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Contribution of Ventral Tegmental GABA Receptors to Cocaine Self-administration in Rats

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Abstract

Recent evidence has suggested that compounds affecting GABAergic transmission may provide useful pharmacological tools for the treatment of cocaine addiction. Using a rat model of self-administration, the present study examined the effects of GABA agonists and antagonists injected directly into the ventral tegmental area (VTA) on cocaine intake in rats trained to self-administer cocaine (0, 125, 250 and 500 μg/infusion) under an FR5 schedule of reinforcement. Separate groups of rats received bilateral intra-VTA injections of the GABA-A antagonist picrotoxin (34 ng/side, n = 7; 68 ng/side, n = 8), GABA-A agonist muscimol (14 ng/side, n = 8), GABA-B agonist baclofen (56 ng/side, n = 7; 100 ng/side, n = 6), picrotoxin (68 ng/side) co-injected with the GABA-B antagonist 2-hydroxysaclofen (100 ng/side, n = 7; 2 μg/side, n = 8) or artificial cerebrospinal fluid (aCSF, n = 6) to assess the effects of the various compounds on the cocaine self-administration dose-response curve. Both picrotoxin and baclofen reduced responding maintained by cocaine, whereas muscimol had no effect on responding. In contrast, neither picrotoxin (n = 6) nor baclofen (n = 8) affected responding maintained by food. Interestingly, 2-hydroxysaclofen effectively blocked the suppression of responding produced by picrotoxin, suggesting that both picrotoxin and baclofen exert their effects via activation of GABA-B receptors. Additionally, these effects appear to be specific to cocaine reinforcement, supporting current investigation of baclofen as a treatment for cocaine addiction.

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References

  1. Backes E, Hemby SE (2003) Discrete cell gene profiling of ventral tegmental dopamine neurons after acute and chronic cocaine self-administration. J Pharmacol Exp Ther 307:450–459

    Article  PubMed  CAS  Google Scholar 

  2. Grubb MC, Welch JR, Finn DA, Mark GP (2002) Cocaine self-administration alters the locomotor response to microinjection of bicuculline into the ventral tegmental area of rats. Brain Res 952:44–51

    Article  PubMed  CAS  Google Scholar 

  3. Hemby SE (2004) Morphine-induced alterations in gene expression of calbindin immunopositive neurons in nucleus accumbens shell and core. Neuroscience 126:689–703

    Article  PubMed  CAS  Google Scholar 

  4. Hemby SE, Co C, Dworkin SI, Smith JE (1999) Synergistic elevations in nucleus accumbens extracellular dopamine concentrations during self-administration of cocaine/heroin combinations (Speedball) in rats. J Pharmacol Exp Ther 288:274–280

    PubMed  CAS  Google Scholar 

  5. Hemby SE, Co C, Koves TR, Smith JE, Dworkin SI (1997) Differences in extracellular dopamine concentrations in the nucleus accumbens during response-dependent and response-independent cocaine administration in the rat. Psychopharmacology (Berl) 133:7–16

    Article  CAS  Google Scholar 

  6. Hemby SE, Co C, Reboussin D, Davies HM, Dworkin SI, Smith JE (1995) Comparison of a novel tropane analog of cocaine, 2 beta-propanoyl−3 beta-(4-tolyl) tropane with cocaine HCl in rats: nucleus accumbens extracellular dopamine concentration and motor activity. J Pharmacol Exp Ther 273:656–666

    PubMed  CAS  Google Scholar 

  7. Hemby SE, Horman B, Tang W (2005) Differential regulation of ionotropic glutamate receptor subunits following cocaine self-administration. Brain Res 1064:75–82

    Article  PubMed  CAS  Google Scholar 

  8. Hemby SE, Martin TJ, Co C, Dworkin SI, Smith JE (1995) The effects of intravenous heroin administration on extracellular nucleus accumbens dopamine concentrations as determined by in vivo microdialysis. J Pharmacol Exp Ther 273:591–598

    PubMed  CAS  Google Scholar 

  9. Hemby SE, Smith JE, Dworkin SI (1996) The effects of eticlopride and naltrexone on responding maintained by food, cocaine, heroin and cocaine/heroin combinations in rats. J Pharmacol Exp Ther 277:1247–1258

    PubMed  CAS  Google Scholar 

  10. Ikemoto S, Murphy JM, McBride WJ (1997) Self-infusion of GABA(A) antagonists directly into the ventral tegmental area and adjacent regions. Behav Neurosci 111:369–380

    Article  PubMed  CAS  Google Scholar 

  11. Johnson BA (2005) Recent advances in the development of treatments for alcohol and cocaine dependence: focus on topiramate and other modulators of GABA or glutamate function. CNS Drugs 19:873–896

    Article  PubMed  CAS  Google Scholar 

  12. Johnson BA (2006) Pills for speedballing or cocaine dependence. Lancet 367:1714–1716

    Article  PubMed  Google Scholar 

  13. Johnson BA, Mann K, Willenbring ML, Litten RZ, Swift RM, Lesch OM, Berglund M (2005) Challenges and opportunities for medications development in alcoholism: an international perspective on collaborations between academia and industry. Alcohol Clin Exp Res 29:1528–1540

    Article  PubMed  Google Scholar 

  14. Johnson SW, North RA (1992) Two types of neurone in the rat ventral tegmental area and their synaptic inputs. J Physiol 450:455–468

    PubMed  CAS  Google Scholar 

  15. Kalivas PW, Duffy P, Eberhardt H (1990) Modulation of A10 dopamine neurons by gamma-aminobutyric acid agonists. J Pharmacol Exp Ther 253:858–866

    PubMed  CAS  Google Scholar 

  16. Koob GF, Bloom FE (1988) Cellular and molecular mechanisms of drug dependence. Science 242:715–723

    Article  PubMed  CAS  Google Scholar 

  17. Lyons D, Friedman DP, Nader MA, Porrino LJ (1996) Cocaine alters cerebral metabolism within the ventral striatum and limbic cortex of monkeys. J Neurosci 16:1230–1238

    PubMed  CAS  Google Scholar 

  18. Paxinos G, Watson C (1998) The rat brain in stereotaxic coordinates. 4th edn. Academic Press

  19. Porrino LJ (1993) Functional consequences of acute cocaine treatment depend on route of administration. Psychopharmacology (Berl) 112:343–351

    Article  CAS  Google Scholar 

  20. Sieghart W (1995) Structure and pharmacology of gamma-aminobutyric acidA receptor subtypes. Pharmacol Rev 47:181–234

    PubMed  CAS  Google Scholar 

  21. Sieghart W, Fuchs K, Tretter V, Ebert V, Jechlinger M, Hoger H, Adamiker D (1999) Structure and subunit composition of GABA(A) receptors. Neurochem Int

  22. Tang W, Wesley M, Freeman WM, Liang B, Hemby SE (2004) Alterations in ionotropic glutamate receptor subunits during binge cocaine self-administration and withdrawal in rats. J Neurochem 89:1021–1033

    Article  PubMed  CAS  Google Scholar 

  23. Volkow ND, Wang GJ, Fowler JS (1997) Imaging studies of cocaine in the human brain and studies of the cocaine addict. Ann NY Acad Sci 820:41–54; discussion 54–45

    Google Scholar 

  24. Whiting PJ, Bonnert TP, McKernan RM, Farrar S, Le Bourdelles B, Heavens RP, Smith DW, Hewson L, Rigby MR, Sirinathsinghji DJ, Thompson SA, Wafford KA (1999) Molecular and functional diversity of the expanding GABA-A receptor gene family. Ann NY Acad Sci 868:645–653

    Article  PubMed  CAS  Google Scholar 

  25. Wise RA (1998) Drug-activation of brain reward pathways. Drug Alcohol Depen 51:13–22

    Article  CAS  Google Scholar 

  26. Wise RA, Bozarth MA (1987) A psychomotor stimulant theory of addiction. Psychol Rev 94:469–492

    Article  PubMed  CAS  Google Scholar 

  27. Xi ZX, Stein EA (1998) Nucleus accumbens dopamine release modulation by mesolimbic GABAA receptors-an in vivo electrochemical study. Brain Res 798:156–165

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

The research was funded in part by NIH grants DA012498, DA003628, and DA006634.

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Authors and Affiliations

  1. Neuroscience Graduate Program, Emory University School of Medicine, Atlanta, GA, USA

    E. N. Backes

  2. Departments of Physiology & Pharmacology, Psychiatry & Behavioral Medicine, Medical Center Boulevard, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA

    S. E. Hemby

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  1. E. N. Backes
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  2. S. E. Hemby
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Correspondence to S. E. Hemby.

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Backes, E.N., Hemby, S.E. Contribution of Ventral Tegmental GABA Receptors to Cocaine Self-administration in Rats. Neurochem Res 33, 459–467 (2008). https://doi.org/10.1007/s11064-007-9454-2

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  • DOI: https://doi.org/10.1007/s11064-007-9454-2

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