, Volume 235, Issue 1, pp 47–58 | Cite as

Behavioral economic analysis of the effects of N-substituted benztropine analogs on cocaine self-administration in rats

  • Claudio Zanettini
  • Derek S. Wilkinson
  • Jonathan L. Katz
Original Investigation


Rationale and objectives

Benztropine (BZT) analogs and other atypical dopamine uptake inhibitors selectively decrease cocaine self-administration at doses that do not affect responding maintained by other reinforcers. Those effects were further characterized in the current study using a behavioral economic assessment of how response requirement (price) affects reinforcers obtained (consumption) in rats.


Two groups of rats were trained to press levers with food (45-mg pellet) or cocaine (0.32 mg/kg/injection) reinforcement under fixed-ratio (FR) 5-response schedules. In selected sessions, the FR requirement was increased (5–80) during successive 20-min components to determine demand curves, which plot consumption against price. An exponential function was fitted to the data to derive the consumption at zero price (Q 0) and the rate of decrease in consumption (essential value, EV) with increased price. The BZT analogs, AHN1-055, AHN2-005, JHW007 (3.2–10 or 17.8 mg/kg, each), vehicle, or comparison drugs (methylphenidate, ketamine), were administered i.p. before selected demand-curve determinations.


Consumption of cocaine or food decreased with increased FR requirement. Each drug shifted the demand curve rightward at the lowest doses and leftward/downward at higher doses. The effects on EV and Q 0 were greater for cocaine than for food-reinforced responding. Additionally, the effects of the BZT analogs on EV and Q 0 were greater than those obtained with a standard dopamine transport inhibitor, methylphenidate, and the NMDA antagonist, ketamine (1.0–10.0 mg/kg, each). With these latter drugs, the demand-curve parameters were affected similarly with cocaine and food-maintained responding.


The current findings, obtained using a behavioral economic assessment, suggest that BZT analogs selectively decrease the reinforcing effectiveness of cocaine.


Cocaine Behavioral economics Demand curves Essential value Self-administration Benztropine analogs Drug abuse Rats 



We thank Maryann Carrigan for administrative assistance and Li Jing for occasional help with the conduct of experiments. We thank Jianjing Cao and Amy H. Newman, of the Medicinal Chemistry Section of the NIDA Intramural Research Program, for synthesis of the BZT analogs reported herein.


The current studies were supported by funding from the National Institute on Drug Abuse (NIDA) Intramural Research Program (IRP).


  1. Agoston GE, Wu JH, Izenwasser S et al (1997) Novel N-substituted 3 alpha-[bis(4′-fluorophenyl)methoxy]tropane analogues: selective ligands for the dopamine transporter. J Med Chem 40:4329–4339. CrossRefPubMedGoogle Scholar
  2. Barrett JE (1976) Effects of alcohol, chlordiazepoxide, cocaine and pentobarbital on responding maintained under fixed-interval schedules of food or shock presentation. J Pharmacol Exp Ther 196:605–615PubMedGoogle Scholar
  3. Bentzley BS, Fender KM, Aston-Jones G (2013) The behavioral economics of drug self-administration: a review and new analytical approach for within-session procedures. Psychopharmacology 226:113–125. CrossRefPubMedGoogle Scholar
  4. 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 111:11822–11827. CrossRefPubMedPubMedCentralGoogle Scholar
  5. Campbell VC, Kopajtic TA, Newman AH, Katz JL (2005) Assessment of the influence of histaminergic actions on cocaine-like effects of 3alpha-diphenylmethoxytropane analogs. J Pharmacol Exp Ther 315:631–640. CrossRefPubMedGoogle Scholar
  6. Christensen CJ, Silberberg A, Hursh SR et al (2008a) Essential value of cocaine and food in rats: tests of the exponential model of demand. Psychopharmacology 198:221–229. CrossRefPubMedGoogle Scholar
  7. Christensen CJ, Silberberg A, Hursh SR et al (2008b) Demand for cocaine and food over time. Pharmacol Biochem Behav 91:209–216. CrossRefPubMedPubMedCentralGoogle Scholar
  8. Czoty PW, Martelle SE, Gould RW, Nader MA (2013) Effects of chronic methylphenidate on cocaine self-administration under a progressive-ratio schedule of reinforcement in rhesus monkeys. J Pharmacol Exp Ther 345:374–382. CrossRefPubMedPubMedCentralGoogle Scholar
  9. Desai RI, Kopajtic TA, French D et al (2005a) Relationship between in vivo occupancy at the dopamine transporter and behavioral effects of cocaine, GBR 12909 [1-{2-[Bis-(4-fluorophenyl)methoxy]ethyl}-4-(3-phenylpropyl)piperazine], and Benztropine analogs. J Pharmacol Exp Ther 315:397–404. CrossRefPubMedGoogle Scholar
  10. Desai RI, Kopajtic TA, Koffarnus M et al (2005b) Identification of a dopamine transporter ligand that blocks the stimulant effects of cocaine. J Neurosci 25:1889–1893. CrossRefPubMedGoogle Scholar
  11. Desai RI, Grandy DK, Lupica CR, Katz JL (2014) Pharmacological characterization of a dopamine transporter ligand that functions as a cocaine antagonist. J Pharmacol Exp Ther 348:106–115. CrossRefPubMedPubMedCentralGoogle Scholar
  12. Dews PB (1964) A behavioral effect of amobarbital. Naunyn-Schmiedebergs Arch Für Exp Pathol Pharmakol 248:296–307Google Scholar
  13. Ferragud A, Velázquez-Sánchez C, Hernández-Rabaza V et al (2009) A dopamine transport inhibitor with markedly low abuse liability suppresses cocaine self-administration in the rat. Psychopharmacology 207:281–289. CrossRefPubMedGoogle Scholar
  14. Ferragud A, Velázquez-Sánchez C, Canales JJ (2014) Modulation of methamphetamine’s locomotor stimulation and self-administration by JHW 007, an atypical dopamine reuptake blocker. Eur J Pharmacol 731:73–79. CrossRefPubMedGoogle Scholar
  15. Ferster CB, Skinner BF (1957) Schedules of reinforcement. Appleton-Century-Crofts, New YorkGoogle Scholar
  16. Foster TM, Kinloch J, Poling A (2011) The effects of session length on demand functions generated using FR schedules. J Exp Anal Behav 95:289. CrossRefPubMedPubMedCentralGoogle Scholar
  17. Grabowski J, Shearer J, Merrill J, Negus SS (2004) Agonist-like, replacement pharmacotherapy for stimulant abuse and dependence. Addict Behav 29:1439–1464. CrossRefPubMedGoogle Scholar
  18. Hiranita T, Soto PL, Newman AH, Katz JL (2009) Assessment of reinforcing effects of benztropine analogs and their effects on cocaine self-administration in rats: comparisons with monoamine uptake inhibitors. J Pharmacol Exp Ther 329:677–686. CrossRefPubMedPubMedCentralGoogle Scholar
  19. 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 332:515–524. CrossRefPubMedPubMedCentralGoogle Scholar
  20. Hiranita T, Soto PL, Kohut SJ et al (2011) Decreases in cocaine self-administration with dual inhibition of the dopamine transporter and σ receptors. J Pharmacol Exp Ther 339:662–677. CrossRefPubMedPubMedCentralGoogle Scholar
  21. Hiranita T, Kohut SJ, Soto PL et al (2014) Preclinical efficacy of N-substituted benztropine analogs as antagonists of methamphetamine self-administration in rats. J Pharmacol Exp Ther 348:174–191. CrossRefPubMedPubMedCentralGoogle Scholar
  22. Hiranita T, Hong WC, Kopajtic T, Katz JL (2017) σ receptor effects of N-substituted benztropine analogs: implications for antagonism of cocaine self-administration. J Pharmacol Exp Ther 362:2–13. CrossRefPubMedPubMedCentralGoogle Scholar
  23. Hong WC, Yano H, Hiranita T et al (2017) The sigma-1 receptor modulates dopamine transporter conformation and cocaine binding and may thereby potentiate cocaine self-administration in rats. J Biol Chem 292:11250–11261. CrossRefPubMedGoogle Scholar
  24. Howell LL, Negus SS (2014) Chapter four—monoamine transporter inhibitors and substrates as treatments for stimulant abuse. In: Dwoskin LP (ed) Advances in pharmacology. Academic Press, Cambridge, pp 129–176Google Scholar
  25. Hursh SR (1984) Behavioral economics. J Exp Anal Behav 42:435–452. CrossRefPubMedPubMedCentralGoogle Scholar
  26. Hursh SR (2014) Behavioral economics and the analysis of consumption and choice. In: McSweeney FK, Murphy ES (eds) The Wiley Blackwell handbook of operant and classical conditioning. John Wiley & Sons, Ltd, Chichester, pp 275–305CrossRefGoogle Scholar
  27. Hursh SR, Roma PG (2013) Behavioral economics and empirical public policy. J Exp Anal Behav 99:98–124. CrossRefPubMedGoogle Scholar
  28. Hursh SR, Silberberg A (2008) Economic demand and essential value. Psychol Rev 115:186–198. CrossRefPubMedGoogle Scholar
  29. Hursh SR, Raslear TG, Shurtleff D et al (1988) A cost-benefit analysis of demand for food. J Exp Anal Behav 50:419–440. CrossRefPubMedPubMedCentralGoogle Scholar
  30. Hursh SR, Galuska CM, Winger G, Woods JH (2005) The economics of drug abuse: a quantitative assessment of drug demand. Mol Interv 5:20–28. CrossRefPubMedGoogle Scholar
  31. Katz JL, Izenwasser S, Kline RH et al (1999) Novel 3α-diphenylmethoxytropane analogs: selective dopamine uptake inhibitors with behavioral effects distinct from those of cocaine. J Pharmacol Exp Ther 288:302–315PubMedGoogle Scholar
  32. Kearns DN, Silberberg A (2016) Dose and elasticity of demand for self-administered cocaine in rats. Behav Pharmacol 27:289–292. CrossRefPubMedPubMedCentralGoogle Scholar
  33. Kearns DN, Kim JS, Tunstall BJ, Silberberg A (2016) Essential values of cocaine and non-drug alternatives predict the choice between them. Addict Biol.
  34. Kohut SJ, Hiranita T, Hong S-K et al (2014) Preference for distinct functional conformations of the dopamine transporter alters the relationship between subjective effects of cocaine and stimulation of mesolimbic dopamine. Biol Psychiatry 76:802–809. CrossRefPubMedPubMedCentralGoogle Scholar
  35. Kopajtic TA, Liu Y, Surratt CK et al (2010) Dopamine transporter-dependent and -independent striatal binding of the benztropine analog JHW 007, a cocaine antagonist with low abuse liability. J Pharmacol Exp Ther 335:703–714. CrossRefPubMedPubMedCentralGoogle Scholar
  36. Lagorio CH, Winger G (2014) Random ratio schedules produce greater demand for i.v. drug administration than fixed ratio schedules in rhesus monkeys. Psychopharmacology 231:2981–2988. CrossRefPubMedPubMedCentralGoogle Scholar
  37. Lenoir M, Serre F, Cantin L, Ahmed SH (2007) Intense sweetness surpasses cocaine reward. PLoS One 2:e698. CrossRefPubMedPubMedCentralGoogle Scholar
  38. Levin FR, Evans SM, Brooks DJ, Garawi F (2007) Treatment of cocaine dependent treatment seekers with adult ADHD: double-blind comparison of methylphenidate and placebo. Drug Alcohol Depend 87:20–29. CrossRefPubMedGoogle Scholar
  39. Li S-M, Newman AH, Katz JL (2005) Place conditioning and locomotor effects of N-substituted, 4′,4″-difluorobenztropine analogs in rats. J Pharmacol Exp Ther 313:1223–1230. CrossRefPubMedGoogle Scholar
  40. Li L, Hiranita T, Hayashi S et al (2013) The stereotypy-inducing effects of N-substituted benztropine analogs alone and in combination with cocaine do not account for their blockade of cocaine self-administration. Psychopharmacology 225:733–742. CrossRefPubMedGoogle Scholar
  41. Loland CJ, Desai RI, Zou M-F et al (2008) Relationship between conformational changes in the dopamine transporter and cocaine-like subjective effects of uptake inhibitors. Mol Pharmacol 73:813–823. CrossRefPubMedGoogle Scholar
  42. Macenski MJ, Meisch RA (1999) Cocaine self-administration under conditions of restricted and unrestricted food access. Exp Clin Psychopharmacol 7:324–337. CrossRefPubMedGoogle Scholar
  43. McKearney JW (1974) Effects of d-amphetamine, morphine and chlorpromazine on responding under fixed-interval schedules of food presentation or electric shock presentation. J Pharmacol Exp Ther 190:141–153PubMedGoogle Scholar
  44. McMillan DE, Katz JL (2002) Continuing implications of the early evidence against the drive-reduction hypothesis of the behavioral effects of drugs. Psychopharmacology 163:251–264. CrossRefPubMedGoogle Scholar
  45. Nader MA, Hedeker D, Woolverton WL (1993) Behavioral economics and drug choice: effects of unit price on cocaine self-administration by monkeys. Drug Alcohol Depend 33:193–199. CrossRefPubMedGoogle Scholar
  46. Newman AH, Kline RH, Allen AC et al (1995) Novel 4′-substituted and 4′,4″-disubstituted 3 alpha-(diphenylmethoxy)tropane analogs as potent and selective dopamine uptake inhibitors. J Med Chem 38:3933–3940CrossRefPubMedGoogle Scholar
  47. Oleson EB, Roberts DCS (2009) Behavioral economic assessment of price and cocaine consumption following self-administration histories that produce escalation of either final ratios or intake. Neuropsychopharmacology 34:796–804. CrossRefPubMedGoogle Scholar
  48. Panlilio LV, Zanettini C, Barnes C et al (2013) Prior exposure to THC increases the addictive effects of nicotine in rats. Neuropsychopharmacology 38:1198–1208. CrossRefPubMedPubMedCentralGoogle Scholar
  49. Pitts RC (2014) Reconsidering the concept of behavioral mechanisms of drug action. J Exp Anal Behav 101:422–441. CrossRefPubMedGoogle Scholar
  50. R Core Team (2013) R: a language and environment for statistical computing. Foundation for Statistical Computing, Vienna Google Scholar
  51. Raje S, Dowling TC, Eddington ND (2002) Determination of the benztropine analog AHN-1055, a dopamine uptake inhibitor, in rat plasma and brain by high-performance liquid chromatography with ultraviolet absorbance detection. J Chromatogr B Analyt Technol Biomed Life Sci 768:305–313CrossRefPubMedGoogle Scholar
  52. Reith ME, Berfield JL, Wang LC et al (2001) The uptake inhibitors cocaine and benztropine differentially alter the conformation of the human dopamine transporter. J Biol Chem 276:29012–29018. CrossRefPubMedGoogle Scholar
  53. Reith MEA, Blough BE, Hong WC et al (2015) Behavioral, biological, and chemical perspectives on atypical agents targeting the dopamine transporter. Drug Alcohol Depend 147:1–19. CrossRefPubMedGoogle Scholar
  54. 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 215:775–784. CrossRefPubMedPubMedCentralGoogle Scholar
  55. Soto PL, Hiranita T, Grandy DK, Katz JL (2014) Choice for response alternatives differing in reinforcement frequency in dopamine D2 receptor mutant and Swiss-Webster mice. Psychopharmacology 231:3169–3177. CrossRefPubMedGoogle Scholar
  56. Tanda G, Ebbs AL, Kopajtic TA et al (2007) Effects of muscarinic M1 receptor blockade on cocaine-induced elevations of brain dopamine levels and locomotor behavior in rats. J Pharmacol Exp Ther 321:334–344. CrossRefPubMedGoogle Scholar
  57. Tanda G, Newman AH, Ebbs AL et al (2009a) Combinations of cocaine with other dopamine uptake inhibitors: assessment of additivity. J Pharmacol Exp Ther 330:802–809. CrossRefPubMedPubMedCentralGoogle Scholar
  58. Tanda G, Newman AH, Katz JL (2009b) Discovery of drugs to treat cocaine dependence: behavioral and neurochemical effects of atypical dopamine transport inhibitors. In: Enna SJ, Williams M (eds) Advances in pharmacology. Academic Press, Cambridge, pp 253–289Google Scholar
  59. Townsend EA, Beloate LN, Huskinson SL et al (2015) Corn oil, but not cocaine, is a more effective reinforcer in obese than in lean Zucker rats. Physiol Behav 143:136–141. CrossRefPubMedPubMedCentralGoogle Scholar
  60. Velázquez-Sánchez C, Ferragud A, Hernández-Rabaza V et al (2009) The dopamine uptake inhibitor 3α-[bis(4′-fluorophenyl)metoxy]-tropane reduces cocaine-induced early-gene expression, locomotor activity, and conditioned reward. Neuropsychopharmacology 34:2497–2507. CrossRefPubMedGoogle Scholar
  61. Velázquez-Sánchez C, Ferragud A, Murga J et al (2010) The high affinity dopamine uptake inhibitor, JHW 007, blocks cocaine-induced reward, locomotor stimulation and sensitization. Eur Neuropsychopharmacol 20:501–508. CrossRefPubMedGoogle Scholar
  62. Wade-Galuska T, Winger G, Woods JH (2007) A behavioral economic analysis of cocaine and remifentanil self-administration in rhesus monkeys. Psychopharmacology 194:563–572. CrossRefPubMedGoogle Scholar
  63. 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 95:75–89. CrossRefPubMedPubMedCentralGoogle Scholar
  64. Wickham H (2007) Reshaping data with the reshape package. J Stat Softw 21(12):1–20 CrossRefGoogle Scholar
  65. Winger G, Woods JH, Hursh SR (1996) Behavior maintained by alfentanil or nalbuphine in rhesus monkeys: fixed-ratio and time-out changes to establish demand curves and relative reinforcing effectiveness. Exp Clin Psychopharmacol 4:131–140. CrossRefGoogle Scholar

Copyright information

© US Government (outside the USA) 2017

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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