COCAINE SELF ADMINISTRATION IN DOPAMINE KNOCKOUT MICE

Summary

Principal Investigator: SIMON B CAINE
Abstract: Studies are proposed to use gene-targeted "knockout" mice to analyze the roles of different dopaminergic systems in the reinforcing effects of cocaine. Compelling pharmacological and neurobiologic evidence suggests that the abuse-related effects of cocaine are mediated by dopaminergic systems, and dopamine-based strategies provide promising avenues for development of new medications to treat cocaine abuse and dependence. The more specific identification of molecular targets for design and synthesis of dopamine-related medications may be greatly assisted by systematic analyses of mechanisms mediating cocaine's reinforcing effects in knockout mice. Although drugs acting at the dopamine transporter or at D1-like or D2- like receptors can modify some abuse-related effects of cocaine, the roles of these proteins in cocaine's effects are not fully understood. Genetic technology in mice that permits the deletion of a single protein by "knockout" of its functional gene provides a highly specific tool that may help to elucidate the roles pharmacologically. For example, the modification of cocaine self-administration by mixed D2/D3 compounds may be due to D2 or D3 actions alone or in combination. Studies in mice that lack the D2 receptor will permit a clearer analysis of the role of the D3 receptor in such effects. The proposed self-administration will: (1) examine the reinforcing effects of cocaine in mice lacking the dopamine transporter or to the D1 or D2 receptor, and (2) use these mice to specify more precisely the receptor mechanisms involved in the modification of cocaine self-administration by non-selective dopaminergic compounds. An important feature of this proposal is that self-administration studies in parental inbred strains and studies of responding maintained by a non-drug reinforcer will be conducted to provide a comprehensive basis for interpreting results of self-administration studies in knockout mice. In addition, studies in male and female mice will allow assessment of gender differences in genetic and pharmacological influences on cocaine self-administration. Overall, this research will increase our understanding of the roles of specific dopaminergic proteins in cocaine's abuse-related effects and help to identify the most appropriate targets for medications development. Moreover, integrating gene-targeting strategies with pharmacological and drug self-administration techniques will provide a framework for future studies using yet more advanced genetic technology to identify molecular mechanisms of cocaine's abuse-related effects.
Funding Period: 1999-03-12 - 2005-02-28
more information: NIH RePORT

Top Publications

  1. pmc Cocaine versus food choice procedure in rats: environmental manipulations and effects of amphetamine
    Morgane Thomsen
    Alcohol and Drug Abuse Research Center, McLean Hospital and Harvard Medical School, Belmont, MA 02478, USA
    J Exp Anal Behav 99:211-33. 2013
  2. pmc Cocaine self-administration in dopamine D₃ receptor knockout mice
    S Barak Caine
    Alcohol and Drug Abuse Research Center, McLean Hospital Harvard Medical School, MA 02478, USA
    Exp Clin Psychopharmacol 20:352-63. 2012
  3. pmc Psychomotor stimulation by dopamine D₁-like but not D₂-like agonists in most mouse strains
    Morgane Thomsen
    Alcohol and Drug Abuse Research Center Harvard Medical School and McLean Hospital, Mail Stop 214, 115 Mill Street, Belmont, MA 02478, USA
    Exp Clin Psychopharmacol 19:342-60. 2011
  4. pmc Psychomotor stimulant effects of cocaine in rats and 15 mouse strains
    Morgane Thomsen
    Alcohol and Drug Abuse Research Center, Harvard Medical School and McLean Hospital, Mail Stop 214, 115 Mill Street, Belmont, MA 02478, USA
    Exp Clin Psychopharmacol 19:321-41. 2011
  5. pmc False positive in the intravenous drug self-administration test in C57BL/6J mice
    Morgane Thomsen
    Alcohol and Drug Abuse Research Center, McLean Hospital Harvard Medical School, Belmont, Massachusetts 02478, USA
    Behav Pharmacol 22:239-47. 2011
  6. pmc Attenuation of cocaine's reinforcing and discriminative stimulus effects via muscarinic M1 acetylcholine receptor stimulation
    Morgane Thomsen
    Alcohol and Drug Abuse Research Center, McLean Hospital Harvard Medical School, 115 Mill Street, Belmont, MA 02478, USA
    J Pharmacol Exp Ther 332:959-69. 2010
  7. pmc Lack of cocaine self-administration in mice expressing a cocaine-insensitive dopamine transporter
    Morgane Thomsen
    Alcohol and Drug Abuse Research Center, McLean Hospital Harvard Medical School, Belmont, MA 02478, USA
    J Pharmacol Exp Ther 331:204-11. 2009
  8. pmc Dramatically decreased cocaine self-administration in dopamine but not serotonin transporter knock-out mice
    Morgane Thomsen
    Alcohol and Drug Abuse Research Center, McLean Hospital Harvard Medical School, Belmont, Massachusetts 02478, USA
    J Neurosci 29:1087-92. 2009
  9. pmc Lack of self-administration of cocaine in dopamine D1 receptor knock-out mice
    S Barak Caine
    Alcohol and Drug Abuse Research Center, McLean Hospital, Harvard Medical School, Belmont, Massachusetts 02478, USA
    J Neurosci 27:13140-50. 2007
  10. ncbi Intravenous drug self-administration in mice: practical considerations
    Morgane Thomsen
    Alcohol and Drug Abuse Research Center, McLean Hospital Harvard Medical School, 115 Mill Street, Belmont, MA 02478, USA
    Behav Genet 37:101-18. 2007

Detail Information

Publications15

  1. pmc Cocaine versus food choice procedure in rats: environmental manipulations and effects of amphetamine
    Morgane Thomsen
    Alcohol and Drug Abuse Research Center, McLean Hospital and Harvard Medical School, Belmont, MA 02478, USA
    J Exp Anal Behav 99:211-33. 2013
    ..The results suggest feasibility and utility of the choice procedure in rats and support its comparability to similar procedures used in humans and monkeys...
  2. pmc Cocaine self-administration in dopamine D₃ receptor knockout mice
    S Barak Caine
    Alcohol and Drug Abuse Research Center, McLean Hospital Harvard Medical School, MA 02478, USA
    Exp Clin Psychopharmacol 20:352-63. 2012
    ..In addition, the D₃ antagonist PG01037 failed to affect cocaine self-administration under an FR 1 schedule in WT mice. The present data do not support a necessary role for the D₃ receptor in the direct reinforcing effects of cocaine...
  3. pmc Psychomotor stimulation by dopamine D₁-like but not D₂-like agonists in most mouse strains
    Morgane Thomsen
    Alcohol and Drug Abuse Research Center Harvard Medical School and McLean Hospital, Mail Stop 214, 115 Mill Street, Belmont, MA 02478, USA
    Exp Clin Psychopharmacol 19:342-60. 2011
    ..These results should aid in the selection of mouse strains for future studies in which D₁ or D₂ responsiveness is a necessary consideration in the experimental design...
  4. pmc Psychomotor stimulant effects of cocaine in rats and 15 mouse strains
    Morgane Thomsen
    Alcohol and Drug Abuse Research Center, Harvard Medical School and McLean Hospital, Mail Stop 214, 115 Mill Street, Belmont, MA 02478, USA
    Exp Clin Psychopharmacol 19:321-41. 2011
    ..Additionally, these results should aid in selecting mouse strains for future studies in which relative locomotor responsiveness to psychostimulants is a necessary consideration...
  5. pmc False positive in the intravenous drug self-administration test in C57BL/6J mice
    Morgane Thomsen
    Alcohol and Drug Abuse Research Center, McLean Hospital Harvard Medical School, Belmont, Massachusetts 02478, USA
    Behav Pharmacol 22:239-47. 2011
    ..We suggest that a necessary criterion for positive results in the intravenous drug self-administration test include an increase in responding when cocaine is made available after extinction with saline self-administration...
  6. pmc Attenuation of cocaine's reinforcing and discriminative stimulus effects via muscarinic M1 acetylcholine receptor stimulation
    Morgane Thomsen
    Alcohol and Drug Abuse Research Center, McLean Hospital Harvard Medical School, 115 Mill Street, Belmont, MA 02478, USA
    J Pharmacol Exp Ther 332:959-69. 2010
    ..These data provide the first demonstration of anticocaine effects of systemically applied, M(1) receptor agonists and suggest the possibility of a new approach to pharmacotherapy for cocaine addiction...
  7. pmc Lack of cocaine self-administration in mice expressing a cocaine-insensitive dopamine transporter
    Morgane Thomsen
    Alcohol and Drug Abuse Research Center, McLean Hospital Harvard Medical School, Belmont, MA 02478, USA
    J Pharmacol Exp Ther 331:204-11. 2009
    ..Thus, molecular engineering technology could advance the development of highly specialized compounds such as a dopamine-sparing "cocaine antagonist."..
  8. pmc Dramatically decreased cocaine self-administration in dopamine but not serotonin transporter knock-out mice
    Morgane Thomsen
    Alcohol and Drug Abuse Research Center, McLean Hospital Harvard Medical School, Belmont, Massachusetts 02478, USA
    J Neurosci 29:1087-92. 2009
    ..These findings support the notion that the DAT, but not the SERT, is critical in mediating the reinforcing effects of cocaine...
  9. pmc Lack of self-administration of cocaine in dopamine D1 receptor knock-out mice
    S Barak Caine
    Alcohol and Drug Abuse Research Center, McLean Hospital, Harvard Medical School, Belmont, Massachusetts 02478, USA
    J Neurosci 27:13140-50. 2007
    ..We conclude that D1 receptor knock-out mice do not reliably self-administer cocaine and that the D1 receptor is critical for the reinforcing effects of cocaine and other dopamine agonists, but not food or opioids, in mice...
  10. ncbi Intravenous drug self-administration in mice: practical considerations
    Morgane Thomsen
    Alcohol and Drug Abuse Research Center, McLean Hospital Harvard Medical School, 115 Mill Street, Belmont, MA 02478, USA
    Behav Genet 37:101-18. 2007
    ..Part II provides a review of recent data that address how the genetic background on which mutations are expressed may influence results from gene-targeting studies...
  11. ncbi Effects of selective dopamine D1-like and D2-like agonists on prepulse inhibition of startle in inbred C3H/HeJ, SPRET/EiJ, and CAST/EiJ mice
    Rebecca J Ralph
    Alcohol and Drug Abuse Research Center, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, MA 02478, USA
    Psychopharmacology (Berl) 191:731-9. 2007
    ..Nevertheless, we recently identified three mouse strains (C3H/HeJ, SPRET/EiJ, and CAST/EiJ) that exhibited locomotor hyperactivity after administration of a selective D2-like agonist...
  12. ncbi Cocaine self-administration under fixed and progressive ratio schedules of reinforcement: comparison of C57BL/6J, 129X1/SvJ, and 129S6/SvEvTac inbred mice
    Morgane Thomsen
    Alcohol and Drug Abuse Research Center, McLean Hospital Harvard Medical School, 115 Mill Street, Belmont, MA, 02478, USA
    Psychopharmacology (Berl) 184:145-54. 2006
    ..Specifically, cocaine may have reduced reinforcing effects in 129 substrains compared to the C57BL/6 strain, commonly used for ES cells and breeding, respectively...
  13. ncbi Reduced cocaine self-administration in muscarinic M5 acetylcholine receptor-deficient mice
    Morgane Thomsen
    Alcohol and Drug Abuse Research Center, McLean Hospital, Harvard Medical School, Belmont, Massachusetts 02478, USA
    J Neurosci 25:8141-9. 2005
    ..Our results indicate that M5 receptor deletion diminished the reinforcing effects of low doses of cocaine and identified specific conditions under which this may be observed...
  14. pmc Effect of GABA agonists and GABA-A receptor modulators on cocaine- and food-maintained responding and cocaine discrimination in rats
    Andrew C Barrett
    Alcohol and Drug Abuse Research Center, McLean Hospital, Harvard Medical School, Belmont, MA 02478, USA
    J Pharmacol Exp Ther 315:858-71. 2005
    ..Together with previous studies, these data suggest that among mechanistically diverse GABA agonists, high-efficacy GABA-A modulators may be the most effective for modifying the abuse-related effects of cocaine...
  15. ncbi Dopamine D1 and D2 agonist effects on prepulse inhibition and locomotion: comparison of Sprague-Dawley rats to Swiss-Webster, 129X1/SvJ, C57BL/6J, and DBA/2J mice
    Rebecca J Ralph
    Alcohol and Drug Abuse Research Center, McLean Hospital Harvard Medical School, 115 Mill Street, Belmont, MA 02478, USA
    J Pharmacol Exp Ther 312:733-41. 2005
    ..These results may have implications for the study of mutant mice to investigate genes involved in psychomotor function in humans...