NEUROBEHAVIORAL PHARMACOLOGY OF STIMULANTS

Summary

Principal Investigator: Kathryn A Cunningham
Abstract: Cocaine dependence remains an alarming health issue, and an important research imperative is the development of effective treatment medications. The behavioral effects of cocaine are modulated by pharmacological manipulation of the 5-HT system and we have demonstrated that two 5-HT receptors, the 5-HT2A receptor (5-HT2AR) and the 5-HT2CR, exert excitatory and inhibitory control, respectively, over the behavioral effects of cocaine in an almost perfectly oppositional manner in rats. We propose that the ventral tegmental area (VTA) is one essential site for the 5-HT2R influence over the rewarding and reinforcing effects of cocaine. The VTA is comprised of dopamine (DA) and gamma- aminobutyric (GABA) neurons that form circuits with limbic and cortical nuclei that play a vital role in the in vivo effects of cocaine. The long term goals of the proposed multidisciplinary project are to elucidate the roles played by the 5-HT2AR and 5-HT2CR in the rewarding and reinforcing effects of cocaine including determination of the anatomical and functional heterogeneity of 5-HT2R regulation of the VTA. These goals will be addressed in four specific aims that have evolved conceptually from the progress reported for this project. Specific Aim 1 will test the hypothesis that an oppositional influence of the 5-HT2AR and 5-HT2CR is important in the rewarding and reinforcing effects of cocaine as measured by the conditioned place preference and self-administration assays, thus extending our current observations to models thought to reflect mechanisms underlying addiction. We will investigate the macrocircuitry and heterogeneity of the VTA that is involved in the oppositional control of behavior by 5-HT2AR (Specific Aim 2) and 5-HT2CR (Specific Aim 3) by employing immunohistochemical, pharmacological, intracranial microinjection, and behavioral techniques to map receptor localization and the loci of actions within the VTA that underlie specific aspects of the rewarding and reinforcing effects of cocaine. In Specific Aim 4, we will utilize virally-mediated gene transfer methodology to stably manipulate the abundance of 5-HT2AR and 5-HT2CR in the VTA to address several specific hypotheses concerning the role of these receptors in the rewarding and reinforcing effects of cocaine and to functionally validate circuitry information gleaned from Aims 2 and 3. Knowledge of the heterogeneity of the 5-HT2AR and 5-HT2CR to control the rewarding and reinforcing effects of cocaine and the role of VTA in these processes will reveal cellular targets that can be exploited in the development of new and effective pharmacotherapy not only for addiction to the abused drug cocaine, but also in other disorders characterized bv dysfunction within mesocorticolimbic circuits.
Funding Period: ----------------1990 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. ncbi Serotonin2C receptors (5-HT2C R) control expression of cocaine-induced conditioned hyperactivity
    Shijing Liu
    Center for Addiction Research, Department of Pharmacology and Toxicology, University of Texas Medical Branch at Galveston, 301 University Blvd, Galveston, TX 77555 1031, USA
    Drug Alcohol Depend 81:275-82. 2006
  2. ncbi Serotonin(2C) receptors in the ventral pallidum regulate motor function in rats
    Steven M Graves
    Department of Pharmacology, Center for Compulsive Behavior and Addiction, Rush University Medical Center, Chicago, Illinois, USA
    Neuroreport 24:605-8. 2013
  3. pmc Peptide inhibitors disrupt the serotonin 5-HT2C receptor interaction with phosphatase and tensin homolog to allosterically modulate cellular signaling and behavior
    NOELLE C ANASTASIO
    Center for Addiction Research, University of Texas Medical Branch, Galveston, Texas 77555, USA
    J Neurosci 33:1615-30. 2013
  4. pmc Serotonin at the nexus of impulsivity and cue reactivity in cocaine addiction
    Kathryn A Cunningham
    Center for Addiction Research, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA Electronic address
    Neuropharmacology 76:460-78. 2014
  5. ncbi Prospects for serotonin 5-HT2R pharmacotherapy in psychostimulant abuse
    Marcy J Bubar
    Center for Addiction Research, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555 0616, USA
    Prog Brain Res 172:319-46. 2008
  6. pmc Serotonergic mechanisms in addiction-related memories
    Bríd A Nic Dhonnchadha
    Center for Addiction Research, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA
    Behav Brain Res 195:39-53. 2008
  7. pmc Fine-tuning serotonin2c receptor function in the brain: molecular and functional implications
    Kelly A Berg
    Department of Pharmacology, University of Texas Health Science Center, San Antonio, TX 78229 3900, USA
    Neuropharmacology 55:969-76. 2008
  8. ncbi Selective ablation of GABA neurons in the ventral tegmental area increases spontaneous locomotor activity
    ERIK J SHANK
    Center for Addiction Research, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555 1031, USA
    Behav Neurosci 121:1224-33. 2007
  9. ncbi The relationship between the locomotor response to a novel environment and behavioral disinhibition in rats
    Erin C Stoffel
    Center for Addiction Research, Department of Pharmacology and Toxicology, University of Texas Medical Branch, 300 University Boulevard, Galveston, TX 77555 1031, USA
    Drug Alcohol Depend 92:69-78. 2008
  10. pmc Serotonin2C receptor localization in GABA neurons of the rat medial prefrontal cortex: implications for understanding the neurobiology of addiction
    S Liu
    Center for Addiction Research, Department of Pharmacology and Toxicology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555 1031, USA
    Neuroscience 146:1677-88. 2007

Scientific Experts

  • Kathryn A Cunningham
  • Marcy J Bubar
  • NOELLE C ANASTASIO
  • Patricia K Seitz
  • Maria Fe Lanfranco
  • Sonja J Stutz
  • Erin C Stoffel
  • M J Bubar
  • Steven M Graves
  • Robert G Fox
  • Cheryl S Watson
  • Elaine K Lau
  • ADRIANE M DELA CRUZ
  • B A Nic Dhonnchadha
  • Bríd A Nic Dhonnchadha
  • Kelly A Berg
  • S Liu
  • ERIK J SHANK
  • Malgorzata Filip
  • Shijing Liu
  • Tao Geng
  • Sarah E Swinford
  • Nicole M Bremer
  • Anton Agarkov
  • James M Briggs
  • Annika A Viskniskki
  • Marc N Charendoff
  • Yowjiun Jeng
  • John W Craft
  • Fernanda M Laezza
  • T Celeste Napier
  • Thressa D Smith
  • Scott R Gilbertson
  • Kenner C Rice
  • Alma L Burlingame
  • Mark von Zastrow
  • Frederick G Moeller
  • SARAH J KOTOWSKI
  • Jonathan C Trinidad
  • Michelle Trester-Zedlitz
  • Andrew N Krutchinsky
  • Andrew G McGinnis
  • R G Fox
  • Elaine Sanders-Bush
  • Michael V Morabito
  • James J Grady
  • S J Stutz
  • David V Herin
  • K C Rice
  • Ronald B Emeson
  • William P Clarke
  • Umberto Spampinato
  • M F Lanfranco
  • G R Hillman
  • Alexander Kurosky
  • Kizhake V Soman
  • Mary L Thomas
  • Bruce A Luxon
  • Bo Xu

Detail Information

Publications24

  1. ncbi Serotonin2C receptors (5-HT2C R) control expression of cocaine-induced conditioned hyperactivity
    Shijing Liu
    Center for Addiction Research, Department of Pharmacology and Toxicology, University of Texas Medical Branch at Galveston, 301 University Blvd, Galveston, TX 77555 1031, USA
    Drug Alcohol Depend 81:275-82. 2006
    ..These results suggest that the 5-HT2C R controls expression of cocaine-induced conditioned hyperactivity and suggest that such ligands may be useful in preventing relapse and promoting abstinence in cocaine-dependent individuals...
  2. ncbi Serotonin(2C) receptors in the ventral pallidum regulate motor function in rats
    Steven M Graves
    Department of Pharmacology, Center for Compulsive Behavior and Addiction, Rush University Medical Center, Chicago, Illinois, USA
    Neuroreport 24:605-8. 2013
    ..These findings indicate negative regulation of motor function by 5-HT(2C) receptors in the ventral pallidum...
  3. pmc Peptide inhibitors disrupt the serotonin 5-HT2C receptor interaction with phosphatase and tensin homolog to allosterically modulate cellular signaling and behavior
    NOELLE C ANASTASIO
    Center for Addiction Research, University of Texas Medical Branch, Galveston, Texas 77555, USA
    J Neurosci 33:1615-30. 2013
    ....
  4. pmc Serotonin at the nexus of impulsivity and cue reactivity in cocaine addiction
    Kathryn A Cunningham
    Center for Addiction Research, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA Electronic address
    Neuropharmacology 76:460-78. 2014
    ..This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'...
  5. ncbi Prospects for serotonin 5-HT2R pharmacotherapy in psychostimulant abuse
    Marcy J Bubar
    Center for Addiction Research, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555 0616, USA
    Prog Brain Res 172:319-46. 2008
    ....
  6. pmc Serotonergic mechanisms in addiction-related memories
    Bríd A Nic Dhonnchadha
    Center for Addiction Research, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA
    Behav Brain Res 195:39-53. 2008
    ..This review briefly traces the history of 5-HT involvement in retrieval of drug-cue associations and future targets of serotonergic manipulation that may reduce the impact that drug cues have on addictive behavior and relapse...
  7. pmc Fine-tuning serotonin2c receptor function in the brain: molecular and functional implications
    Kelly A Berg
    Department of Pharmacology, University of Texas Health Science Center, San Antonio, TX 78229 3900, USA
    Neuropharmacology 55:969-76. 2008
    ....
  8. ncbi Selective ablation of GABA neurons in the ventral tegmental area increases spontaneous locomotor activity
    ERIK J SHANK
    Center for Addiction Research, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555 1031, USA
    Behav Neurosci 121:1224-33. 2007
    ..This loss of GABA VTA neurons was associated with hypermotility, further supporting their important regulatory role in the generation of behavior...
  9. ncbi The relationship between the locomotor response to a novel environment and behavioral disinhibition in rats
    Erin C Stoffel
    Center for Addiction Research, Department of Pharmacology and Toxicology, University of Texas Medical Branch, 300 University Boulevard, Galveston, TX 77555 1031, USA
    Drug Alcohol Depend 92:69-78. 2008
    ....
  10. pmc Serotonin2C receptor localization in GABA neurons of the rat medial prefrontal cortex: implications for understanding the neurobiology of addiction
    S Liu
    Center for Addiction Research, Department of Pharmacology and Toxicology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555 1031, USA
    Neuroscience 146:1677-88. 2007
    ....
  11. pmc Distribution of serotonin 5-HT2C receptors in the ventral tegmental area
    M J Bubar
    Center for Addiction Research, Department of Pharmacology and Toxicology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555 1031, USA
    Neuroscience 146:286-97. 2007
    ..The present results suggest that the inhibitory influence of the 5-HT2CR over DA neurotransmission in the VTA is a multifaceted and complex interplay of 5-HT2CR control of the output of both GABA and DA neurons within this region...
  12. ncbi Contribution of serotonin (5-HT) 5-HT2 receptor subtypes to the discriminative stimulus effects of cocaine in rats
    Malgorzata Filip
    Institute of Pharmacology, Polish Academy of Sciences, 31 343, Cracow, Poland
    Psychopharmacology (Berl) 183:482-9. 2006
    ..The serotonin (5-hydroxytryptamine; 5-HT) 5-HT2 receptor (5-HT2R) family is an important regulator of the behavioral responsiveness to cocaine...
  13. ncbi Serotonin 5-HT2A and 5-HT2C receptors as potential targets for modulation of psychostimulant use and dependence
    Marcy J Bubar
    Center for Addiction Research and the Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555 1031, USA
    Curr Top Med Chem 6:1971-85. 2006
    ....
  14. ncbi Use of surface enhanced laser desorption/ionization-time of flight mass spectrometry (SELDI-TOF MS) to study protein expression in a rat model of cocaine withdrawal
    Tao Geng
    Center for Addiction Research, Department of Pharmacology and Toxicology, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555 1031, United States
    J Neurosci Methods 158:1-12. 2006
    ..05) in cocaine-treated rats compared to saline-treated rats. In summary, the application of SELDI-TOF MS to the study of protein expression in a rat model of cocaine withdrawal is feasible and has the potential to generate new hypotheses...
  15. pmc Quantitative encoding of the effect of a partial agonist on individual opioid receptors by multisite phosphorylation and threshold detection
    Elaine K Lau
    Department of Psychiatry, University of California, San Francisco, CA 94158, USA
    Sci Signal 4:ra52. 2011
    ..Thus, quantitative encoding of agonist-selective endocytosis at the level of individual opioid receptors was based on the conserved biochemical principles of multisite phosphorylation and threshold detection...
  16. pmc 5-HT(2C) receptors localize to dopamine and GABA neurons in the rat mesoaccumbens pathway
    Marcy J Bubar
    Department of Pharmacology and Toxicology and Center for Addiction Research, University of Texas Medical Branch, Galveston, Texas, United States of America
    PLoS ONE 6:e20508. 2011
    ..Further, the indication that a proportion of NAc-projecting VTA neurons synthesize and potentially release both dopamine and GABA adds intriguing complexity to the framework of the VTA and its postulated neuroanatomical roles...
  17. pmc Selective serotonin 5-HT(2C) receptor activation suppresses the reinforcing efficacy of cocaine and sucrose but differentially affects the incentive-salience value of cocaine- vs. sucrose-associated cues
    Kathryn A Cunningham
    Center for Addiction Research, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77550 0615, USA
    Neuropharmacology 61:513-23. 2011
    ....
  18. pmc Serotonin (5-hydroxytryptamine) 5-HT(2A) receptor: association with inherent and cocaine-evoked behavioral disinhibition in rats
    NOELLE C ANASTASIO
    Center for Addiction Research, University of Texas Medical Branch, Galveston, Texas, USA
    Behav Pharmacol 22:248-61. 2011
    ..These data point to the 5-HT(2A)R as an important regulatory substrate in impulse control...
  19. ncbi Quantification of RNA editing of the serotonin 2C receptor (5-HT(₂C)R) ex vivo
    Maria Fe Lanfranco
    Center for Addiction Research, University of Texas Medical Branch, Galveston, Texas, USA
    Methods Enzymol 485:311-28. 2010
    ..In addition, the general technique can be adapted easily to investigate edited mRNA from other genes, thus facilitating the development of a broader knowledge base of the physiological role of mRNA editing...
  20. pmc Serotonin 5-HT2C receptor protein expression is enriched in synaptosomal and post-synaptic compartments of rat cortex
    NOELLE C ANASTASIO
    Center for Addiction Research, University of Texas Medical Branch, Galveston, Texas, USA
    J Neurochem 113:1504-15. 2010
    ..Taken together, these data support the hypothesis that the 5-HT(2C)R is localized within the post-synaptic thickening of synapses and is therefore positioned to directly modulate synaptic plasticity in cortical neurons...
  21. pmc Novel approach to data analysis in cocaine-conditioned place preference
    ADRIANE M DELA CRUZ
    Department of Pharmacology and Toxicology, Center for Addiction Research, University of Texas Medical Branch, Galveston, Texas 77555 0615, USA
    Behav Pharmacol 20:720-30. 2009
    ..125 mg/kg) treatment in a subgroup of rats. These data support the utility of the criterion analysis as an adjunct to traditional methods that compare group averages in CPP...
  22. pmc Blockade of the serotonin 5-HT2A receptor suppresses cue-evoked reinstatement of cocaine-seeking behavior in a rat self-administration model
    B A Nic Dhonnchadha
    Center for Addiction Research, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77550 1031, USA
    Behav Neurosci 123:382-96. 2009
    ....
  23. pmc An innovative real-time PCR method to measure changes in RNA editing of the serotonin 2C receptor (5-HT(2C)R) in brain
    Maria Fe Lanfranco
    Center for Addiction Research and Department of Pharmacology and Toxicology, University of Texas Medical Branch, 301 University Blvd, Route 0616, Galveston, TX 77555 0616, USA
    J Neurosci Methods 179:247-57. 2009
    ....