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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA007741-07
Application #
6693443
Study Section
Special Emphasis Panel (ZRG1-IFCN-2 (01))
Program Officer
Thadani, Pushpa
Project Start
1993-04-01
Project End
2006-09-30
Budget Start
2004-01-01
Budget End
2006-09-30
Support Year
7
Fiscal Year
2003
Total Cost
$342,000
Indirect Cost
Name
Loyola University Chicago
Department
Pharmacology
Type
Schools of Medicine
DUNS #
791277940
City
Maywood
State
IL
Country
United States
Zip Code
60153
Carrasco, Gonzalo A; Van de Kar, Louis D; Jia, Cuihong et al. (2007) Single exposure to a serotonin 1A receptor agonist, (+)8-hydroxy-2-(di-n-propylamino)-tetralin, produces a prolonged heterologous desensitization of serotonin 2A receptors in neuroendocrine neurons in vivo. J Pharmacol Exp Ther 320:1078-86
Carrasco, Gonzalo A; Battaglia, George (2007) Withdrawal from a single exposure to cocaine increases 5-HT2A receptor and G protein function. Neuroreport 18:51-5
Chen, Zhuo; Tetzlaff, Julie; Sripathirathan, Kumar et al. (2005) Paroxetine is effective in desensitizing 5-HT1A receptor function in adult offspring exposed prenatally to cocaine. Psychopharmacology (Berl) 180:316-26
Chen, Zhuo; Waimey, Kate; Van de Kar, Louis D et al. (2004) Prenatal cocaine exposure potentiates paroxetine-induced desensitization of 5-HT2A receptor function in adult male rat offspring. Neuropharmacology 46:942-53
Carrasco, Gonzalo A; Damjanoska, Katerina J; D'Souza, Deborah N et al. (2004) Short-term cocaine treatment causes neuroadaptive changes in Galphaq and Galpha11 proteins in rats undergoing withdrawal. J Pharmacol Exp Ther 311:349-55
Carrasco, Gonzalo A; Zhang, Yahong; Damjanoska, Katerina J et al. (2003) A region-specific increase in Galphaq and Galpha11 proteins in brains of rats during cocaine withdrawal. J Pharmacol Exp Ther 307:1012-9
Battaglia, G; Cabrera-Vera, T M; Van De Kar, L D (2000) Prenatal cocaine exposure potentiates 5-HT(2a) receptor function in male and female rat offspring. Synapse 35:163-72
Cabrera-Vera, T M; Garcia, F; Pinto, W et al. (2000) Neurochemical changes in brain serotonin neurons in immature and adult offspring prenatally exposed to cocaine. Brain Res 870:9-Jan
Vicentic, A; Cabrera-Vera, T M; Pinto, W et al. (2000) 5-HT(1A) and 5-HT(2A) serotonin receptor turnover in adult rat offspring prenatally exposed to cocaine. Brain Res 877:141-8
Battaglia, G; Napier, T C (1998) The effects of cocaine and the amphetamines on brain and behavior: a conference report. Drug Alcohol Depend 52:41-8

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