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A behavioral economic analysis of the effects of rimcazole on reinforcing effects of cocaine injection and food presentation in rats

  • Martin O. Job
  • Jonathan L. KatzEmail author
Original Investigation
  • 47 Downloads

Abstract

Rationale and objectives

Rimcazole, a σ-receptor antagonist with affinity for the dopamine transporter (DAT), decreases rates of cocaine self-administration at doses lower than those that affect food-reinforced responding. As response rates are multiply determined, behavioral-economic analyses were used to provide measures of the reinforcing effectiveness of cocaine and food after rimcazole treatment. Further, effects of combinations of the DAT inhibitor, methylphenidate, and σ-receptor antagonists (BD1008, BD1063) were compared to those of rimcazole to assess mechanism of rimcazole effects.

Methods

Male Sprague-Dawley rats were trained to lever press with food reinforcement (one or three 20-mg sucrose pellets) or cocaine injection (0.1 or 0.32 mg/kg) under fixed-ratio (FR) 5-response schedules. Drugs or vehicle were administered (i.p.) 5-min before sessions in which FR value was increased from 5 to 80. Economic demand functions were generated from effects of FR value (price) on intake (consumption), with the parameters of demand, consumption at no cost (Q0) and sensitivity to price (essential value, EV), derived.

Results

Rimcazole dose-dependently decreased Q0 and EV at both cocaine doses/injection. In contrast, rimcazole had no effect on these parameters at either food amount. Combinations of methylphenidate and the σ-receptor antagonists decreased Q0 at the lower cocaine dose/injection but had no effect on EV; these treatments were ineffective on both economic parameters at the higher cocaine dose/injection and at either food amount.

Conclusions

Though the drug combinations only replicated rimcazole’s effects incompletely, the present results suggest a specific decrease in the reinforcing effects of cocaine due to dual DAT σ-receptor blockade.

Keywords

Cocaine Rimcazole Sigma receptors Dopamine transporter Behavioral economics Self-administration 

Notes

Acknowledgments

We thank Claudio Zanettini for expert advice in the conduct of the experiment, its analysis, and comments on the manuscript. We also thank Jean Lud Cadet for support, Maryann Carrigan for administrative assistance, and Amy H. Newman for supplies of rimcazole. The second author thanks Drs. James H. Woods and James E. Barrett for sustained encouragement, and the National Institute on Drug Abuse (NIDA) Intramural Research Program (IRP) for years of funding.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. Banks ML, Gould RW, Czoty PW, Nader MA (2008) Relationship between response rates and measures of reinforcing strength using a choice procedure in monkeys. Behav Pharmacol 19:365–369CrossRefGoogle Scholar
  2. Bentzley BS, Aston-Jones G (2015) Orexin-1 receptor signaling increases motivation for cocaine-associated cues. Eur J Neurosci 41:1149–1156CrossRefGoogle Scholar
  3. Bentzley BS, Jhou TC, Aston-Jones G (2014) Economic demand predicts addiction-like behavior and therapeutic efficacy of oxytocin in the rat. Proc Natl Acad Sci U S A 111:11822–11827CrossRefGoogle Scholar
  4. Brodnik ZD, Ferris MJ, Jones SR, Espana RA (2017) Reinforcing doses of intravenous cocaine produce only modest dopamine uptake inhibition. ACS Chem Neurosci 8:281–289CrossRefGoogle Scholar
  5. Christensen CJ, Silberberg A, Hursh SR, Huntsberry ME, Riley AL (2008a) Essential value of cocaine and food in rats: tests of the exponential model of demand. Psychopharmacology 198:221–229CrossRefGoogle Scholar
  6. Christensen CJ, Silberberg A, Hursh SR, Roma PG, Riley AL (2008b) Demand for cocaine and food over time. Pharmacol Biochem Behav 91:209–216CrossRefGoogle Scholar
  7. Cosgrove KP, Carroll ME (2002) Effects of bremazocine on self-administration of smoked cocaine base and orally delivered ethanol, phencyclidine, saccharin, and food in rhesus monkeys: a behavioral economic analysis. J Pharmacol Exp Ther 301:993–1002CrossRefGoogle Scholar
  8. Gilmore DL, Liu Y, Matsumoto RR (2004) Review of the pharmacological and clinical profile of rimcazole. CNS Drug Rev 10:1–22CrossRefGoogle Scholar
  9. Hiranita T, Soto PL, Tanda G, Katz JL (2010) Reinforcing effects of sigma-receptor agonists in rats trained to self-administer cocaine. J Pharmacol Exp Ther 332:515–524CrossRefGoogle Scholar
  10. Hiranita T, Soto PL, Kohut SJ, Kopajtic T, Cao J, Newman AH, Tanda G, Katz JL (2011) Decreases in cocaine self-administration with dual inhibition of the dopamine transporter and sigma receptors. J Pharmacol Exp Ther 339:662–677CrossRefGoogle Scholar
  11. Hiranita T, Hong WC, Kopajtic T, Katz JL (2017) Sigma receptor effects of N-substituted benztropine analogs: implications for antagonism of cocaine self-administration. J Pharmacol Exp Ther 362:2–13CrossRefGoogle Scholar
  12. Hofford RS, Beckmann JS, Bardo MT (2016) Rearing environment differentially modulates cocaine self-administration after opioid pretreatment: a behavioral economic analysis. Drug Alcohol Depend 167:89–94CrossRefGoogle Scholar
  13. Hong WC, Yano H, Hiranita T, Chin FT, McCurdy CR, Su TP, Amara SG, Katz JL (2017) The sigma-1 receptor modulates dopamine transporter conformation and cocaine binding and may thereby potentiate cocaine self-administration in rats. J Biol Chem 292:11250–11261CrossRefGoogle Scholar
  14. Hursh SR (1991) Behavioral economics of drug self-administration and drug abuse policy. J Exp Anal Behav 56:377–393CrossRefGoogle Scholar
  15. Hursh SR, Roma PG (2013) Behavioral economics and empirical public policy. J Exp Anal Behav 99:98–124CrossRefGoogle Scholar
  16. Hursh SR, Silberberg A (2008) Economic demand and essential value. Psychol Rev 115:186–198CrossRefGoogle Scholar
  17. Hursh SR, Winger G (1995) Normalized demand for drugs and other reinforcers. J Exp Anal Behav 64:373–384CrossRefGoogle Scholar
  18. Hursh SR, Galuska CM, Winger G, Woods JH (2005) The economics of drug abuse: a quantitative assessment of drug demand. Mol Interv 5:20–28CrossRefGoogle Scholar
  19. Iglauer C, Woods JH (1974) Concurrent performances: reinforcement by different doses of intravenous cocaine in rhesus monkeys. J Exp Anal Behav 22:179–196CrossRefGoogle Scholar
  20. Izenwasser S, Newman AH, Katz JL (1993) Cocaine and several sigma receptor ligands inhibit dopamine uptake in rat caudate-putamen. Eur J Pharmacol 243:201–205CrossRefGoogle Scholar
  21. Johanson CE, Schuster CR (1975) A choice procedure for drug reinforcers: cocaine and methylphenidate in the rhesus monkey. J Pharmacol Exp Ther 193:676–688Google Scholar
  22. Katz JL, Libby TA, Kopajtic T, Husbands SM, Newman AH (2003) Behavioral effects of rimcazole analogues alone and in combination with cocaine. Eur J Pharmacol 468:109–119CrossRefGoogle Scholar
  23. Katz JL, Hiranita T, Hong WC, Job MO, McCurdy CR (2017) A role for sigma receptors in stimulant self-administration and addiction. Handb Exp Pharmacol 244:177–218CrossRefGoogle Scholar
  24. Kearns DN, Silberberg A (2016) Dose and elasticity of demand for self-administered cocaine in rats. Behav Pharmacol 27:289–292CrossRefGoogle Scholar
  25. Ko MC, Terner J, Hursh S, Woods JH, Winger G (2002) Relative reinforcing effects of three opioids with different durations of action. J Pharmacol Exp Ther 301:698–704CrossRefGoogle Scholar
  26. Lever JR, Fergason-Cantrell EA, Watkinson LD, Carmack TL, Lord SA, Xu R, Miller DK, Lever SZ (2016) Cocaine occupancy of sigma1 receptors and dopamine transporters in mice. Synapse 70:98–111CrossRefGoogle Scholar
  27. Macenski MJ, Meisch RA (1999) Cocaine self-administration under conditions of restricted and unrestricted food access. Exp Clin Psychopharmacol 7:324–337CrossRefGoogle Scholar
  28. Oleson EB, Roberts DC (2009) Behavioral economic assessment of price and cocaine consumption following self-administration histories that produce escalation of either final ratios or intake. Neuropsychopharmacology 34:796–804CrossRefGoogle Scholar
  29. Oleson EB, Richardson JM, Roberts DC (2011) A novel IV cocaine self-administration procedure in rats: differential effects of dopamine, serotonin, and GABA drug pre-treatments on cocaine consumption and maximal price paid. Psychopharmacology 214:567–577CrossRefGoogle Scholar
  30. Panlilio LV, Zanettini C, Barnes C, Solinas M, Goldberg SR (2013) Prior exposure to THC increases the addictive effects of nicotine in rats. Neuropsychopharmacology 38:1198–1208CrossRefGoogle Scholar
  31. Porter-Stransky KA, Bentzley BS, Aston-Jones G (2017) Individual differences in orexin-I receptor modulation of motivation for the opioid remifentanil. Addict Biol 22:303–317CrossRefGoogle Scholar
  32. Reith ME, Blough BE, Hong WC, Jones KT, Schmitt KC, Baumann MH, Partilla JS, Rothman RB, Katz JL (2015) Behavioral, biological, and chemical perspectives on atypical agents targeting the dopamine transporter. Drug Alcohol Depend 147:1–19CrossRefGoogle Scholar
  33. Sambo DO, Lin M, Owens A, Lebowitz JJ, Richardson B, Jagnarine DA, Shetty M, Rodriquez M, Alonge T, Ali M, Katz J, Yan L, Febo M, Henry LK, Bruijnzeel AW, Daws L, Khoshbouei H (2017) The sigma-1 receptor modulates methamphetamine dysregulation of dopamine neurotransmission. Nat Commun 8:2228CrossRefGoogle Scholar
  34. Soto PL, Grandy DK, Hursh SR, Katz JL (2011) Behavioral economics of food reinforcement and the effects of prefeeding, extinction, and eticlopride in dopamine D2 receptor mutant mice. Psychopharmacology 215:775–784CrossRefGoogle Scholar
  35. Soto PL, Hiranita T, Xu M, Hursh SR, Grandy DK, Katz JL (2016) Dopamine D2-like receptors and behavioral economics of food reinforcement. Neuropsychopharmacology 41(4):971–978Google Scholar
  36. Valchar M, Hanbauer I (1993) Comparison of [3H]WIN 35,428 binding, a marker for dopamine transporter, in embryonic mesencephalic neuronal cultures with striatal membranes of adult rats. J Neurochem 60:469–476CrossRefGoogle Scholar
  37. Wade-Galuska T, Galuska CM, Winger G (2011) Effects of daily morphine administration and deprivation on choice and demand for remifentanil and cocaine in rhesus monkeys. J Exp Anal Behav 95:75–89CrossRefGoogle Scholar
  38. Winger G, Hursh SR, Casey KL, Woods JH (2002) Relative reinforcing strength of three N-methyl-D-aspartate antagonists with different onsets of action. J Pharmacol Exp Ther 301:690–697CrossRefGoogle Scholar
  39. Yates JR, Bardo MT, Beckmann JS (2019) Environmental enrichment and drug value: a behavioral economic analysis in male rats. Addict Biol 24:65–75CrossRefGoogle Scholar
  40. Zanettini C, Wilkinson DS, Katz JL (2018) Behavioral economic analysis of the effects of N-substituted benztropine analogs on cocaine self-administration in rats. Psychopharmacology 235:47–58CrossRefGoogle Scholar

Copyright information

© This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2019

Authors and Affiliations

  1. 1.Psychobiology Section, Molecular Neuropsychiatry Research Branch, Intramural Research ProgramNational Institute on Drug Abuse, National Institutes of HealthBaltimoreUSA

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