Skip to main content

Advertisement

SpringerLink
Log in

Aripiprazole maintenance increases smoked cocaine self-administration in humans

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

Partial dopamine receptor agonists have been proposed as candidate pharmacotherapies for cocaine dependence.

Objective

This 42-day, within-subject, human laboratory study assessed how maintenance on aripiprazole, a partial D2 receptor agonist, influenced smoked cocaine self-administration, cardiovascular measures, subjective effects, and cocaine craving in nontreatment-seeking, cocaine-dependent volunteers.

Methods

In order to achieve steady-state concentrations, participants (n = 8 men) were administered placebo and aripiprazole (15 mg/day) capsules in counter-balanced order for 21 days. A smoked cocaine dose–response curve (0, 12, 25, 50 mg) was determined twice under placebo and aripiprazole maintenance. Sessions comprised a “sample” trial, when participants smoked the cocaine dose available that session, and five choice trials, when they responded on a progressive-ratio schedule of reinforcement to receive the cocaine dose or receive $5.00.

Results

Cocaine’s reinforcing, subjective, and cardiovascular effects were dose-dependent. Aripiprazole significantly increased cocaine (12, 25 mg) self-administration. Following a single administration of cocaine (25 mg), aripiprazole decreased ratings of how much participants would pay for that dose. Following repeated cocaine (50 mg) self-administration, aripiprazole decreased ratings of cocaine quality, craving, and good drug effect as compared to placebo.

Conclusions

These data suggest that aripiprazole may have increased self-administration to compensate for a blunted subjective cocaine effect. Overall, the findings do not suggest aripiprazole would be useful for treating cocaine dependence.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Amato L, Minozzi S, Pani PP, Davoli M (2010) Antipsychotic medications for cocaine dependence (Review). Cochrane Libr 3:1–37

    Google Scholar 

  • Beresford TP, Clapp L, Martin B, Wiberg JL, Alfers J, Beresford HF (2005) Aripiprazole in schizophrenia with cocaine dependence: a pilot study. J Clin Psychopharmacol 25:363–366

    Article  PubMed  CAS  Google Scholar 

  • Bergman J (2008) Medications for stimulant abuse: agonist-based strategies and preclinical evaluation of the mixed-action D2 partial agonist aripiprazole (Abilify®). Exp Clin Psychopharmacol 16:475–483

    Article  PubMed  CAS  Google Scholar 

  • Berman RM, Marcus RN, Swanink R, McQuade R, Carson WH, Corey-Lisle PK, Khan A (2007) The efficacy and safety of aripiprazole as adjunctive therapy in major depressive disorder: a multicenter, randomized, double-blind, placebo-controlled study. J Clin Psychiatr 68:843–853

    Article  CAS  Google Scholar 

  • Brown ES, Jeffress J, Liggin JD, Garza M, Beard L (2005) Switching outpatients with bipolar or schizoaffective disorders and substance abuse from their current antipsychotic to aripiprazole. J Clin Psychiatr 66:756–760

    Article  Google Scholar 

  • Cahill K, Stead L, Lancaster T (2009) A preliminary benefit-risk assessment of varenicline in smoking cessation. Drug Saf 2:119–135

    Article  Google Scholar 

  • Comer SD, Sullivan MA, Yu E, Rothenberg JL, Kleber HD, Kampman K, Dackis C, O'Brien CP (2006) Injectable, sustained-release naltrexone for the treatment of opioid dependence: a randomized, placebo-controlled trial. Arch Gen Psychiatr 63:210–218

    Article  PubMed  CAS  Google Scholar 

  • Crits-Christoph P, Siqueland L, Blaine J, Frank A, Luborsky L, Onken LS, Muenz LR, Thase ME, Weiss RD, Gastfriend DR, Woody GE, Barber JP, Butler SF, Daley D, Salloum I, Bishop S, Najavits LM, Lis J, Mercer D, Griffin ML, Moras K, Beck AT (1999) Psychosocial treatments for cocaine dependence: National Institute on Drug Abuse Collaborative Cocaine Treatment Study. Arch Gen Psychiatr 56:493–502

    Article  PubMed  CAS  Google Scholar 

  • Dutra L, Stathopoulou G, Basden SL, Leyro TM, Powers MB, Otto MW (2008) A meta-analytic review of psychosocial interventions for substance abuse use disorders. Am J Psychiatr 165:179–187

    Article  PubMed  Google Scholar 

  • Evans SM, Haney M, Foltin RW (2002) The effects of smoked cocaine during the follicular and luteal phases of the menstrual cycle in women. Psychopharmacology (Berl) 159:397–406

    Google Scholar 

  • Feltenstein MW, Altar CA, See RE (2007) Aripiprazole blocks reinstatement of cocaine seeking in an animal model of relapse. Biol Psychiatr 61:582–590

    Article  CAS  Google Scholar 

  • Feltenstein MW, Do PH, See RE (2009) Repeated aripiprazole administration attenuates cocaine seeking in a rat model of relapse. Psychopharmacology 207:401–411

    Article  PubMed  CAS  Google Scholar 

  • Grabowski JA, 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 

  • Haney M, Spealman R (2008) Controversies in translational research: drug self-administration. Psychopharmacology 199:403–419

    Article  PubMed  CAS  Google Scholar 

  • Haney M, Ward AS, Foltin RW, Fischman MW (2001) Effects of ecopipam, a selective dopamine D1 antagonist, on smoked cocaine self-administration by humans. Psychopharmacology 155:330–337

    Article  PubMed  CAS  Google Scholar 

  • Haney M, Gunderson EW, Jiang H, Collins ED, Foltin RW (2010) Cocaine-specific antibodies blunt the subjective effects of smoked cocaine in humans. Biol Psychiatr 67:59–65

    Article  CAS  Google Scholar 

  • Howell LL, Kimmel HL (2008) Monoamine transporters and psychostimulant addition. Biochem Pharmacol 75:196–217

    Article  PubMed  CAS  Google Scholar 

  • Inoue T, Domae M, Yamada K, Furukawa T (1996) Effects of the novel antipsychotic agent 7-(4-[4-(2, 3-dichlorophenyl)-1-piperazinyl]butyloxy)-3, 4-dihydro−2(1H)-quinolinone (OPC-14597) on prolactin release from the rat anterior pituitary gland. J Pharmacol Exp Ther 277:137–143

    PubMed  CAS  Google Scholar 

  • Johnson RE, Chutuape MA, Strain EC, Walsh SL, Stitzer ML, Bigelow GE (2000) A comparison of levomethadyl acetate, buprenorphine, and methadone for opioid dependence. N Engl J Med 343:1290–1297

    Article  PubMed  CAS  Google Scholar 

  • Keck PE, Marcus R, Tourkodimitris S, Ali M, Liebeskind A, Saha A, Ingentio G (2003) A placebo-controlled, double-blind study of the efficacy and safety of aripiprazole in patients with acute bipolar mania. Am J Psychiatr 160:1651–1658

    Article  PubMed  Google Scholar 

  • Lawler CP, Prioleau C, Lewis MM, Mak C, Jiang D, Schetz JA, Gonzalez AM, Sibley DR, Mailman RB (1999) Interactions of the novel antipsychotic aripiprazole (OPC-14597) with dopamine and serotonin receptor subtypes. Neuropsychopharmacology 20:612–627

    Article  PubMed  CAS  Google Scholar 

  • Lieberman JA (2004) Dopamine partial agonists: a new class of antipsychotic. CNS Drugs 18:251–267

    Article  PubMed  CAS  Google Scholar 

  • Lile JA, Stoops WW, Vansickel AR, Glaser PE, Hays LR, Rush CR (2005) Aripiprazole attenuates the discriminative-stimulus and subject-rated effects of D-amphetamine in humans. Neuropsychopharmacology 30:2103–2114

    Article  PubMed  CAS  Google Scholar 

  • Lile JA, Stoops WW, Hays LR, Rush CR (2008) The safety, tolerability, and subject-rated effects of acute intranasal cocaine administration during aripiprazole maintenance II: increased aripipirazole dose and maintenance period. Am J Drug Alcohol Abuse 34:721–729

    Article  PubMed  Google Scholar 

  • Lile JA, Stoops WW, Glaser PE, Hays LR, Rush CR (2011). Discriminative stimulus, subject-rated and cardiovascular effects of cocaine alone and in combination with aripiprazole in humans. J Psychopharmacology October 15 (in press)

  • Mamo D, Graff A, Mizrahi R, Shammi CM, Romeyer F, Kapur S (2007) Differential effects of aripiprazole on D(2), 5-HT(2), and 5-HT(1A) receptor occupancy in patients with schizophrenia: a triple tracer PET study. Am J Psychiatr 164:1411–1417

    Article  PubMed  Google Scholar 

  • Martell BA, Orson FM, Poling J, Mitchell E, Rossen RD, Gardner T, Kosten TR (2009) Cocaine vaccine for the treatment of cocaine dependence in methadone-maintained patients: a randomized, double-blind, placebo-controlled efficacy trial. Arch Gen Psychiatr 66:1116–1123

    Article  PubMed  CAS  Google Scholar 

  • Martinez D, Narendran R, Foltin RW, Slifstein M, Hwang DR, Broft A, Huang Y, Cooper TB, Fischman MW, Kleber HD, Laruelle M (2007) Amphetamine-induced dopamine release: markedly blunted in cocaine dependence and predictive of the choice to self-administer cocaine. Am J Psychiatr 164:622–629

    Article  PubMed  Google Scholar 

  • Martinez D, Greene K, Broft A, Kumar D, Liu F, Narendran R, Slifstein M, Van Heertum R, Kleber HD (2009) Lower level of endogenous dopamine in patients with cocaine dependence: findings from PET imaging of D(2)/D(3) receptors following acute dopamine depletion. Am J Psychiatr 166:1170–1177

    Article  PubMed  Google Scholar 

  • Newcomer JW (2005) Second-generation (atypical) antipsychotics and metabolic effects: a comprehensive literature review. CNS Drugs 19(Suppl 1):1–93

    PubMed  CAS  Google Scholar 

  • Newton TF, Reid MS, De La Garza R, Mahoney JJ, Abad A, Condos R, Palamar J, Halkitis PN, Mojisak J, Anderson A, Li SH, Elkashef A (2008) Evaluation of subjective effects of aripiprazole and methamphetamine in methamphetamine-dependent volunteers. Int J Neuropsychopharmacol 11:1037–1045

    Article  PubMed  CAS  Google Scholar 

  • Owen L, Sikich RN, Marcus et al (2009) Aripiprazole in the treatment of irritability in children and adolescents with autistic disorder. Pediatrics 124:1533–1540

    Article  PubMed  Google Scholar 

  • Platt DM, Rodefer JS, Rowlett JK (2002) Suppression of cocaine- and food-maintained behavior by the D2-like receptor partial agonist terguride in squirrel monkeys. Psychopharmacology (Berl) 166:298–305

    Google Scholar 

  • Pulvirenti L, Koob GF (2002) Being partial to psychostimulant addiction therapy. Trends in Pharmacol Sci 23:151–153

    Article  CAS  Google Scholar 

  • Sørensen G, Sager TN, Petersen JH, Brennum LT, Thøgersen P, Hee Bengtsen C, Thomsen M, Wörtwein G, Fink-Jensen A, Woldbye DP (2008) Aripiprazole blocks acute self-administration of cocaine and is not self-administered in mice. Psychopharmacology 199:37–46

    Article  PubMed  Google Scholar 

  • Stoops WW (2006) Aripiprazole as a potential pharmacotherapy for stimulant dependence: human laboratory studies with d-amphetamine. Exp Clin Psychopharmacol 4:413–421

    Google Scholar 

  • Stoops WW, Lile JA, Lofwall MR, Rush CR (2007) The safety, tolerability, and subject-rated effects of acute intranasal cocaine administration during aripiprazole maintenance. Am J Drug Alcohol Abuse 33:769–776

    Article  PubMed  Google Scholar 

  • Thomsen M, Fink-Jensen A, Woldbye DP, Wörtwein G, Sager TN, Holm R, Pepe LM, Caine SB (2008) Effects of acute and chronic aripiprazole treatment on choice between cocaine self-administration and food under a concurrent schedule of reinforcement in rats. Psychopharmacology 201:43–53

    Article  PubMed  CAS  Google Scholar 

  • Tiihonen J, Kuoppasalmi K, Föhr J, Tuomola P, Kuikanmäki O, Vorma H, Sokero P, Haukka J, Meririnne E (2007) A comparison of aripiprazole, methylphenidate, and placebo for amphetamine dependence. Am J Psychiatr 164:160–162

    Article  PubMed  Google Scholar 

  • Vocci FJ, Ling WW (2005) Medications development: successes and challenges. Pharmacol Ther 108:94–108

    Article  PubMed  CAS  Google Scholar 

  • Volkow ND, Wang GJ, Fischman MW, Foltin RW, Fowler JS, Abumrad NN, Vitkun S, Logan J, Pappas N, Hitzermann R, Shea CE (1997) Relationship between subjective effects of cocaine and dopamine transporter occupancy. Nature 386:827–830

    Article  PubMed  CAS  Google Scholar 

  • Volkow ND, Fowler JS, Wang GJ, Swanson JM (2004) Dopamine in drug abuse and addiction: results from imaging studies and treatment implications. Mol Psychiatr 9:557–569

    Article  CAS  Google Scholar 

  • Wee S, Wang Z, Woolverton WL, Pulvirenti L, Koob GF (2007) Effect of aripiprazole, a partial dopamine D2 receptor agonist, on increased rate of methamphetamine self-administration in rats with prolonged session duration. Neuropsychopharmacology 32:2238–2247

    Article  PubMed  CAS  Google Scholar 

  • Yokoi F, Gründer G, Biziere K, Stephane M, Dogan AS, Dannals RF, Ravert H, Suri A, Bramer S, Wong DF (2002) Dopamine D2 and D3 receptor occupancy in normal humans treated with the antipsychotic drug aripiprazole (OPC 14597): a study using positron emission tomography and [11C]raclopride. Neuropsychopharmacology 27:248–259

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors would also like to thank the nurses, physicians, and research assistants working in the Marian W. Fischman Cocaine Research Laboratory, and appreciate the contributions of their fellow investigators: Drs. Carl L. Hart, Suzanne Vosburg, Nehal Vadhan, Suzette Evans, and Stephanie Collins Reed.

Financial disclosures

Dr. Haney received consultant fees from Celtic Pharmaceuticals in 2007. Dr. Foltin currently receives research support for an investigator-initiated protocol from Aztra Zeneca. Dr. Rubin reported no biomedical financial interests or potential conflicts of interest. This research was supported by both NIDA (DA10755/Haney; DA006234/Foltin) and funding from Bristol-Meyers Squibb. Participants resided on the Irving Institute for Clinical and Translational Research of The New York-Presbyterian Medical Center, supported by Grant No. MOI-RR-00645 from the National Institutes of Health.

Author information

Authors and Affiliations

  1. Department of Psychiatry, College of Physicians and Surgeons of Columbia University and the Division on Substance Abuse, New York State Psychiatric Institute, 1051 Riverside Dr., Unit 120, New York, NY, 10032, USA

    Margaret Haney, Eric Rubin & Richard W. Foltin

Authors
  1. Margaret Haney
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eric Rubin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Richard W. Foltin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Margaret Haney.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Haney, M., Rubin, E. & Foltin, R.W. Aripiprazole maintenance increases smoked cocaine self-administration in humans. Psychopharmacology 216, 379–387 (2011). https://doi.org/10.1007/s00213-011-2231-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-011-2231-6

Keywords

Search

Navigation