposed prenatally to cocaine. Thus, the long-term objective of this research is to determine the effectiveness of clinically prescribed serotonin-selective reuptake inhibitors (SSRIs) to treat mood disorders in offspring resulting from prenatal exposure to cocaine. The clinical efficacy of SSRIs is related to their ability to produce neuroadaptive changes in 5-HT systems. This renewal application will determine if clinically used SSRIs, such as paroxetine (Paxil), will be effective in reversing the serotonergic deficits in rats produced by prenatal cocaine exposure. Our HYPOTHESIS is that SSRIs will be effective in restoring brain 5-HT function and producing neuroadaptive changes in 5-HT receptor signal transduction in prenatal cocaine-exposed offspring. This proposal will determine the mechanisms responsible for 5-HT impairments and the restoration of 5-HT function by SSRIs in offspring using biochemical, neurochemical and neuroendocrine measures to study pre- and postsynaptic components of 5-HT pathways. Each aim will study the mechanism of neuroadaptive changes in different components of the 5-HT signal transduction pathway due to prenatal cocaine and subsequent postnatal SSRI treatment. Aim 1 will focus on presynaptic 5-HT terminal function; aim 2 will investigate the sensitivity of somatodendritic 5-HT1A autoreceptors on 5-HT cell bodies; and aims 3 & 4 will investigate postsynaptic function of 5-HT1A and 5-HT2A receptor signal transduction systems, respectively. Because neuroendocrine challenge can also be used in humans, the correspondence between neurochemical changes in brain induced changes in 5-HT-mediated neuroendocrine responses will provide the foundation to assess prenatal cocaine-induced changes in 5-HT function in human offspring. In addition, our studies will identify the mechanisms mediating SSRI-induced neuroadaptive changes in 5-HT systems in offspring impaired by prenatal cocaine. Data obtained from the proposed studies will be important in predicting the potential efficacy of SSRIs in treating disorders in individuals previously exposed to cocaine in utero. To our knowledge, these studies are the first to determine the utility of SSRIs to treat impairments in 5-HT function due to prenatal cocaine exposure.