Skip to main content

Advertisement

SpringerLink
Log in

Cocaine and heroin (‘speedball’) self-administration: the involvement of nucleus accumbens dopamine and μ-opiate, but not δ-opiate receptors

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

Abstract

Rationale

The combined administration of heroin and cocaine (‘speedball’) is common among intravenous drug users. Dopamine receptors in the nucleus accumbens play a key role in cocaine self-administration; however, their role in speedball self-administration is unknown, as is the role of opiate receptors in this region.

Objectives

The effect of blocking dopamine D1, D2, μ-opiate or δ-opiate receptors in the nucleus accumbens on the intravenous self-administration of combined heroin and cocaine was examined in rats.

Methods

Rats with bilateral cannulae implanted into the nucleus accumbens were trained to self-administer intravenous speedball (ratio of cocaine/heroin, 17:1) under a progressive ratio (PR) schedule. Prior to their self-administration session, rats were then microinjected with the dopamine D1 receptor antagonist SCH 23390 (1 and 6 nmol side−1), the D2 receptor antagonist raclopride (3 and 10 nmol side−1), the μ-opiate receptor antagonist CTOP (0.1, 0.3 and 1.0 nmol side−1), the δ-opiate receptor antagonist naltrindole (1.0, 3.0 and 10 nmol side−1) or a cocktail of SCH 23390 (1 nmol side−1) and CTOP (0.1 nmol side−1) into the nucleus accumbens.

Results

Microinjection of SCH 23390, raclopride or CTOP into the nucleus accumbens produced dose-dependent decreases in breakpoints under the PR schedule, while naltrindole was without effect. The highest dose of SCH 23390 also significantly reduced locomotor activity measured during speedball self-administration. The combination of SCH 23390 and CTOP significantly reduced breakpoints, while not affecting locomotor activity.

Conclusions

These results indicate that dopamine and μ-opiate receptors, but not δ-opiate receptors, in the nucleus accumbens are involved in the reinforcing effects of speedball. Combined administration of D1 and μ-opiate receptor antagonists may be more selective at reducing the reinforcing effects of speedball self-administration than either drug alone.

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

Similar content being viewed by others

References

  • Arnold JM, Roberts DC (1997) A critique of fixed and progressive ratio schedules used to examine the neural substrates of drug reinforcement. Pharmacol Biochem Behav 57:441–447

    Article  CAS  PubMed  Google Scholar 

  • Awasaki M, Nishida TL, Sasaki Y, Sato S (1997) Dopamine D1 antagonist SCH-23390 attenuates self-administration of both cocaine and fentanyl in rats. Environ Toxicol Pharmacol 3:115–122

    Google Scholar 

  • Badiani A, Leone P, Stewart J (1995) Intra-VTA injections of the mu-opioid antagonist CTOP enhance locomotor activity. Brain Res 690(1):112–116

    Google Scholar 

  • Caine SB, Koob GF (1994) Effects of dopamine D1 and D2 antagonists on cocaine self-administration under different schedules of reinforcement in the rat. J Pharmacol Exp Ther 270:209–218

    CAS  PubMed  Google Scholar 

  • Caine SB, Heinrichs SC, Coffin VL, Koob GF (1995) Effects of the dopamine D1 antagonist SCH 23390 microinjected into the accumbens, amygdala or striatum on cocaine self-administration in the rat. Brain Res 692:47–56

    Article  CAS  PubMed  Google Scholar 

  • Cardinal RN, Everitt BJ (2004) Neural and psychological mechanisms underlying appetitive learning: links to drug addiction. Curr Opinion Neurobiol 14:156–162

    Google Scholar 

  • Carlezon WA, Devine DP, Wise RA (1995) Habit-forming actions of nomifensine in nucleus accumbens. Psychopharmacology 122:194–197

    Google Scholar 

  • Cornish JL, Duffy P, Kalivas PW (1999) A role for nucleus accumbens glutamate transmission in the relapse to cocaine-seeking behavior. Neuroscience 93:1359–1367

    Google Scholar 

  • Corrigall WA, Coen KM (1991a) Cocaine self-administration is increased by both D1 and D2 dopamine antagonists. Pharmacol Biochem Behav 39:799–802

    Google Scholar 

  • Corrigall WA, Coen KM (1991b) Opiate antagonists reduce cocaine but not nicotine self-administration. Psychopharmacology 104:167–170

    Google Scholar 

  • David V, Durkin TP, Cazala P (2002) Differential effects of the dopamine D2/D3 receptor antagonist sulpiride on self-administration of morphine into the ventral tegmental area or the nucleus accumbens. Psychopharmacology 160:307–317

    Google Scholar 

  • De Vries TJ, Babovic-Vuksanovic D, Elmer G (1995) Lack of involvement of delta-opioid receptors in mediating the rewarding effects of cocaine. Psychopharmacology 120:442–448

    Google Scholar 

  • DiChiara G, Imperato A (1988) Opposite effects of mu and kappa opiate agonists on dopamine release in the nucleus accumbens and the dorsal caudate of freely moving rats. J Pharmacol Exp Ther 244:1067–1080

    Google Scholar 

  • Duvauchelle CL, Sapoznik T, Kornetsky C (1998) The synergistic effects of combining cocaine and heroin (“speedball”) using a progressive-ratio schedule of drug reinforcement. Pharmacol Biochem Behav 61:297–302

    Google Scholar 

  • Dworkin SI, Guerin GF, Co C, Goeders NE, Smith JE (1988) Lack of an effect of 6-hydroxydopamine lesions of the nucleus accumbens on intravenous morphine self-administration. Pharmacol Biochem Behav 30:1051–1057

    Google Scholar 

  • Foltin RW, Fischman MW (1992) The cardiovascular and subjective effects of intravenous cocaine and morphine combination in humans. J Pharmacol Exp Ther 261:623–632

    Google Scholar 

  • Gerasimov MR, Dewey SL (1999) Gamma-vinyl γ-aminobutyric acid attenuates the synergistic elevations of nucleus accumbens dopamine produced by a cocaine/heroin (speedball) challenge. Eur J Pharmacol 380:1–4

    Google Scholar 

  • Goeders NE, Lane LD, Smith JE (1984) Self-administration of methionine enkephalin into the nucleus accumbens. Pharmacol Biochem Behav 20:451–455

    Google Scholar 

  • Hemby SE, Smith JE, Dworkin SI (1996) The effects of eticlopride and naltrexone on responding maintained by food, cocaine, heroin and cocaine/heroin combinations in rats. J Pharmacol Exp Ther 277:1247–1258

    Google Scholar 

  • Hemby SE, Co C, Dworkin SI, Smith JE (1999) Synergistic elevations in nucleus accumbens extracellular dopamine concentrations during self-administration of cocaine/heroin combinations (speedball) in rats. J Pharmacol Exp Ther 288:274–280

    Google Scholar 

  • Hyytia P, Kiianmaa K (2001) Suppression of ethanol responding by centrally administered CTOP and Naltrindole in AA and Wistar rats. Alcohol Clin Exp Res 25:25–33

    Google Scholar 

  • Ikemoto S, Glazier BS, Murphy JM, McBride WJ (1997) Role of dopamine D1 and D2 receptors in the nucleus accumbens in mediating reward. J Neurosci 17:8580–8587

    Google Scholar 

  • Johnson SW, North RA (1992) Opioids excite dopamine neurons by hyperpolarization of local interneurons. J Neurosci 12:483–488

    Google Scholar 

  • Johnson PI, Goodman JB, Condon R, Stellar JR (1995) Reward shifts and motor responses following microinjections of opiate-specific agonists into either the core or shell of the nucleus accumbens. Psychopharmacology 120:195–202

    Google Scholar 

  • Killian AK, Bonese K, Schuster CR (1978) The effects of naloxone on behaviour maintained by cocaine and heroin injections in rhesus monkeys. Drug Alcohol Depend 3:243–251

    Google Scholar 

  • Koob GF, Pettit HO, Ettenberg A, Bloom FE (1984) Effects of opiate antagonists and their quaternary derivatives on heroin self-administration in the rat. J Pharmacol Exp Ther 229:481–486

    Google Scholar 

  • Le Moine C, Kieffer B, Gaveriaux-Ruff C, Befort K, Bloch B (1994) Delta-opioid receptor gene expression in the mouse forebrain: localization in cholinergic neurons of the striatum. Neuroscience 62:635–640

    Google Scholar 

  • Leri F, Bruneau J, Stewart J (2003) Understanding polydrug use: review of heroin and cocaine use. Addiction 98:7–22

    Google Scholar 

  • Maisonneuve IM, Warner LM, Glick SD (2001) Biphasic dose-related effects of morphine on dopamine release. Drug Alcohol Depend 65:55–63

    Google Scholar 

  • Martin TJ, Kim SA, Lyupina Y, Smith JE (2002) Differential involvement of mu-opioid receptors in the rostral versus caudal nucleus accumbens in the reinforcing effects of heroin in rats: evidence from focal injections of β-funaltrexamine. Psychopharmacology 161:152–159

    Google Scholar 

  • McGregor A, Roberts DC (1993) Dopaminergic antagonism within the nucleus accumbens or the amygdala produces differential effects on intravenous cocaine self-administration under fixed and progressive ratio schedules of reinforcement. Brain Res 624:245–252

    Article  CAS  PubMed  Google Scholar 

  • McGregor IS (1996) Using strawberry tree workbenchmac and workbench PC software for data acquisition and control in the animal learning laboratory. J Behav Res Meth Instrum Comput 28:38–48

    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

    Google Scholar 

  • Mello NK, Negus SS (1999) Effects of flupenthixol and quadazocine on self-administration of speedball combinations of cocaine and heroin by rhesus monkeys. Neuropsychopharmacology 21:575–588

    Google Scholar 

  • Mello NK, Mendelson JH, Bree MP, Lukas SE (1990) Buprenorphine and naltrexone effects on cocaine self-administration by rhesus monkeys. J Pharmacol Exp Ther 254:926–939

    Google Scholar 

  • Mendelson JH, Mello NK (1996) Management of cocaine abuse and dependence. N Engl J Med 334:965–972

    Google Scholar 

  • Meyer ME, McLaurin BI, Allen M, Meyer ME (1994) Biphasic effects of intra-accumbens μ-opioid peptide agonist DAMGO on locomotor activities. Pharmacol Biochem Behav 47:827–831

    Google Scholar 

  • National Institute on Drug Abuse (1998) Epidemiologic trends in drug abuse. NIH Publication No 98-4300, Washington DC, USA, p 79

  • Negus S, Henriksen S, Mattox A, Pasternak G, Portoghese P (1993) Effect of opioid agonists selective for mu, delta and kappa opioid receptors on the reinforcing effects of heroin in rats. J Pharmacol Exp Ther 265:1245–1252

    Google Scholar 

  • Negus SS, Mello NK, Portoghese PS, Lukas SE, Mendelson JH (1995) Role of delta opioid receptors in the reinforcing and discriminative stimulus effects of cocaine in rhesus monkeys. J Pharmacol Exp Ther 273:1245–1256

    Google Scholar 

  • Norwood CS, Cornish JL, Mallet PE, McGregor IS (2003) Pre-exposure to the cannabinoid receptor agonist CP 55940 enhances morphine behavioral sensitization and alters morphine self-administration in Lewis rats. Eur J Pharmacol 465:105–114

    Google Scholar 

  • Olds M (1982) Reinforcing effects of morphine in the nucleus accumbens. Brain Res 237:429–440

    Google Scholar 

  • Paxinos G, Watson C (1998) The rat brain in stereotaxic co-ordinates, 4th edn. Academic Press, CA, USA

    Google Scholar 

  • Pert A, Sivit C (1977) Neuroanatomical focus for morphine and enkephalin-induced hypermotility. Nature 265:645–647

    Google Scholar 

  • Pettit HO, Ettenberg A, Bloom FE, Koob GF (1984) Destruction of dopamine in the nucleus accumbens selectively attenuates cocaine but not heroin self-administration in rats. Psychopharmacology 84:167–173

    Google Scholar 

  • Phillips GD, Howes SR, Whitelaw RB, Wilkinson LS, Robbins TW, Everitt BJ (1994). Isolation rearing impairs the reinforcing efficacy of intravenous cocaine or intra-accumbens d-amphetamine: impaired response to intra-accumbens D1 and D2/D3 dopamine receptor antagonists. Psychopharmacology 115:419–429

    Google Scholar 

  • Ranaldi R, Wise RA (2000) Intravenous self-administration of methamphetamine–heroin (speedball) combinations under a progressive-ratio schedule of reinforcement in rats. NeuroReport 11:2621–2623

    Google Scholar 

  • Reid LD, Glick SD, Menkens KA, French ED, Bilsky EJ, Porreca F (1995) Cocaine self-administration and naltrindole, a delta-selective opioid antagonist. NeuroReport 6:1409–1412

    Google Scholar 

  • Richardson NR, Piercey MF, Svensson K, Collins RJ, Myers JE, Roberts DCS (1993) Antagonism of cocaine self-administration by the preferential dopamine autoreceptor antagonist, (+)-AJ 76. Brain Res 619:15–21

    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

    CAS  PubMed  Google Scholar 

  • Rowlett JK, Wilcox KM, Woolverton WL (1998) Self-administration of cocaine–heroin combinations by rhesus monkeys: antagonism by naltrexone. J Pharmacol Exp Ther 286:61–69

    Google Scholar 

  • Schad CA, Justice JB Jr, Holtzman SG (1996) Differential effects of delta- and mu-opioid receptor antagonists on the amphetamine-induced increase in extracellular dopamine in striatum and nucleus accumbens. J Neurochem 67:2292–2299

    Google Scholar 

  • Schutz CG, Vlahov D, Anthony JC, Graham NMH (1994) Comparison of self-reported injection frequencies for past 30 days and 6 months among intravenous drug users. J Clin Epidemiol 47:191–195

    Google Scholar 

  • Self DW, McClenahan AW, Beitner-Johnson D, Terwilliger RZ, Nestler EJ (1995) Biochemical adaptations in the mesolimbic dopamine system in response to heroin self-administration. Synapse 21:312–318

    Google Scholar 

  • Sieden LS, Sabol KE, Ricuarte GA (1993) Amphetamine: effects on catecholamine system and behaviour. Annu Rev Pharmacol Toxicol 33:634–677

    Google Scholar 

  • Spanagel R, Herz A, Shippenberg TS (1990) The effects of opioid peptides on dopamine release in the nucleus accumbens: an vivo microdialysis study. J Neurochem 55:1734–1740

    Google Scholar 

  • Svingos AL, Moriwaki A, Wang JB, Uhl GR, Pickel VM (1997) μ Opioid receptors are localised to extrasynaptic plasma membranes of GABAergic neurons and their targets in the rat nucleus accumbens. J Neurosci 17:2585–2594

    Google Scholar 

  • Svingos AL, Clarke CL, Pickel VM (1998) Cellular sites for activation of μ-opioid receptors in the rat nucleus accumbens shell: relationship with Met5-enkephalin. J Neurosci 18:1923–1933

    Google Scholar 

  • Tempel A, Zukin SR (1987) Neuroanatomical patterns of the μ, δ, and κ opioid receptors of rat brain as determined by quantitative in vitro autoradiography. Proc Natl Acad Sci 84:4308–4312

    Google Scholar 

  • Van Der Kooy D, Mucha RF, O’Shaughessy M, Bucenieks P (1982) Reinforcing effects of brain microinjection of morphine revealed by conditioned place preference. Brain Res 243:107–117

    Google Scholar 

  • Ward S, Martin T, Roberts D (2003) Beta-funaltrexamine affects cocaine self-administration in rats responding on a progressive ratio schedule of reinforcement. Pharmacol Biochem Behav 75:301–307

    Article  Google Scholar 

  • Wise RA (2002) Brain reward circuitry: insights from unsensed incentives. Neuron 36:229–240

    Article  CAS  PubMed  Google Scholar 

  • Wise RA, Leone P, Rivest R, Leeb K (1995) Elevations of nucleus accumbens dopamine and DOPAC levels during intravenous heroin self-administration. Synapse 21:140–148

    Google Scholar 

  • Xi Z-X, Stein EA (1999) Baclofen inhibits heroin self-administration behaviour and mesolimbic dopamine release. J Pharmacol Exp Ther 290:1369–1374

    Google Scholar 

  • Yu L (1996) The mu opioid receptor: from molecular cloning to functional studies. Addict Biol 1:19–30

    Google Scholar 

Download references

Acknowledgements

This work was supported by a University of Sydney Sesqui Fellowship Grant (J.L.C.).

Author information

Authors and Affiliations

  1. School of Psychology A19, University of Sydney, 2006, Sydney, Australia

    Jennifer L. Cornish, Jaclyn M. Lontos, Kelly J. Clemens & Iain S. McGregor

Authors
  1. Jennifer L. Cornish
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jaclyn M. Lontos
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kelly J. Clemens
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Iain S. McGregor
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jennifer L. Cornish.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cornish, J.L., Lontos, J.M., Clemens, K.J. et al. Cocaine and heroin (‘speedball’) self-administration: the involvement of nucleus accumbens dopamine and μ-opiate, but not δ-opiate receptors. Psychopharmacology 180, 21–32 (2005). https://doi.org/10.1007/s00213-004-2135-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-004-2135-9

Keywords

Search

Navigation