Psychopharmacology

, Volume 173, Issue 1–2, pp 210–216

Combined low dose treatment with opioid and cannabinoid receptor antagonists synergistically reduces the motivation to consume alcohol in rats

  • Jason E. Gallate
  • Paul E. Mallet
  • Iain S. McGregor
Original Investigation
  • 83 Downloads

Abstract

Rationale

Opioid and cannabinoid CB1 receptor antagonists reduce the motivation to consume alcohol when taken individually but their effectiveness in combination is not yet known.

Objective

The effects of naloxone/naltrexone and SR 141716 alone and in combination were examined on beer consumption in rats.

Methods

In a progressive ratio paradigm rats were trained to lick at a tube for either beer (4.5% ethanol v/v) or near-beer (beer containing <0.5% ethanol v/v) under a progressive ratio schedule of reinforcement. They were then tested with naloxone (0.3, 0.6 or 1.2 mg/kg IP), SR 141716 (0.15, 0.3 or 0.6 mg/kg IP) and their combination. In a continuous access paradigm, other rats were given beer or near-beer in their home cages for several weeks and the effects of repeated (4 day) administration of naltrexone (0.3, 0.6 or 1.2 mg/kg), SR 141716 (0.15, 0.3 or 0.6 mg/kg) and their combination were assessed.

Results

In the progressive ratio paradigm SR 141716, naloxone and their combination were more effective in reducing the break points for beer rather than near-beer. The two lowest dose combinations produced a synergistic reduction in break points. The highest dose combination reduced break points for both beer and near-beer and effects were more additive than synergistic. In the continuous access paradigm, the low doses of the drugs selectively reduced beer consumption in a synergistic fashion with higher doses having a less selective and more additive effect.

Conclusions

The combined, low dose treatment has possible clinical efficacy in treating alcohol craving in humans.

Keywords

SR 141716 Naloxone Naltrexone Rat Beer Alcohol Self-administration 

References

  1. Arnone M, Maruani J, Chaperon F, Thiebot MH, Poncelet M, Soubrie P, Le Fur G (1997) Selective inhibition of sucrose and ethanol intake by SR 141716, an antagonist of central cannabinoid (CB1) receptors. Psychopharmacology 132:104–106Google Scholar
  2. Bassareo V, Dichiara G (1997) Differential influence of associative and nonassociative learning mechanisms on the responsiveness of prefrontal and accumbal dopamine transmission to food stimuli in rats fed ad libitum. J Neurosci 17:851–861PubMedGoogle Scholar
  3. Benjamin D, Grant ER, Pohorecky LA (1993) Naltrexone reverses ethanol-induced dopamine release in the nucleus accumbens in awake, freely moving rats. Brain Res 621:137–40PubMedGoogle Scholar
  4. Cohen C, Perrault G, Voltz C, Steinberg R, Soubrie P (2002) SR141716, a central cannabinoid [CB(1)] receptor antagonist, blocks the motivational and dopamine-releasing effects of nicotine in rats. Behav Pharmacol 13:451–463PubMedGoogle Scholar
  5. Colombo G, Agabio R, Fa M, Guano L, Lobina C, Loche A, Reali R, Gessa GL (1998) Reduction of voluntary ethanol intake in ethanol-preferring SP rats by the cannabinoid antagonist SR-141716. Alcohol Alcohol 33:126–130PubMedGoogle Scholar
  6. Colombo G, Serra S, Brunetti G, Gomez R, Melis S, Vacca G, Carai MAM, Gessa GL (2002) Stimulation of voluntary ethanol intake by cannabinoid receptor agonists in ethanol-preferring sP rats. Psychopharmacology 159:181–187CrossRefPubMedGoogle Scholar
  7. COMBINE Study Research Group (2003) Testing combined pharmacotherapies and behavioral interventions in alcohol dependence: rationale and methods. Alcohol Clin Exp Res 27:1107–1122PubMedGoogle Scholar
  8. Gallate JE, McGregor IS (1999) The motivation for beer in rats: effects of ritanserin, naloxone and SR 141716. Psychopharmacology 142:302–308Google Scholar
  9. Gallate JE, Saharov T, Mallet PE, McGregor IS (1999) Increased motivation for beer in rats following administration of a cannabinoid CB1 receptor agonist. Eur J Pharmacol 370:233–240PubMedGoogle Scholar
  10. Gallate JE, Morley KC, Ambermoon P, McGregor IS (2003) The consequences of beer consumption in rats: acute anxiolytic and ataxic effects and withdrawal-induced anxiety. Psychopharmacology 166:51–60PubMedGoogle Scholar
  11. Gonzales RA, Weiss F (1998) Suppression of ethanol-reinforced behavior by naltrexone is associated with attenuation of the ethanol-induced increase in dialysate dopamine levels in the nucleus accumbens. J Neurosci 18:10663–10671PubMedGoogle Scholar
  12. Hartmann PM (1997) Naltrexone in alcohol dependence. Am Family Phys 55:1877–1879Google Scholar
  13. Herz A (1997) Endogenous opioid systems and alcohol addiction. Psychopharmacology 129:99–111PubMedGoogle Scholar
  14. Hungund BL, Szakall I, Adam A, Basavarajappa BS, Vadasz C (2003) Cannabinoid CB1 receptor knockout mice exhibit markedly reduced voluntary alcohol consumption and lack alcohol-induced dopamine release in the nucleus accumbens. J Neurochem 84:698–704CrossRefPubMedGoogle Scholar
  15. Kirkham TC, Williams CM (2001) Synergistic effects of opioid and cannabinoid antagonists on food intake. Psychopharmacology 153:267–270Google Scholar
  16. Krystal JH, Cramer JA, Krol WF, Kirk GF, Rosenheck RA, Veterans Affairs Naltrexone Cooperative Study G (2001) Naltrexone in the treatment of alcohol dependence. N Engl J Med 345:1734–1739CrossRefPubMedGoogle Scholar
  17. Litten RZ, Allen JP (1998) Advances in development of medications for alcoholism treatment. Psychopharmacology 139:20–33CrossRefPubMedGoogle Scholar
  18. Manzanares J, Corchero J, Romero J, Fernandez-Ruiz JJ, Ramos JA, Fuentes JA (1999) Pharmacological and biochemical interactions between opioids and cannabinoids. Trends Pharmacol Sci 20:287–294PubMedGoogle Scholar
  19. McGregor IS (1996) Using Strawberry Tree WorkbenchMac and Workbench PC software for data acquisition and control in the animal learning laboratory. Behav Res Meth Instr Comp 28:38–48Google Scholar
  20. Nichols ML, Hubbell CL, Kalsher MJ, Reid LD (1991) Morphine increases intake of beer among rats. Alcohol 8:237–240PubMedGoogle Scholar
  21. Rezvani AH, Overstreet DH, Mason GA, Janowsky DS, Hamedi M, Clark E Jr, Yang Y (2000) Combination pharmacotherapy: a mixture of small doses of naltrexone, fluoxetine, and a thyrotropin-releasing hormone analogue reduces alcohol intake in three strains of alcohol-preferring rats. Alcohol Alcohol 35:76–83CrossRefPubMedGoogle Scholar
  22. Serra S, Brunetti G, Pani M, Vacca G, Carai MA, Gessa GL, Colombo G (2002) Blockade by the cannabinoid CB(1) receptor antagonist, SR 141716, of alcohol deprivation effect in alcohol-preferring rats. Eur J Pharmacol 443:95–97CrossRefPubMedGoogle Scholar
  23. Shannon HE, Holtzman SG (1976) Blockade of the discriminative effects of morphine in the rat by naltrexone and naloxone. Psychopharmacology 50:119–124PubMedGoogle Scholar
  24. Spanagel R, Zieglgansberger W (1997) Anti-craving compounds for ethanol: new pharmacological tools to study addictive processes. Trends Pharmacol Sci 18:54–59PubMedGoogle Scholar
  25. Tanda GL, Dichiara G (1998) A dopamine µ(1) opioid link in the rat ventral tegmentum shared by palatable food (Fonzies) and non-psychostimulant drugs of abuse. Eur J Neurosci 10:1179–1187PubMedGoogle Scholar
  26. Tanda G, Pontieri FE, Dichiara G (1997) Cannabinoid and heroin activation of mesolimbic dopamine transmission by a common µ-1 opioid receptor mechanism. Science 276:2048–2050PubMedGoogle Scholar
  27. Topple AN, Hunt GE, McGregor IS (1998) Possible neural substrates of beer-craving in rats. Neurosci Lett 252:99–102CrossRefPubMedGoogle Scholar
  28. Vacca G, Serra S, Brunetti G, Carai MAM, Gessa GL, Colombo G (2002) Boosting effect of morphine on alcohol drinking is suppressed not only by naloxone but also by the cannabinoid CB1 receptor antagonist, SR 141716. Eur J Pharmacol 445:55–59CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  • Jason E. Gallate
    • 1
  • Paul E. Mallet
    • 2
  • Iain S. McGregor
    • 1
  1. 1.School of PsychologyUniversity of SydneySydneyAustralia
  2. 2.School of PsychologyUniversity of New EnglandArmidaleAustralia

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