Skip to main content
SpringerLink
Log in

Extracellular dopamine, acetylcholine, and activation of dopamine D1 and D2 receptors after selective breeding for cocaine self-administration in rats

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

Abstract

Rationale

The low self-administration (LS)/Kgras (LS) and high self-administration (HS)/Kgras (HS) rat lines were generated by selective breeding for low- and high-intravenous cocaine self-administration, respectively, from a common outbred Wistar stock (Crl:WI). This trait has remained stable after 13 generations of breeding.

Objective

The objective of the present study is to compare cocaine preference, neurotransmitter release, and dopamine receptor activation in LS and HS rats.

Methods

Levels of dopamine, acetylcholine, and cocaine were measured in the nucleus accumbens (NA) shell of HS and LS rats by tandem mass spectrometry of microdialysates. Cocaine-induced locomotor activity and conditioned-place preference were compared between LS and HS rats.

Results

HS rats displayed greater conditioned-place preference scores compared to LS and reduced basal extracellular concentrations of dopamine and acetylcholine. However, patterns of neurotransmitter release did not differ between strains. Low-dose cocaine increased locomotor activity in LS rats, but not in HS animals, while high-dose cocaine augmented activity only in HS rats. Either dose of cocaine increased immunoreactivity for c-Fos in the NA shell of both strains, with greater elevations observed in HS rats. Activation identified by cells expressing both c-Fos and dopamine receptors was generally greater in the HS strain, with a similar pattern for both D1 and D2 dopamine receptors.

Conclusions

Diminished levels of dopamine and acetylcholine in the NA shell, with enhanced cocaine-induced expression of D1 and D2 receptors, are associated with greater rewarding effects of cocaine in HS rats and an altered dose-effect relationship for cocaine-induced locomotor activity.

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

  • Avena NM, Rada PV (2012) Cholinergic modulation of food and drug satiety and withdrawal. Physiol Behav 106:332–336

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bell SM, Stewart RB, Thompson SC, Meisch RA (1997) Food-deprivation increases cocaine-induced conditioned place preference and locomotor activity in rats. Psychopharmacology 131:1–8

  • Bell RL, Rodd ZA, Lumeng L, Murphy JM, McBride WJ (2006) The alcohol-preferring P rat and animal models of excessive alcohol drinking. Addict Biol 11:270–288

    Article  PubMed  Google Scholar 

  • Bertran-Gonzalez J, Bosch C, Maroteaux M, Matamales M, Herve D, Valjent E, Girault JA (2008) Opposing patterns of signaling activation in dopamine D1 and D2 receptor-expressing striatal neurons in response to cocaine and haloperidol. J Neurosci 28:5671–5685

    Article  CAS  PubMed  Google Scholar 

  • Bezard E, Gross CE, Brotchie JM (2003) Presymptomatic compensation in Parkinson’s disease is not dopamine-mediated. Trends Neurosci 26:215–221

    Article  CAS  PubMed  Google Scholar 

  • Bough KJ, Amur S, Lao G, Hemby SE, Tannu NS, Kampman KM, Schmitz JM, Martinez D, Merchant KM, Green C, Sharma J, Dougherty AH, Moeller FG (2014) Biomarkers for the development of new medications for cocaine dependence. Neuropsychopharmacology 39:202–219

    Article  CAS  PubMed  Google Scholar 

  • Cabeza de Vaca S, Carr KD (1998) Food restriction enhances the central rewarding effect of abused drugs. J Neurosci 18:7502–7510

  • Collins RJ, Weeks JR, Cooper MM, Good PI, Russell RR (1984) Prediction of abuse liability of drugs using IV self-administration by rats. Psychopharmacology 82:6–13

    Article  CAS  PubMed  Google Scholar 

  • Committee for the Update of the Guide for the Care and Use of Laboratory Animals (2011) Guide for care and use of laboratory animals, Eighth edn. The National Academies Press, Washington, D.C.

    Google Scholar 

  • Conrad KL, Louderback KM, Milano EJ, Winder DG (2013) Assessment of the impact of pattern of cocaine dosing schedule during conditioning and reconditioning on magnitude of cocaine CPP, extinction, and reinstatement. Psychopharmacology 227:109–116

    Article  CAS  PubMed  Google Scholar 

  • Faraone SV, Adamson JJ, Wilens TE, Monuteaux MC, Biederman J (2008) Familial transmission of derived phenotypes for molecular genetic studies of substance use disorders. Drug Alcohol Depend 92:100–107

    Article  CAS  PubMed  Google Scholar 

  • Gardoni F, Bellone C (2015) Modulation of the glutamatergic transmission by dopamine: a focus on Parkinson, Huntington and addiction diseases. Front Cell Neurosci 9:25

    Article  PubMed  PubMed Central  Google Scholar 

  • Gerrits MA, Petromilli P, Westenberg HG, Di Chiara G, Van Ree JM (2002) Decrease in basal dopamine levels in the nucleus accumbens shell during daily drug-seeking behaviour in rats. Brain Res 924:141–150

    Article  CAS  PubMed  Google Scholar 

  • Grasing K (2016) A threshold model for opposing actions of acetylcholine on reward behavior: molecular mechanisms and implications for treatment of substance abuse disorders. Behav Brain Res 312:148–162

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • He S, Yang Y, Mathur D, Grasing K (2008) Selective breeding for intravenous drug self-administration in rats: a pilot study. Behav Pharmacol 19:751–764

    Article  CAS  PubMed  Google Scholar 

  • Huston JP, Silva MA, Topic B, Muller CP (2013) What’s conditioned in conditioned place preference? Trends Pharmacol Sci 34:162–166

    Article  CAS  PubMed  Google Scholar 

  • Ikemoto S, Yang C, Tan A (2015) Basal ganglia circuit loops, dopamine and motivation: a review and enquiry. Behav Brain Res 290:17–31

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Itzhak Y, Anderson KL (2012) Changes in the magnitude of drug-unconditioned stimulus during conditioning modulate cocaine-induced place preference in mice. Addict Biol 17:706–716

    Article  CAS  PubMed  Google Scholar 

  • Jones JD, Comer SD (2013) A review of human drug self-administration procedures. Behav Pharmacol 24:384–395

    Article  PubMed  PubMed Central  Google Scholar 

  • Kamens HM, Burkhart-Kasch S, McKinnon CS, Li N, Reed C, Phillips TJ (2005) Sensitivity to psychostimulants in mice bred for high and low stimulation to methamphetamine. Genes Brain Behav 4:110–125

    Article  CAS  PubMed  Google Scholar 

  • Kharkwal G, Radl D, Lewis R, Borrelli E (2016) Dopamine D2 receptors in striatal output neurons enable the psychomotor effects of cocaine. Proc Natl Acad Sci U S A 113:11609–11614

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Larson EB, Akkentli F, Edwards S, Graham DL, Simmons DL, Alibhai IN, Nestler EJ, Self DW (2010) Striatal regulation of DeltaFosB, FosB, and cFos during cocaine self-administration and withdrawal. J Neurochem 115:112–122

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lester DB, Rogers TD, Blaha CD (2010) Acetylcholine-dopamine interactions in the pathophysiology and treatment of CNS disorders. CNS Neurosci Ther 16:137–162

    Article  CAS  PubMed  Google Scholar 

  • Lobo MK, Covington HE III, Chaudhury D, Friedman AK, Sun H, Damez-Werno D, Dietz DM, Zaman S, Koo JW, Kennedy PJ, Mouzon E, Mogri M, Neve RL, Deisseroth K, Han MH, Nestler EJ (2010) Cell type-specific loss of BDNF signaling mimics optogenetic control of cocaine reward. Science 330:385–390

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Luedtke RR, Griffin SA, Conroy SS, Jin X, Pinto A, Sesack SR (1999) Immunoblot and immunohistochemical comparison of murine monoclonal antibodies specific for the rat D1a and D1b dopamine receptor subtypes. J Neuroimmunol 101:170–187

    Article  CAS  PubMed  Google Scholar 

  • Mark GP, Hajnal A, Kinney AE, Keys AS (1999) Self-administration of cocaine increases the release of acetylcholine to a greater extent than response-independent cocaine in the nucleus accumbens of rats. Psychopharmacology 143:47–53

    Article  CAS  PubMed  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 Psychiatry 164:622–629

    Article  PubMed  Google Scholar 

  • Martinez D, Carpenter KM, Liu F, Slifstein M, Broft A, Friedman AC, Kumar D, Van HR, Kleber HD, Nunes E (2011) Imaging dopamine transmission in cocaine dependence: link between neurochemistry and response to treatment. Am J Psychiatry 168:634–641

    Article  PubMed  PubMed Central  Google Scholar 

  • Mateo Y, Lack CM, Morgan D, Roberts DC, Jones SR (2005) Reduced dopamine terminal function and insensitivity to cocaine following cocaine binge self-administration and deprivation. Neuropsychopharmacology 30:1455–1463

    Article  CAS  PubMed  Google Scholar 

  • McShane TM, Wise PM (1996) Life-long moderate caloric restriction prolongs reproductive life span in rats without interrupting estrous cyclicity: effects on the gonadotropin-releasing hormone/luteinizing hormone axis. Biol Reprod 54:70–75

  • Noori HR, Fliegel S, Brand I, Spanagel R (2012) The impact of acetylcholinesterase inhibitors on the extracellular acetylcholine concentrations in the adult rat brain: a meta-analysis. Synapse 66:893–901

    Article  CAS  PubMed  Google Scholar 

  • Ouzir M, Errami M (2016) Etiological theories of addiction: a comprehensive update on neurobiological, genetic and behavioural vulnerability. Pharmacol Biochem Behav 148:59–68

    Article  CAS  PubMed  Google Scholar 

  • Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates, Second edn. Academic Press, New York

    Google Scholar 

  • Pellegrino D, Cicchetti F, Wang X, Zhu A, Yu M, Saint-Pierre M, Brownell AL (2007) Modulation of dopaminergic and glutamatergic brain function: PET studies on parkinsonian rats. J Nucl Med 48:1147–1153

    Article  CAS  PubMed  Google Scholar 

  • Piazza PV, Dominiére JM, LeMoal M, Simon H (1989) Factors that effect individual vulnerability to amphetamine self-administration. Science 245:1511–1513

    Article  CAS  PubMed  Google Scholar 

  • Piazza PV, Deroche-Gamonent V, Rouge-Pont F, Le MM (2000) Vertical shifts in self-administration dose-response functions predict a drug-vulnerable phenotype predisposed to addiction. J Neurosci 20:4226–4232

    CAS  PubMed  Google Scholar 

  • Pontieri FE, Tanda G, Di Chiara G (1995) Intravenous cocaine, morphine, and amphetamine preferentially increase extracellular dopamine in the “shell” as compared with the “core” of the rat nucleus accumbens. Proc Natl Acad Sci U S A 92:12304–12308

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rocha BA (2003) Stimulant and reinforcing effects of cocaine in monoamine transporter knockout mice. Eur J Pharmacol 479:107–115

    Article  CAS  PubMed  Google Scholar 

  • Sanchis-Segura C, Spanagel R (2006) Behavioural assessment of drug reinforcement and addictive features in rodents: an overview. Addict Biol 11:2–38

    Article  PubMed  Google Scholar 

  • Sankoh AJ, Huque MF, Dubey SD (1997) Some comments on frequently used multiple endpoint adjustment methods in clinical trials. Stat Med 16:2529–2542

    Article  CAS  PubMed  Google Scholar 

  • Scibelli AC, McKinnon CS, Reed C, Burkhart-Kasch S, Li N, Baba H, Wheeler JM, Phillips TJ (2011) Selective breeding for magnitude of methamphetamine-induced sensitization alters methamphetamine consumption. Psychopharmacology 214:791–804

    Article  CAS  PubMed  Google Scholar 

  • Sesack SR, Grace AA (2010) Cortico-basal ganglia reward network: microcircuitry. Neuropsychopharmacology 35:27–47

    Article  PubMed  Google Scholar 

  • Trifilieff P, Martinez D (2014) Blunted dopamine release as a biomarker for vulnerability for substance use disorders. Biol Psychiatry 76:4–5

    Article  CAS  PubMed  Google Scholar 

  • Volkow ND, Morales M (2015) The brain on drugs: from reward to addiction. Cell 162:712–725

    Article  CAS  PubMed  Google Scholar 

  • Volkow ND, Wang GJ, Fowler JS, Logan J, Gatley SJ, Hitzemann R, Chen AD, Dewey SL, Pappas N (1997) Decreased striatal dopaminergic responsiveness in detoxified cocaine-dependent subjects. Nature 386:830–833

    Article  CAS  PubMed  Google Scholar 

  • Weiss JM, West CH, Emery MS, Bonsall RW, Moore JP, Boss-Williams KA (2008) Rats selectively-bred for behavior related to affective disorders: proclivity for intake of alcohol and drugs of abuse, and measures of brain monoamines. Biochem Pharmacol 75:134–159

    Article  CAS  PubMed  Google Scholar 

  • Williams MJ, Adinoff B (2008) The role of acetylcholine in cocaine addiction. Neuropsychopharmacology 33:1779–1797

    Article  CAS  PubMed  Google Scholar 

  • Wiltshire T, Ervin RB, Duan H, Bogue MA, Zamboni WC, Cook S, Chung W, Zou F, Tarantino LM (2015) Initial locomotor sensitivity to cocaine varies widely among inbred mouse strains. Genes Brain Behav 14:271–280

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yager LM, Garcia AF, Wunsch AM, Ferguson SM (2015) The ins and outs of the striatum: role in drug addiction. Neuroscience 301:529–541

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yamamoto DJ, Nelson AM, Mandt BH, Larson GA, Rorabaugh JM, Ng CM, Barcomb KM, Richards TL, Allen RM, Zahniser NR (2013) Rats classified as low or high cocaine locomotor responders: a unique model involving striatal dopamine transporters that predicts cocaine addiction-like behaviors. Neurosci Biobehav Rev 37:1738–1753

    Article  CAS  PubMed  Google Scholar 

  • You ZB, Wang B, Zitzman D, Wise RA (2008) Acetylcholine release in the mesocorticolimbic dopamine system during cocaine seeking: conditioned and unconditioned contributions to reward and motivation. J Neurosci 28:9021–9029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This study is supported by grants R21-DA029787 and R21-DA037556 issued to KG from the National Institutes of Health, National Institute on Drug Abuse, and grant 589-KG-0012 from the Medical Research Service, Department of Veterans Affairs.

Author information

Authors and Affiliations

  1. Substance Abuse Research Laboratory, 151, Kansas City Veterans Affairs Medical Center, 4801 Linwood Boulevard, Kansas City, MO, 64128, USA

    Haiyang Xu & Kenneth Grasing

  2. Molecular Bio-Nanotechnology, Imaging and Therapeutic Research Unit, 151, Kansas City Veterans Affairs Medical Center, 4801 Linwood Boulevard, Kansas City, MO, 64128, USA

    Sasmita Das

  3. Division of Hematology and Oncology, Department of Medicine, University of Kansas School of Medicine, Kansas City, KS, 66160, USA

    Sasmita Das

  4. Department of Pharmacy Practice and Administration, Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey, Piscataway, NJ, 08854, USA

    Marc Sturgill

  5. Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, 9000 Rockville Pike, Bethesda, MD, 20852, USA

    Colin Hodgkinson, Qiaoping Yuan & David Goldman

  6. Division of Clinical Pharmacology, Department of Medicine, University of Kansas School of Medicine, Kansas City, KS, 66160, USA

    Kenneth Grasing

Authors
  1. Haiyang Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sasmita Das
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marc Sturgill
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Colin Hodgkinson
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Qiaoping Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. David Goldman
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kenneth Grasing
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kenneth Grasing.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xu, H., Das, S., Sturgill, M. et al. Extracellular dopamine, acetylcholine, and activation of dopamine D1 and D2 receptors after selective breeding for cocaine self-administration in rats. Psychopharmacology 234, 2475–2487 (2017). https://doi.org/10.1007/s00213-017-4640-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-017-4640-7

Keywords

Search

Navigation