Research Topics
| TREATMENT OF COCAINE-INDUCED 5-HT DYSFUNCTIONSummaryPrincipal Investigator: George Battaglia Affiliation: Loyola University Medical Center Country: USA Abstract: The long term objective of this program is to find novel treatments for the mood disorders associated with cocaine withdrawal. A major problem with cocaine abuse is the return to cocaine use after a period of abstinence (relapse). contributing factor to cocaine relapse is withdrawal-induced anxiety and depression which stimulate re-administration as form of self-medication. Withdrawal from cocaine results in supersensitivity of serotonin-2A (5-HT2A ) receptors. 5-HT2A receptor supersensitivity is associated with depression and anxiety. Therefore, treating 5-HT2A receptor supersensitivity may alleviate the anxiety and depression that contribute to cocaine relapse. However, to date, no studies have investigated the mechanisms responsible for cocaine-induced 5-HT2A receptor supersensitivity. The proposed studies will investigate the mechanisms through which withdrawal from cocaine induces supersensitivity of 5-HT2A receptor-mediated secretion of hormones. In addition, two potential therapeutic approaches will be tested to reverse the supersensitivity of post-synaptic 5-HT2A receptors during cocaine withdrawal. Our hypothesis is that the cocaine-induced changes in sensitivity of 5-HT2A receptors are due to changes in specific components of the intracellular signaling cascade. The proposed studies will investigate signaling mechanisms underlying the supersensitivity of 5-HT2A receptor systems in the hypothalamic paraventricular nucleus after withdrawal from cocaine and their response to treatment. Aim 1 will determine the minimum number of cocaine injection days that will produce supersensitivity of 5-HT2A receptor signaling. One of the characteristics of drug dependence is that a drug must be administered repeatedly before withdrawal effects appear. Aim 2 will determine the onset of supersensitivity of 5-HT2A receptors after exposure to cocaine and to determine whether these effects are irreversible. This study also will establish the treatment parameters to be used in aims 3-4. The cocaine withdrawal effect may be a compensatory supersensitivity of 5-HT2A receptors due to reduced 5-HT release. Thus, Aim 3 will determine how the cocaine withdrawal effects on 5-HT2A receptors can be reversed by increasing the levels of 5-HT in the synapse with selective monoamine oxidase-A (MAO-A) inhibitors. Aim 4 will determine how the cocaine withdrawal effects on 5-HT2A receptors can be reversed by 5-HT2A antagonists. Our results from these studies on the treatment with selective 5-HT2A antagonists and MAO-A inhibitors may lead to novel therapeutic approaches to reverse the supersensitivity of 5-HT2A receptors and hence treat mood disorders associated with cocaine withdrawal and relapse. Funding Period: 2001-02-01 - 2008-01-31 more information: NIH RePORT Top Publications
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Publications
Paroxetine is effective in desensitizing 5-HT1A receptor function in adult offspring exposed prenatally to cocaineZhuo Chen
Department of Pharmacology and Center for Serotonin Disorders Research, Stritch School of Medicine, Loyola University of Chicago, 2160 South First Avenue, Maywood, IL 60153, USA
Psychopharmacology (Berl) 180:316-26. 2005..These data suggest that paroxetine may be clinically effective in treating mood disorders in adults exposed in utero to cocaine...- Cocaine-mediated supersensitivity of 5-HT2A receptors in hypothalamic paraventricular nucleus is a withdrawal-induced phenomenonG A Carrasco
Department of Pharmacology, Loyola University Chicago, Stritch School of Medicine, Maywood, IL 60153, USA
Neuroscience 143:7-13. 2006.... - 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 vivoGonzalo A Carrasco
Department of Pharmacology, Loyola University of Chicago, Stritch School of Medicine, 2160 S First Ave, Maywood, IL 60153, USA
J Pharmacol Exp Ther 320:1078-86. 2007.... - Withdrawal from a single exposure to cocaine increases 5-HT2A receptor and G protein functionGonzalo A Carrasco
Department of Pharmacology, Loyola University Chicago, Maywood, Illinois, USA
Neuroreport 18:51-5. 2007.... - Agonist induced-phosphorylation of Galpha11 protein reduces coupling to 5-HT2A receptorsJu Shi
Department of Pharmacology and Experimental Therapeutics, Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois, USA
J Pharmacol Exp Ther 323:248-56. 2007..These data suggest that DOI causes phosphorylation of Galphaq/11 in vivo and could thereby contribute to the desensitization of 5-HT2A receptors... - 5-HT1A receptors mediate (+)8-OH-DPAT-stimulation of extracellular signal-regulated kinase (MAP kinase) in vivo in rat hypothalamus: time dependence and regional differencesJames W Crane
Department of Pharmacology, Loyola University Chicago, Stritch School of Medicine, 2160 S First Avenue, Maywood, IL 60153, USA
Brain Res 1183:51-9. 2007..In conclusion, these results demonstrate that 8-OH-DPAT activation of MAP kinase signaling in vivo is a transient and region-specific phenomenon and in rat hypothalamus and hippocampus is mediated by 5-HT1A receptors... - Prolonged 5-HT1A/5-HT2A receptor cross-talk is absent prior to adulthood in ratsMaureen L Petrunich
Neuroscience Institute, Loyola University Chicago, Maywood, Illinois, USA
Neuroreport 19:1457-61. 2008..These data suggest that 5-HT1A heterologous desensitization of 5-HT2A receptor function does not develop until adulthood, is more transient, or follows a different time course before maturation... - Extra-nuclear estrogen receptor GPR30 regulates serotonin function in rat hypothalamusH Xu
Department of Pharmacology and Experimental Therapeutics, Loyola University Chicago School of Medicine, Maywood, IL 60153, USA
Neuroscience 158:1599-607. 2009....