Skip to main content
SpringerLink
Log in

A dopamine transport inhibitor with markedly low abuse liability suppresses cocaine self-administration in the rat

Psychopharmacology volume 207, pages 281–289 (2009)Cite this article

Abstract

Rationale

N-substituted benztropine analogs are potent dopamine uptake inhibitors that display pharmacokinetic/dynamic properties consistent with the profile of a substitute medication for cocaine addiction.

Objectives

The purpose of the present experiments was to characterize in rats the addictive-like properties of one such analog, 3α-[bis(4′-fluorophenyl)methoxy]-tropane (AHN-1055), incorporating probes of its stimulant and incentive/motivational effects and of its ability to influence cocaine self-administration.

Methods

We used open field activity and drug self-administration assays. To examine the effects of AHN-1055 on locomotor behavior, the analog was administered alone (0, 1, 3, and 10 mg/kg intraperitoneally) and in combination with cocaine (15 mg/kg i.p.). The influence of AHN-1055 on cocaine's intake was studied by administering the analog (0, 3, and 10 mg/kg i.p.) before the start of the self-administration sessions. To compare the addictive-like properties of AHN-1055 and cocaine, progressive ratio performance and abstinence-induced context-conditioned relapse were evaluated.

Results

AHN-1055 evoked robust and sustained locomotor activity when administered alone and increased cocaine-induced locomotor stimulation. Notably, the analog showed by comparison to cocaine weak reinforcing efficacy in a modified progressive ratio schedule of drug reinforcement, and contrary to cocaine, it showed no ability to promote context-conditioned relapse to drug seeking following stable self-administration and abstinence. Further, AHN-1055 treatment blocked cocaine intake dose-dependently in rats with a steady history of cocaine self-administration without reducing responding for sucrose, a natural reward.

Conclusions

These findings demonstrate essential psychopharmacological differences between AHN-1055 and cocaine and highlight important properties of the analog as a possible pharmacotherapy in cocaine addiction.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  • Agoston GE, Wu JH, Izenwasser S, George C, Katz J, Kline RH, Newman AH (1997) Novel N-substituted 3 alpha-[bis(4'-fluorophenyl)methoxy]tropane analogues: selective ligands for the dopamine transporter. J Med Chem 40:4329–4339

    Article  CAS  PubMed  Google Scholar 

  • Ahmed SH, Koob GF (2004) Changes in response to a dopamine receptor antagonist in rats with escalating cocaine intake. Psychopharmacology (Berl) 172:450–454

    Article  CAS  Google Scholar 

  • Beecher MD, Jackson DE (1976) Rate-dependent effect of amphetamine in rats: extension to between-subjects effect. Psychopharmacologia 46:307–309

    Article  CAS  PubMed  Google Scholar 

  • Beuming T, Kniazeff J, Bergmann ML, Shi L, Gracia L, Raniszewska K, Newman AH, Javitch JA, Weinstein H, Gether U, Loland CJ (2008) The binding sites for cocaine and dopamine in the dopamine transporter overlap. Nat Neurosci 11:780–789

    Article  CAS  PubMed  Google Scholar 

  • Botly LC, Burton CL, Rizos Z, Fletcher PJ (2008) Characterization of methylphenidate self-administration and reinstatement in the rat. Psychopharmacology (Berl) 199:55–66

    Article  CAS  Google Scholar 

  • Briscoe RJ, Vanecek SA, Vallett M, Baird TJ, Holloway FA, Gauvin DV (1998) Reinforcing effects of caffeine, ephedrine, and their binary combination in rats. Pharmacol Biochem Behav 60:685–693

    Article  CAS  PubMed  Google Scholar 

  • Carrigan KA, Dykstra LA (2007) Behavioral effects of morphine and cocaine in M1 muscarinic acetylcholine receptor-deficient mice. Psychopharmacology (Berl) 191:985–993

    Article  CAS  Google Scholar 

  • Chen N, Reith ME (2007) Substrates and inhibitors display different sensitivity to expression level of the dopamine transporter in heterologously expressing cells. J Neurochem 101:377–388

    Article  CAS  PubMed  Google Scholar 

  • Chen N, Zhen J, Reith ME (2004) Mutation of Trp84 and Asp313 of the dopamine transporter reveals similar mode of binding interaction for GBR12909 and benztropine as opposed to cocaine. J Neurochem 89:853–864

    Article  CAS  PubMed  Google Scholar 

  • Crespo JA, Sturm K, Saria A, Zernig G (2006) Activation of muscarinic and nicotinic acetylcholine receptors in the nucleus accumbens core is necessary for the acquisition of drug reinforcement. J Neurosci 26:6004–6010

    Article  CAS  PubMed  Google Scholar 

  • Dar DE, Mayo C, Uhl GR (2005) The interaction of methylphenidate and benztropine with the dopamine transporter is different than other substrates and ligands. Biochem Pharmacol 70:461–469

    Article  CAS  PubMed  Google Scholar 

  • Davids E, Gastpar M (2004) Buprenorphine in the treatment of opioid dependence. Eur Neuropsychopharmacol 14:209–216

    Article  CAS  PubMed  Google Scholar 

  • Desai RI, Kopajtic TA, French D, Newman AH, Katz JL (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

    Article  CAS  PubMed  Google Scholar 

  • Desai RI, Kopajtic TA, Koffarnus M, Newman AH, Katz JL (2005b) Identification of a dopamine transporter ligand that blocks the stimulant effects of cocaine. J Neurosci 25:1889–1893

    Article  CAS  PubMed  Google Scholar 

  • Dutta AK, Zhang S, Kolhatkar R, Reith ME (2003) Dopamine transporter as target for drug development of cocaine dependence medications. Eur J Pharmacol 479:93–106

    Article  CAS  PubMed  Google Scholar 

  • Gorelick DA, Gardner EL, Xi ZX (2004) Agents in development for the management of cocaine abuse. Drugs 64:1547–1573

    Article  CAS  PubMed  Google Scholar 

  • Grabowski J, Roache JD, Schmitz JM, Rhoades H, Creson D, Korszun A (1997) Replacement medication for cocaine dependence: methylphenidate. J Clin Psychopharmacol 17:485–488

    Article  CAS  PubMed  Google Scholar 

  • Grabowski J, Shearer J, Merrill J, Negus SS (2004) Agonist-like, replacement pharmacotherapy for stimulant abuse and dependence. Addict Behav 29:1439–1464

    Article  PubMed  Google Scholar 

  • Harris RA, Snell D, Loh HH (1978) Effects of d-amphetamine, monomethoxyamphetamines and hallucinogens on schedule-controlled behavior. J Pharmacol Exp Ther 204:103–117

    CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Huang X, Zhan CG (2007) How dopamine transporter interacts with dopamine: insights from molecular modeling and simulation. Biophys J 93:3627–3639

    Article  CAS  PubMed  Google Scholar 

  • Karila L, Gorelick D, Weinstein A, Noble F, Benyamina A, Coscas S, Blecha L, Lowenstein W, Martinot JL, Reynaud M, Lepine JP (2008) New treatments for cocaine dependence: a focused review. Int J Neuropsychopharmacol 11:425–438

    Article  CAS  PubMed  Google Scholar 

  • Katz JL, Newman AH, Izenwasser S (1997) Relations between heterogeneity of dopamine transporter binding and function and the behavioral pharmacology of cocaine. Pharmacol Biochem Behav 57:505–512

    Article  CAS  PubMed  Google Scholar 

  • Katz JL, Agoston GE, Alling KL, Kline RH, Forster MJ, Woolverton WL, Kopajtic TA, Newman AH (2001) Dopamine transporter binding without cocaine-like behavioral effects: synthesis and evaluation of benztropine analogs alone and in combination with cocaine in rodents. Psychopharmacology (Berl) 154:362–374

    Article  CAS  Google Scholar 

  • Katz JL, Kopajtic TA, Agoston GE, Newman AH (2004) Effects of N-substituted analogs of benztropine: diminished cocaine-like effects in dopamine transporter ligands. J Pharmacol Exp Ther 309:650–660

    Article  CAS  PubMed  Google Scholar 

  • Koob GF, Le HT, Creese I (1987) The D1 dopamine receptor antagonist SCH 23390 increases cocaine self-administration in the rat. Neurosci Lett 79:315–320

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Li SM, 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

    Article  CAS  PubMed  Google Scholar 

  • Lile JA, Morgan D, Birmingham AM, Davies HM, Nader MA (2004) Effects of the dopamine reuptake inhibitor PTT on reinstatement and on food- and cocaine-maintained responding in rhesus monkeys. Psychopharmacology (Berl) 174:246–253

    Article  CAS  Google Scholar 

  • Lile JA, Wang Z, Woolverton WL, France JE, Gregg TC, Davies HM, Nader MA (2003) The reinforcing efficacy of psychostimulants in rhesus monkeys: the role of pharmacokinetics and pharmacodynamics. J Pharmacol Exp Ther 307:356–366

    Article  CAS  PubMed  Google Scholar 

  • Loland CJ, Desai RI, Zou MF, Cao J, Grundt P, Gerstbrein K, Sitte HH, Newman AH, Katz JL, Gether U (2008) Relationship between conformational changes in the dopamine transporter and cocaine-like subjective effects of uptake inhibitors. Mol Pharmacol 73:813–823

    Article  CAS  PubMed  Google Scholar 

  • Minozzi S, Amato L, Davoli M, Farrell M, Lima Reisser AA, Pani PP, Silva de LM, Soares B, Vecchi S (2008) Anticonvulsants for cocaine dependence. Cochrane Database Syst Rev CD006754

  • Negus SS, Mello NK, Lamas X, Mendelson JH (1996) Acute and chronic effects of flupenthixol on the discriminative stimulus and reinforcing effects of cocaine in rhesus monkeys. J Pharmacol Exp Ther 278:879–890

    CAS  PubMed  Google Scholar 

  • Negus SS, Mello NK, Kimmel HL, Howell LL, Carroll FI (2008) Effects of the monoamine uptake inhibitors RTI-112 and RTI-113 on cocaine- and food-maintained responding in rhesus monkeys. Pharmacol.Biochem.Behav

  • Newman AH, Agoston GE (1998) Novel benztropine [3a-(diphenylmethoxy)tropane] analogs as probes for the dopamine transporter. Curr Med Chem 5:305–319

    CAS  PubMed  Google Scholar 

  • Orson FM, Kinsey BM, Singh RA, Wu Y, Gardner T, Kosten TR (2008) Substance abuse vaccines. Ann NY Acad Sci 1141:257–269

    Article  CAS  PubMed  Google Scholar 

  • Preti A (2000) Vanoxerine National Institute on Drug Abuse. Curr Opin Investig Drugs 1:241–251

    CAS  PubMed  Google Scholar 

  • Raje S, Cao J, Newman AH, Gao H, Eddington ND (2003) Evaluation of the blood-brain barrier transport, population pharmacokinetics, and brain distribution of benztropine analogs and cocaine using in vitro and in vivo techniques. J Pharmacol Exp Ther 307:801–808

    Article  CAS  PubMed  Google Scholar 

  • Raje S, Cornish J, Newman AH, Cao J, Katz JL, Eddington ND (2005) Pharmacodynamic assessment of the benztropine analogues AHN-1055 and AHN-2005 using intracerebral microdialysis to evaluate brain dopamine levels and pharmacokinetic/pharmacodynamic modeling. Pharm Res 22:603–612

    Article  CAS  PubMed  Google Scholar 

  • Richardson NR, Roberts DC (1996) Progressive ratio schedules in drug self-administration studies in rats: a method to evaluate reinforcing efficacy. J Neurosci Methods 66:1–11

    Article  CAS  PubMed  Google Scholar 

  • Roberts DC (1993) Self-administration of GBR 12909 on a fixed ratio and progressive ratio schedule in rats. Psychopharmacology (Berl) 111:202–206

    Article  CAS  Google Scholar 

  • Rothman RB, Baumann MH, Prisinzano TE, Newman AH (2008) Dopamine transport inhibitors based on GBR12909 and benztropine as potential medications to treat cocaine addiction. Biochem Pharmacol 75:2–16

    Article  CAS  PubMed  Google Scholar 

  • Rush CR, Essman WD, Simpson CA, Baker RW (2001) Reinforcing and subject-rated effects of methylphenidate and d-amphetamine in non-drug-abusing humans. J Clin Psychopharmacol 21:273–286

    Article  CAS  PubMed  Google Scholar 

  • Sagvolden T, Slatta K, Arntzen E (1988) Low doses of methylphenidate (Ritalin) may alter the delay-of-reinforcement gradient. Psychopharmacology (Berl) 95:303–312

    Article  CAS  Google Scholar 

  • Sanger DJ, Blackman DE (1976) Rate-dependent effects of drugs: a review of the literature. Pharmacol Biochem Behav 4:73–83

    Article  CAS  PubMed  Google Scholar 

  • Sofuoglu M, Kosten TR (2005) Novel approaches to the treatment of cocaine addiction. CNS Drugs 19:13–25

    Article  CAS  PubMed  Google Scholar 

  • Stafford D, Rice KC, Lewis DB, Glowa JR (2000) Response requirements and unit dose modify the effects of GBR 12909 on cocaine-maintained behavior. Exp Clin Psychopharmacol 8:539–548

    Article  CAS  PubMed  Google Scholar 

  • Uchtenhagen A (2003) Substitution management in opioid dependence. J Neural Transm Suppl 33–60

  • Ukairo OT, Bondi CD, Newman AH, Kulkarni SS, Kozikowski AP, Pan S, Surratt CK (2005) Recognition of benztropine by the dopamine transporter (DAT) differs from that of the classical dopamine uptake inhibitors cocaine, methylphenidate, and mazindol as a function of a DAT transmembrane 1 aspartic acid residue. J Pharmacol Exp Ther 314:575–583

    Article  CAS  PubMed  Google Scholar 

  • Vaughan RA, Agoston GE, Lever JR, Newman AH (1999) Differential binding of tropane-based photoaffinity ligands on the dopamine transporter. J Neurosci 19:630–636

    CAS  PubMed  Google Scholar 

  • Woolverton WL, Hecht GS, Agoston GE, Katz JL, Newman AH (2001) Further studies of the reinforcing effects of benztropine analogs in rhesus monkeys. Psychopharmacology (Berl) 154:375–382

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by grants to J.J.C. from Plan Nacional de Biomedicina (Ministerio de Ciencia e Innovación), Plan Nacional Sobre Drogas (Ministerio de Sanidad y Consumo), Red de Trastornos Adictivos (RETICS, Instituto de Salud Carlos III), and FEPAD (Fundación para el Estudio y Prevención de las Adicciones y Drogodependencias, Generalitat Valenciana). A. Ferragud is in receipt of a graduate FPU (Formación del Personal Universitario) contract studentship from the Ministerio de Ciencia e Innovación of Spain. We thank Alexandra Arcusa for technical assistance.

Author information

Authors and Affiliations

  1. Biopsychology and Comparative Neuroscience Group, Cavanilles Institute (ICBiBE), University of Valencia-General Foundation & Red de Trastornos Adictivos (RETICS), Polígono de la Coma s/n, Paterna, 46980, Valencia, Spain

    Antonio Ferragud, Clara Velázquez-Sánchez & Vicente Hernández-Rabaza

  2. Department of Pharmacy and Pharmaceutical Technology, University of Valencia, Valencia, Spain

    Amparo Nácher & Virginia Merino

  3. Department of Organic and Inorganic Chemistry, University Jaime I, Castellón, Spain

    Miguel Cardá & Juan Murga

  4. Biopsychology and Comparative Neuroscience Group, Cavanilles Institute (ICBiBE), University of Valencia-General Foundation & Red de Trastornos Adictivos (RETICS), & Faculty of Medicine, Catholic University of Valencia, Polígono de la Coma s/n, Paterna, 46980, Valencia, Spain

    Juan J. Canales

Authors
  1. Antonio Ferragud
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Clara Velázquez-Sánchez
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Vicente Hernández-Rabaza
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Amparo Nácher
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Virginia Merino
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Miguel Cardá
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Juan Murga
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Juan J. Canales
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Juan J. Canales.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Ferragud, A., Velázquez-Sánchez, C., Hernández-Rabaza, V. et al. A dopamine transport inhibitor with markedly low abuse liability suppresses cocaine self-administration in the rat. Psychopharmacology 207, 281–289 (2009). https://doi.org/10.1007/s00213-009-1653-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-009-1653-x

Keywords

search

Navigation