Skip to main content
SpringerLink
Log in

Cocaine-like discriminative stimulus effects of “norepinephrine-preferring” monoamine releasers: time course and interaction studies in rhesus monkeys

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

Abstract

Rationale

The therapeutic potential of monoamine releasers with prominent dopaminergic effects is hindered by their high abuse liability.

Objectives

The present study examined the effects of several novel “norepinephrine (NE)-preferring” monoamine releasers relative to non-selective monoamine releasers, d-amphetamine and d-methamphetamine, in rhesus monkeys trained to discriminate cocaine. NE-preferring releasers were approximately 13-fold more potent for NE compared to dopamine release and ranged in potency for serotonin release (PAL-329 < l-methamphetamine < PAL-169).

Methods

Adult rhesus macaques were trained to discriminate 0.4 mg/kg, IM cocaine on a 30-response fixed ratio schedule of food reinforcement. Substitution studies determined the extent to which test drugs produced cocaine-like discriminative stimulus effects and their time course. Drug interaction studies determined whether pretreatment with test drugs altered the discriminable effects of cocaine.

Results

Results show that cocaine, d-amphetamine, and d-methamphetamine dose-dependently substituted for cocaine with similar potencies. Among the “NE-preferring” releasers, PAL-329 and l-methamphetamine also dose-dependently substituted for cocaine but differed in potency. PAL-169 failed to substitute for cocaine up to a dose that disrupted responding. When administered prior to cocaine, only d-amphetamine and PAL-329 significantly shifted the cocaine dose-effect function leftward indicating enhancement of cocaine’s discriminative stimulus effects.

Conclusions

These data suggest that greater potency for NE relative to dopamine release (up to 13-fold) does not interfere with the ability of a monoamine releaser to produce cocaine-like discriminative effects but that increased serotonin release may have an inhibitory effect. Further characterization of these and other “NE-preferring” monoamine releasers should provide insight into their potential for the management of cocaine addiction.

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
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Banks ML, Blough BE, Negus SS (2011) Effects of monoamine releasers with varying selectivity for releasing dopamine/norepinephrine versus serotonin on choice between cocaine and food in rhesus monkeys. Behav Pharmacol 22:824–836

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Banks ML, Bauer CT, Blough BE, Rothman RB, Partilla JS, Baumann MH, Negus SS (2014) Abuse-related effects of dual dopamine/serotonin releasers with varying potency to release norepinephrine in male rats and rhesus monkeys. Exp Clin Psychopharmacology 22:274–284

    Article  CAS  Google Scholar 

  • Baumann MH, Clark RD, Woolverton WL, Wee S, Blough BE, Rothman RB (2011) In vivo effects of amphetamine analogs reveal evidence for serotonergic inhibition of mesolimbic dopamine transmission in the rat. J Pharmacol Exp Ther 337:218–225

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cline EJ, Scheffel U, Boja JW, Carroll FI, Katz JL, Kuhar MJ (1992) Behavioral effects of novel cocaine analogs: a comparison with in vivo receptor binding potency. J Pharmacol Exp Ther 260:1174–1179

    CAS  PubMed  Google Scholar 

  • Cooper DA, Kimmel HL, Manvich DF, Schmidt KT, Weinshenker D, Howell LL (2014) Effects of pharmacologic dopamine β-hydroxylase inhibition on cocaine-induced reinstatement and dopamine neurochemistry in squirrel monkeys. J Pharmacol Exp Ther 350:144–152

    Article  PubMed  PubMed Central  Google Scholar 

  • Czoty PW, Stoops WW, Rush CR (2016) Evaluation of the “pipeline” for development of medications for cocaine use disorder: a review of translational preclinical, human laboratory, and clinical trial research. Pharmacol Rev 68:533–562

    Article  PubMed  PubMed Central  Google Scholar 

  • Desai RI, Bergman J (2010) Drug discrimination in methamphetamine-trained rats: effects of cholinergic nicotinic compounds. J Pharmacol Exp Ther 335:807–816

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fowler JS, Kroll C, Ferrieri R, Alexoff D, Logan J, Dewey SL, Schiffer W, Schlyer D, Carter P, King P, Shea C, Xu Y, Muench L, Benveniste H, Vaska P, Volkow ND (2007) PET studies of d-methamphetamine pharmacokinetics in primates: comparison with l-methamphetamine and ( )-cocaine. J Nuclear Med 48:1724–1732

    Article  CAS  Google Scholar 

  • Glowa JR, Fantegrossi WE (1997) Effects of dopaminergic drugs on food- and cocaine-maintained responding. IV: continuous cocaine infusions. Drug Alcohol Depend 45:71–79

    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 

  • Hart C, Ward A, Haney M, Foltin R, Fischman M (2001) Methamphetamine self-administration by humans. Psychopharmacology 157:75–81

    Article  CAS  PubMed  Google Scholar 

  • Howell LL, Cunningham KA (2015) Serotonin 5-HT2 receptor interactions with dopamine function: implications for therapeutics in cocaine use disorder. Pharmacol Rev 67:176–197

    Article  PubMed  PubMed Central  Google Scholar 

  • Kirkpatrick MG, Gunderson EW, Johanson CE, Levin FR, Foltin RW, Hart CL (2012) Comparison of intranasal methamphetamine and d-amphetamine self-administration by humans. Addiction 107:783–791

    Article  PubMed  PubMed Central  Google Scholar 

  • Kleven MS, Koek W (1997) Discriminative stimulus properties of cocaine: enhancement by beta-adrenergic receptor antagonists. Psychopharmacology 131:307–312

    Article  CAS  PubMed  Google Scholar 

  • Kohut SJ, Fivel PA, Mello NK, Mello NK (2013) Differential effects of acute and chronic treatment with the α2-adrenergic agonist, lofexidine, on cocaine self-administration in rhesus monkeys. Drug Alcohol Depend 133:593–599

    Article  CAS  PubMed  Google Scholar 

  • Kohut SJ, Hiranita T, Hong S-K, Ebbs AL, Tronci V, Green J, Garcés-Ramírez L, Chun LE, Mereu M, Newman AH, Katz JL, Tanda G (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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kohut SJ, Bergman J, Blough BE (2016) Effects of L-methamphetamine treatment on cocaine- and food-maintained behavior in rhesus monkeys. Psychopharmacology 233:1067–1075

    Article  CAS  PubMed  Google Scholar 

  • Kuczenski R, Segal DS, Cho AK, Melega W (1995) Hippocampus norepinephrine, caudate dopamine and serotonin, and behavioral responses to the stereoisomers of amphetamine and methamphetamine. J Neurosci 15:1308–1317

    CAS  PubMed  Google Scholar 

  • Li S-M, Campbell BL, Katz JL (2006) Interactions of cocaine with dopamine uptake inhibitors or dopamine releasers in rats discriminating cocaine. J Pharmacol Exp Ther 317:1088–1096

    Article  CAS  PubMed  Google Scholar 

  • Li L, Everhart T, Jacob P III, Jones R, Mendelson J (2010) Stereoselectivity in the human metabolism of methamphetamine. British J Clin Pharmacol 69:187–192

    Article  CAS  Google Scholar 

  • Lile JA, Charnigo RJ, Nader MA (2013) The relative reinforcing strength of methamphetamine and D-amphetamine in monkeys self-administering cocaine. Behav Pharmacol 24:482–485

    Article  CAS  PubMed  Google Scholar 

  • Manvich DF, Manvich DF, DePoy LM, DePoy LM, Weinshenker D, Weinshenker D (2013) Dopamine β-hydroxylase inhibitors enhance the discriminative stimulus effects of cocaine in rats. J Pharmacol Exp Ther 347:564–573

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Melega WP, Cho AK, Schmitz D, Kuczenski R, Segal DS (1999) L-methamphetamine pharmacokinetics and pharmacodynamics for assessment of in vivo deprenyl-derived l-methamphetamine. J Pharmacol Exp Ther 288:752–758

    CAS  PubMed  Google Scholar 

  • Mello NK, Negus SS (1996) Preclinical evaluation of pharmacotherapies for treatment of cocaine and opioid abuse using drug self-administration procedures. Neuropsychopharmacology 14:375–424

    Article  CAS  PubMed  Google Scholar 

  • Mendelson J, Uemura N, Harris D, Nath R, Fernandez E, Jacobelli P, Everhart E, Jones R (2006) Human pharmacology of the methamphetamine stereoisomers. Clin Pharmacol Ther 80:403–420

    Article  CAS  PubMed  Google Scholar 

  • National Research Council (2011) Guide for the care and use of laboratory animals, 8th edition (Institute of Laboratory Animal Resources, Commission on Life Sciences, National Research Council). The National Academies press 125

  • Negus SS, Mello NK, Blough BE, Baumann MH, Rothman RB (2007) Monoamine releasers with varying selectivity for dopamine/norepinephrine versus serotonin release as candidate “agonist” medications for cocaine dependence: studies in assays of cocaine discrimination and cocaine self-administration in rhesus monkeys. J Pharmacol Exp Ther 320:627–636

    Article  CAS  PubMed  Google Scholar 

  • Negus SS, Baumann MH, Rothman RB, Mello NK, Blough BE (2009) Selective suppression of cocaine- versus food-maintained responding by monoamine releasers in rhesus monkeys: benzylpiperazine, (+)phenmetrazine, and 4-benzylpiperidine. J Pharmacol Exp Ther 329:272–281

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Newton TF, De La Garza R, Kalechstein AD, Nestor L (2005) Cocaine and methamphetamine produce different patterns of subjective and cardiovascular effects. Pharmacol Biochem Behav 82:90–97

    Article  CAS  PubMed  Google Scholar 

  • Platt DM, Rowlett JK, Spealman RD (2007) Noradrenergic mechanisms in cocaine-induced reinstatement of drug seeking in squirrel monkeys. J Pharmacol Exp Ther 322:894–902

    Article  CAS  PubMed  Google Scholar 

  • Ritz MC, Lamb RJ, Goldberg SR, Kuhar MJ (1987) Cocaine receptors on dopamine transporters are related to self-administration of cocaine. Science 237:1219–1223

    Article  CAS  PubMed  Google Scholar 

  • Rothman RB, Baumann MH (2003) Monoamine transporters and psychostimulant drugs. Eur J Pharmacol 479:23–40

    Article  CAS  PubMed  Google Scholar 

  • Rothman RB, Baumann MH (2006) Balance between dopamine and serotonin release modulates behavioral effects of amphetamine-type drugs. Ann N Y Acad Sci 1074:245–260

    Article  CAS  PubMed  Google Scholar 

  • Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, Partilla JS (2000) Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin. Synapse 39:32–41

    Article  Google Scholar 

  • Rothman RB, Blough BE, Baumann MH (2006) Appetite suppressants as agonist substitution therapies for stimulant dependence. Ann N Y Acad Sci 965:109–126

    Article  Google Scholar 

  • Schmidt KT, Weinshenker D (2014) Adrenaline rush: the role of adrenergic receptors in stimulant-induced behaviors. Mol Pharmacol 85:640–650

    Article  PubMed  PubMed Central  Google Scholar 

  • Schroeder JP, Epps SA, Grice TW, Weinshenker D (2013) The selective dopamine β-hydroxylase inhibitor nepicastat attenuates multiple aspects of cocaine-seeking behavior. Neuropsychopharmacology 38:1032–1038

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sidman M (1980) A note on the measurement of a conditional discrimination. J Exp Anal Behav 33:285–289

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Spealman RD (1995) Noradrenergic involvement in the discriminative stimulus effects of cocaine in squirrel monkeys. J Pharmacol Exp Ther 275:53–62

    CAS  PubMed  Google Scholar 

  • Terry P, Witkin JM, Katz JL (1994) Pharmacological characterization of the novel discriminative stimulus effects of a low dose of cocaine. J Pharmacol Exp Ther 270:1041–1048

    CAS  PubMed  Google Scholar 

  • Walsh SL, Middleton LS, Wong CJ, Nuzzo PA, Campbell CL, Rush CR, Lofwall MR (2013) Atomoxetine does not alter cocaine use in cocaine dependent individuals: a double blind randomized trial. Drug Alcohol Depend 130:150–157

    Article  CAS  PubMed  Google Scholar 

  • Wee S, Woolverton WL (2004) Evaluation of the reinforcing effects of atomoxetine in monkeys: comparison to methylphenidate and desipramine. Drug Alcohol Depend 75:271–276

    Article  CAS  PubMed  Google Scholar 

  • Wee S, Woolverton WL (2006) Self-administration of mixtures of fenfluramine and amphetamine by rhesus monkeys. Pharmacol Biochem Beh 84:337–343

    Article  CAS  Google Scholar 

  • Wee S, Anderson KG, Baumann MH, Rothman RB, Blough BE, Woolverton WL (2005) Relationship between the serotonergic activity and reinforcing effects of a series of amphetamine analogs. J Pharmacol Exp Ther 313:848–854

    Article  CAS  PubMed  Google Scholar 

  • Wee S, Wang Z, He R, Zhou J, Kozikowski AP, Woolverton WL (2006) Role of the increased noradrenergic neurotransmission in drug self-administration. Drug Alcohol Depend 82:151–157

    Article  CAS  PubMed  Google Scholar 

  • Winger GD, Yasar S, Negus SS, Goldberg SR (1994) Intravenous self-administration studies with l-deprenyl (selegiline) in monkeys*. Clin Pharmacol Ther 56:774–780

    Article  CAS  PubMed  Google Scholar 

  • Wood AJJ, Henningfield JE (1995) Nicotine medications for smoking cessation. N Engl J Med 333:1196–1203

    Article  Google Scholar 

  • Woods JH, Tessel RE (1974) Fenfluramine: amphetamine congener that fails to maintain drug-taking behavior in the rhesus monkey. Science 185:1067–1069

    Article  CAS  PubMed  Google Scholar 

  • Yasar S, Bergman J (1994) Amphetamine-like effect of l-deprenyl (selegiline) in drug discrimination studies*. Clin Pharmacol Ther 56:768–773

    Article  CAS  PubMed  Google Scholar 

  • Yokel RA, Pickens R (1973) Self-administration of optical isomers of amphetamine and methylamphetamine by rats. J Pharmacol Exp Ther 187:27–33

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was funded by National Institutes of Health grants DA002519 (to JB), DA039306 (to SJK), and DA12970 (to BEB). The authors thank Olga Smirnova and Kevin Costa for assistance with conducting these studies, and Dr. Roger D. Spealman for comments on an earlier version of this manuscript.

Author information

Authors and Affiliations

  1. McLean Hospital - Harvard Medical School, 115 Mill Street, Belmont, MA, 02478, USA

    Stephen J. Kohut, David S. Jacobs & Jack Bergman

  2. National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, USA

    Richard B. Rothman & John S. Partilla

  3. Research Triangle Institute, Research Triangle Park, NC, USA

    Bruce E. Blough

Authors
  1. Stephen J. Kohut
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David S. Jacobs
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Richard B. Rothman
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. John S. Partilla
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jack Bergman
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Bruce E. Blough
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stephen J. Kohut.

Ethics declarations

Conflicts of interest

The authors declare that they have no conflicts of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kohut, S.J., Jacobs, D.S., Rothman, R.B. et al. Cocaine-like discriminative stimulus effects of “norepinephrine-preferring” monoamine releasers: time course and interaction studies in rhesus monkeys. Psychopharmacology 234, 3455–3465 (2017). https://doi.org/10.1007/s00213-017-4731-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-017-4731-5

Keywords

Search

Navigation