George Battaglia, PhD

George Battaglia, PhD

  • Professor
  • Molecular Pharmacology and Therapeutics

Effects of drugs of abuse and anti-depressants on serotonin function during development

Serotonin (5-HT) systems play a prominent role in a number of physiologic functions and clinical disorders. Dysfunction in 5-HT systems has been implicated in mood disorders such as anxiety and depression. In addition, profound changes in 5-HT function can be produced by drugs of abuse, such as methamphetamine, MDMA and cocaine. Our research program has focused on the study of brain serotonergic systems with respect to issues concerning 5-HT receptor-mediated signal transduction and drug-induced neuroadaptive changes at different developmental ages. More specifically, we have been interested in the following: (1) investigating 5-HT1A receptor signaling of hormone and kinase pathways in hypothalamic neuroendocrine neurons (2) delineating the mechanism of regulation of serotonin receptor subtypes and receptor-mediated signal transduction in response to therapeutic agents and drugs of abuse; (3) determining the consequences of prenatal exposure to antidepressants or cocaine on serotonergic function in young and adult offspring; (4) elucidating the consequences of early developmental exposure to drugs of abuse and clinically prescribed drugs on the immediate and long-term functional status of 5-HT systems;(5) delineating the mechanisms of 5-HT receptor "cross-talk" and heterologous desensitization between 5-HT1A and 5-HT2A receptors on neuroendocrine neurons, (6) investigating the intracellular mechanisms mediating the desensitization in forebrain 5-HT1A receptor signaling produced by serotonin selective reuptake inhibitors (SSRIs) such as fluoxetine and other serotonin altering drugs; and (7) understanding the effects of acute and chronic cocaine on 5-HT systems and the mechanisms mediating withdrawal-induced supersensitivity in 5-HT2A receptor systems. Given the increasing use of clinically prescribed drugs across all age groups, these studies may have significant implications with respect to understanding the long-term consequences in serotonin signaling and function due to drug exposure at different developmental ages.

  • Xu,H.; Qin,S.; Carrasco,G. A.; Dai,Y.; Filardo,E. J.; Prossnitz,E. R.; Battaglia,G.; Doncarlos,L. L.; Muma,N. A.Extra-nuclear estrogen receptor GPR30 regulates serotonin function in rat hypothalamus. Neuroscience 2009 ;158(4):1599-1607
  • Shi,J.; Landry,M.; Carrasco,G. A.; Battaglia,G.; Muma,N. A.Sustained treatment with a 5-HT(2A) receptor agonist causes functional desensitization and reductions in agonist-labeled 5-HT(2A) receptors despite increases in receptor protein levels in rats Neuropharmacology 2008 ;55(5):687-692
  • Petrunich,M. L.; Garcia,F.; Carrasco,G. A.; Battaglia,G.Prolonged 5-HT1A/5-HT2A receptor cross-talk is absent prior to adulthood in rats. Neuroreport 2008 ;19(15):1457-1461
  • Carrasco,G. A.; Battaglia,G.Withdrawal from a single exposure to cocaine increases 5-HT2A receptor and G protein function. Neuroreport 2007 ;18(1):51-55
  • Shi,J.; Damjanoska,K. J.; Singh,R. K.; Carrasco,G. A.; Garcia,F.; Grippo,A. J.; Landry,M.; Sullivan,N. R.; Battaglia,G.; Muma,N. A.Agonist induced-phosphorylation of Galpha11 protein reduces coupling to 5-HT2A receptors. Journal of Pharmacology & Experimental Therapeutics 2007 ;323(1):248-256
  • Carrasco,G. A.; Van de Kar,L. D.; Jia,C.; Xu,H.; Chen,Z.; Chadda,R.; Garcia,F.; Muma,N. A.; Battaglia,G.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. Journal of Pharmacology & Experimental Therapeutics 2007 ;320(3):1078-1086
  • Crane,J. W.; Shimizu,K.; Carrasco,G. A.; Garcia,F.; Jia,C.; Sullivan,N. R.; D'Souza,D. N.; Zhang,Y.; Van de Kar,L. D.; Muma,N. A.; Battaglia,G.5-HT1A receptors mediate (+)8-OH-DPAT-stimulation of extracellular signal-regulated kinase (MAP kinase) in vivo in rat hypothalamus: time dependence and regional differences. Brain research 2007 ;1183:51-59
  • Muma,N. A.; Singh,R. K.; Vercillo,M. S.; D'Souza,D. N.; Zemaitaitis,B.; Garcia,F.; Damjanoska,K. J.; Zhang,Y.; Battaglia,G.; Van de Kar,L. D.Chronic olanzapine activates the Stat3 signal transduction pathway and alters expression of components of the 5-HT2A receptor signaling system in rat frontal cortex. Neuropharmacology 2007 ;53(4):552-562
  • Carrasco,G. A.; Van de Kar,L. D.; Sullivan,N. R.; Landry,M.; Garcia,F.; Muma,N. A.; Battaglia,G.Cocaine-mediated supersensitivity of 5-HT2A receptors in hypothalamic paraventricular nucleus is a withdrawal-induced phenomenon. Neuroscience 2006 ;143(1):7-13
  • Shi,J.; Damjanoska,K. J.; Zemaitaitis,B.; Garcia,F.; Carrasco,G.; Sullivan,N. R.; She,Y.; Young,K. H.; Battaglia,G.; Van De kar,L. D.; Howland,D. S.; Muma,N. A.Alterations in 5-HT2A receptor signaling in male and female transgenic rats over-expressing either Gq or RGS-insensitive Gq protein. Neuropharmacology 2006 ;51(3):524-535
  • Landry,M.; Frasier,M.; Chen,Z.; Van De Kar,L. D.; Zhang,Y.; Garcia,F.; Battaglia,G.Fluoxetine treatment of prepubescent rats produces a selective functional reduction in the 5-HT2A receptor-mediated stimulation of oxytocin. Synapse 2005 ;58(2):102-109
  • Chen,Z.; Tetzlaff,J.; Sripathirathan,K.; Carrasco,G. A.; Shankaran,M.; Van De Kar,L. D.; Muma,N. A.; Battaglia,G.Paroxetine is effective in desensitizing 5-HT1A receptor function in adult offspring exposed prenatally to cocaine. Psychopharmacology 2005 ;180(2):316-326
  • Chen,Z.; Waimey,K.; Van de Kar,L. D.; Carrasco,G. A.; Landry,M.; Battaglia,G.Prenatal cocaine exposure potentiates paroxetine-induced desensitization of 5-HT2A receptor function in adult male rat offspring. Neuropharmacology 2004 ;46(7):942-953
  • D'Souza,D. N.; Zhang,Y.; Damjanoska,K. J.; Carrasco,G. A.; Sullivan,N. R.; Garcia,F.; Battaglia,G.; Doncarlos,L. L.; Muma,N. A.; Van de Kar,L. D.Estrogen reduces serotonin-1A receptor-mediated oxytocin release and Galpha(i/o/z) proteins in the hypothalamus of ovariectomized rats. Neuroendocrinology 2004 ;80(1):31-41
  • D'Souza,D. N.; Zhang,Y.; Garcia,F.; Battaglia,G.; Van de Kar,L. D.Fluoxetine-induced changes in body weight and 5-HT1A receptor-mediated hormone secretion in rats on a tryptophan-deficient diet. American Journal of Physiology - Regulatory Integrative & Comparative Physiology 2004 ;286(2):R390-7
  • Damjanoska,K. J.; Heidenreich,B. A.; Kindel,G. H.; D'Souza,D. N.; Zhang,Y.; Garcia,F.; Battaglia,G.; Wolf,W. A.; Van de Kar,L. D.; Muma,N. A.Agonist-induced serotonin 2A receptor desensitization in the rat frontal cortex and hypothalamus. Journal of Pharmacology & Experimental Therapeutics 2004 ;309(3):1043-1050
  • Carrasco,G. A.; Damjanoska,K. J.; D'Souza,D. N.; Zhang,Y.; Garcia,F.; Battaglia,G.; Muma,N. A.; Van de Kar,L. D.Short-term cocaine treatment causes neuroadaptive changes in Galphaq and Galpha11 proteins in rats undergoing withdrawal. Journal of Pharmacology & Experimental Therapeutics 2004 ;311(1):349-355
  • Zhang,Y.; Gray,T. S.; D'Souza,D. N.; Carrasco,G. A.; Damjanoska,K. J.; Dudas,B.; Garcia,F.; Zainelli,G. M.; Sullivan Hanley,N. R.; Battaglia,G.; Muma,N. A.; Van de Kar,L. D.Desensitization of 5-HT1A receptors by 5-HT2A receptors in neuroendocrine neurons in vivo. Journal of Pharmacology & Experimental Therapeutics 2004 ;310(1):59-66
  • Heidenreich,B. A.; Mitrovic,I.; Battaglia,G.; Napier,T. C.Limbic pallidal adaptations following long-term cessation of dopaminergic transmission: lack of upregulation of dopamine receptor function. Experimental neurology 2004 ;186(2):145-157
  • Carrasco,G. A.; Zhang,Y.; Damjanoska,K. J.; D'Souza,D. N.; Garcia,F.; Battaglia,G.; Muma,N. A.; Van de Kar,L. D.A region-specific increase in Galphaq and Galpha11 proteins in brains of rats during cocaine withdrawal. Journal of Pharmacology & Experimental Therapeutics 2003 ;307(3):1012-1019
  • Damjanoska,K. J.; Van de Kar,L. D.; Kindel,G. H.; Zhang,Y.; D'Souza,D. N.; Garcia,F.; Battaglia,G.; Muma,N. A.Chronic fluoxetine differentially affects 5-hydroxytryptamine (2A) receptor signaling in frontal cortex, oxytocin- and corticotropin-releasing factor-containing neurons in rat paraventricular nucleus. Journal of Pharmacology & Experimental Therapeutics 2003 ;306(2):563-571
  • Van de Kar,L. D.; Raap,D. K.; Battaglia,G.; Muma,N. A.; Garcia,F.; DonCarlos,L. L.Treatment of cycling female rats with fluoxetine induces desensitization of hypothalamic 5-HT(1A) receptors with no change in 5-HT(2A) receptors Neuropharmacology 2002 ;43(1):45-54
  • Raap,D. K.; DonCarlos,L. L.; Garcia,F.; Zhang,Y.; Muma,N. A.; Battaglia,G.; Van de Kar,L. D.Ovariectomy-induced increases in hypothalamic serotonin-1A receptor function in rats are prevented by estradiol Neuroendocrinology 2002 ;76(6):348-356
  • Zhang,Y.; Damjanoska,K. J.; Carrasco,G. A.; Dudas,B.; D'Souza,D. N.; Tetzlaff,J.; Garcia,F.; Hanley,N. R.; Scripathirathan,K.; Petersen,B. R.; Gray,T. S.; Battaglia,G.; Muma,N. A.; Van de Kar,L. D.Evidence that 5-HT2A receptors in the hypothalamic paraventricular nucleus mediate neuroendocrine responses to (-)DOI The Journal of neuroscience : the official journal of the Society for Neuroscience 2002 ;22(21):9635-9642
  • D'Souza,D. N.; Zhang,Y.; Garcia,F.; Battaglia,G.; Van De Kar,L. D.Destruction of serotonergic nerve terminals prevents fluoxetine-induced desensitization of hypothalamic 5-HT(1A) receptors Psychopharmacology 2002 ;164(4):392-400
  • Zhang,Y.; D'Souza,D.; Raap,D. K.; Garcia,F.; Battaglia,G.; Muma,N. A.; Van de Kar,L. D.Characterization of the functional heterologous desensitization of hypothalamic 5-HT(1A) receptors after 5-HT(2A) receptor activation The Journal of neuroscience : the official journal of the Society for Neuroscience 2001 ;21(20):7919-7927
  • Battaglia,G.; Cabrera-Vera,T. M.; Van De Kar,L. D.Prenatal cocaine exposure potentiates 5-HT(2a) receptor function in male and female rat offspring Synapse (New York, N.Y.) 2000 ;35(3):163-172
  • Vicentic,A.; Cabrera-Vera,T. M.; Pinto,W.; Battaglia,G.5-HT(1A) and 5-HT(2A) serotonin receptor turnover in adult rat offspring prenatally exposed to cocaine Brain research 2000 ;877(2):141-148
  • Zhang,Y.; Raap,D. K.; Garcia,F.; Serres,F.; Ma,Q.; Battaglia,G.; Van de Kar,L. D.Long-term fluoxetine produces behavioral anxiolytic effects without inhibiting neuroendocrine responses to conditioned stress in rats Brain research 2000 ;855(1):58-66
  • Raap,D. K.; DonCarlos,L.; Garcia,F.; Muma,N. A.; Wolf,W. A.; Battaglia,G.; Van de Kar,L. D.Estrogen desensitizes 5-HT(1A) receptors and reduces levels of G(z), G(i1) and G(i3) proteins in the hypothalamus Neuropharmacology 2000 ;39(10):1823-1832
  • Serres,F.; Li,Q.; Garcia,F.; Raap,D. K.; Battaglia,G.; Muma,N. A.; Van de Kar,L. D.Evidence that G(z)-proteins couple to hypothalamic 5-HT(1A) receptors in vivo The Journal of neuroscience : the official journal of the Society for Neuroscience 2000 ;20(9):3095-3103
  • Serres,F.; Muma,N. A.; Raap,D. K.; Garcia,F.; Battaglia,G.; Van de Kar,L. D.Coadministration of 5-hydroxytryptamine(1A) antagonist WAY-100635 prevents fluoxetine-induced desensitization of postsynaptic 5-hydroxytryptamine(1A) receptors in hypothalamus The Journal of pharmacology and experimental therapeutics 2000 ;294(1):296-301
  • Cabrera-Vera,T. M.; Garcia,F.; Pinto,W.; Battaglia,G.Neurochemical changes in brain serotonin neurons in immature and adult offspring prenatally exposed to cocaine Brain research 2000 ;870(1-2):1-9