Skip to main content
SpringerLink
Log in

Dose-related effects of the acetylcholinesterase inhibitor tacrine on cocaine and food self-administration in rats

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

Abstract

Rationale

Acetylcholine (ACh) is involved in brain reward and learning functions and contributes to opiate- and psychostimulant-motivated behaviors. Tacrine is a centrally acting, reversible cholinesterase inhibitor that also inhibits monoamine oxidase (MAO) and blocks reuptake of dopamine (DA) and serotonin.

Objectives

To determine the effects of pretreatment with tacrine on self-administration of cocaine and nondrug reinforcers.

Materials and methods

Male Wistar rats were trained to self-administer cocaine under a fixed-ratio-5 (FR-5) schedule during 2-h multiple-component sessions in which 0.1, 0.2, and 0.4 mg/kg per injection of cocaine were each available for 40 min. Other animals self-administered 45 mg food pellets under FR-30 or 20% Ensure (liquid food) under FR-5 in amounts of 30, 60, or 120 μl. Vehicle or tacrine was administered as single intravenous doses 20 min before self-administration of cocaine, food pellets, or liquid food.

Results

Although pretreatment with 0.032 mg/kg of tacrine increased self-administration of food pellets, pretreatment with higher doses of tacrine attenuated self-administration of cocaine, food pellets, or liquid food. Tacrine’s ED50 value for attenuating self-administration of 0.1 mg/kg per injection of cocaine was more than sixfold lower than values for attenuating liquid food- or food pellet-reinforced behavior. However, ED50 values for attenuating self-administration of higher doses of cocaine were similar to those observed for 30 or 60 μl of liquid food.

Conclusions

Tacrine can selectively attenuate self-administration of low-dose cocaine, but its effects on higher doses of cocaine are similar to its ability to decrease self-administration of nondrug reinforcers.

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

  • Adem A, Jossan SS, Oreland L (1989) Tetrahydroaminoacridine inhibits human and rat brain monoamine oxidase. Neurosci Lett 107:313–317

    Article  PubMed  CAS  Google Scholar 

  • Baldwin HA, De Souza RJ, Sarna GS, Murray TK, Green AR, Cross AJ (1991) Measurements of tacrine and monoamines in brain by in vivo microdialysis argue against release of monoamines by tacrine at therapeutic doses. Br J Pharmacol 103:1946–1950

    PubMed  CAS  Google Scholar 

  • Blaha CD, Allen LF, Das S, Inglis WL, Latimer MP, Vincent SR, Winn P (1996) Modulation of dopamine efflux in the nucleus accumbens after cholinergic stimulation of the ventral tegmental area in intact, pedunculopontine tegmental nucleus-lesioned, and laterodorsal tegmental nucleus-lesioned rats. J Neurosci 16:714–722

    PubMed  CAS  Google Scholar 

  • Branch MN (1984) Rate dependency, behavioral mechanisms, and behavioral pharmacology. J Exp Anal Behav 42:511–522

    Article  PubMed  CAS  Google Scholar 

  • Caine SB, Lintz R, Koob GF (1993) Intravenous drug self-administration techniques in animals. In: Sahgal A (ed) Behavioral neuroscience: a practical approach. Oxford University Press, Oxford, pp 117–143

    Google Scholar 

  • Caine SB, Negus SS, Mello NK, Bergman J (1999) Effects of dopamine D(1-like) and D(2-like) agonists in rats that self-administer cocaine. J Pharmacol Exp Ther 291:353–360

    PubMed  CAS  Google Scholar 

  • Caine SB, Negus SS, Mello NK, Patel S, Bristow L, Kulagowski J, Vallone D, Saiardi A, Borrelli E (2002) Role of dopamine D2-like receptors in cocaine self-administration: studies with D2 receptor mutant mice and novel D2 receptor antagonists. J Neurosci 22:2977–2988

    PubMed  CAS  Google Scholar 

  • Cryan JF, Hoyer D, Markou A (2003) Withdrawal from chronic amphetamine induces depressive-like behavioral effects in rodents. Biol Psychiatry 54:49–58

    Article  PubMed  CAS  Google Scholar 

  • De Vry J, Donselaar I, Van Ree JM (1989) Food deprivation and acquisition of intravenous cocaine self-administration in rats: effect of naltrexone and haloperidol. J Pharmacol Exp Ther 251:735–740

    PubMed  Google Scholar 

  • Dews PB (1964) A behavioral effect of amobarbital. Naunyn Schmiedebergs Arch Exp Pathol Pharmakol 248:296–307

    Article  PubMed  CAS  Google Scholar 

  • Drukarch B, Leysen JE, Stoof JC (1988) Further analysis of the neuropharmacological profile of 9-amino-1,2,3,4-tetrahydroacridine (THA), an alleged drug for the treatment of Alzheimer’s disease. Life Sci 42:1011–1017

    Article  PubMed  CAS  Google Scholar 

  • Dworkin SI, Mirkis S, Smith JE (1990) Reinforcer interactions under concurrent schedules of food, water, and intravenous cocaine. Behav Pharmacol 1:327–338

    PubMed  Google Scholar 

  • Freeman SE, Dawson RM (1991) Tacrine: a pharmacological review. Prog Neurobiol 36:257–277

    Article  PubMed  CAS  Google Scholar 

  • Gorelick DA (1998) The rate hypothesis and agonist substitution approaches to cocaine abuse treatment. Adv Pharmacol 42:995–997

    Article  PubMed  CAS  Google Scholar 

  • Grasing K, Li N, He S, Parrish C, Delich J, Glowa J (2003) A new progressive ratio schedule for support of morphine self-administration in opiate dependent rats. Psychopharmacol 168:387–396

    Article  CAS  Google Scholar 

  • He S, Grasing K (2006) l-methamphetamine and selective MAO inhibitors decrease morphine-reinforced and non-reinforced behavior in rats; Insights towards selegiline’s mechanism of action. Pharmacol Biochem Behav 85:675–688

    Article  PubMed  CAS  Google Scholar 

  • Hikida T, Kitabatake Y, Pastan I, Nakanishi S (2003) Acetylcholine enhancement in the nucleus accumbens prevents addictive behaviors of cocaine and morphine. Proc Natl Acad Sci USA 100:6169–6173

    Article  PubMed  CAS  Google Scholar 

  • Hurd YL, Weiss F, Koob G, Ungerstedt U (1990) The influence of cocaine self-administration on in vivo dopamine and acetylcholine neurotransmission in rat caudate-putamen. Neurosci Lett 109:227–233

    Article  PubMed  CAS  Google Scholar 

  • Jossan SS, Adem A, Winblad B, Oreland L (1992) Characterisation of dopamine and serotonin uptake inhibitory effects of tetrahydroaminoacridine in rat brain. Pharmacol Toxicol 71:213–215

    Article  PubMed  CAS  Google Scholar 

  • Kameda G, Dadmarz M, Vogel WH (2000) Influence of various drugs on the voluntary intake of nicotine by rats. Neuropsychobiology 41:205–209

    Article  PubMed  CAS  Google Scholar 

  • Khantzian EJ (1997) The self-medication hypothesis of substance use disorders: a reconsideration and recent applications. Harv Rev Psychiatr 4:231–244

    Article  CAS  Google Scholar 

  • Kosten TR, George TP, Kosten TA (2002) The potential of dopamine agonists in drug addiction. Expert Opin Investig Drugs 11:491–499

    Article  PubMed  CAS  Google Scholar 

  • Liu WF (2000) Effects of cholinesterase inhibitors on a two-component chained schedule performance in rats. Neurotoxicol Teratol 22:389–396

    Article  PubMed  Google Scholar 

  • Mark GP, Weinberg JB, Rada PV, Hoebel BG (1995) Extracellular acetylcholine is increased in the nucleus accumbens following the presentation of an aversively conditioned taste stimulus. Brain Res 688:184–188

    Article  PubMed  CAS  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  PubMed  CAS  Google Scholar 

  • Mayorga AJ, Carriero DL, Cousins MS, Gianutsos G, Salamone JD (1997) Tremulous jaw movements produced by acute tacrine administration: possible relation to parkinsonian side effects. Pharmacol Biochem Behav 56:273–279

    Article  PubMed  CAS  Google Scholar 

  • McNally WP, Pool WF, Sinz MW, Dehart P, Ortwine DF, Huang CC, Chang T, Woolf TF (1996) Distribution of tacrine and metabolites in rat brain and plasma after single- and multiple-dose regimens. Evidence for accumulation of tacrine in brain tissue. Drug Metab Dispos 24:628–633

    PubMed  CAS  Google Scholar 

  • Ogura H, Kosasa T, Kuriya Y, Yamanishi Y (2001) Central and peripheral activity of cholinesterase inhibitors as revealed by yawning and fasciculation in rats. Eur J Pharmacol 415:157–164

    Article  PubMed  CAS  Google Scholar 

  • Parsons LH, Weiss F, Koob GF (1998) Serotonin1B receptor stimulation enhances cocaine reinforcement. J Neurosci 18:10078–10089

    PubMed  CAS  Google Scholar 

  • Rada PV, Hoebel BG (2001) Aversive hypothalamic stimulation releases acetylcholine in the nucleus accumbens, and stimulation-escape decreases it. Brain Res 888:60–65

    Article  PubMed  CAS  Google Scholar 

  • Rada P, Hoebel BG (2005) Acetylcholine in the accumbens is decreased by diazepam and increased by benzodiazepine withdrawal: a possible mechanism for dependency. Eur J Pharmacol 508:131–138

    Article  PubMed  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  PubMed  CAS  Google Scholar 

  • Sizemore GM, Gaspard TM, Kim SA, Walker LE, Vrana SL, Dworkin SI (1997) Dose–effect functions for cocaine self-administration: effects of schedule and dosing procedure. Pharmacol Biochem Behav 57:523–531

    Article  PubMed  CAS  Google Scholar 

  • Telting-Diaz M, Lunte CE (1993) Distribution of tacrine across the blood–brain barrier in awake, freely moving rats using in vivo microdialysis sampling. Pharm Res 10:44–48

    Article  PubMed  CAS  Google Scholar 

  • Volkow ND, Fowler JS, Wang GJ (2002) Role of dopamine in drug reinforcement and addiction in humans: results from imaging studies. Behav Pharmacol 13:355–366

    PubMed  CAS  Google Scholar 

  • Wagstaff AJ, McTavish D (1994) Tacrine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in Alzheimer’s disease. Drugs Aging 4:510–540

    Article  PubMed  CAS  Google Scholar 

  • Wilson MC, Schuster CR (1973) Cholinergic influence on intravenous cocaine self-administration by rhesus monkeys. Pharmacol Biochem Behav 1:643–649

    Article  PubMed  CAS  Google Scholar 

  • Zhang L, Zhou FM, Dani JA (2004) Cholinergic drugs for Alzheimer’s disease enhance in vitro dopamine release. Mol Pharmacol 66:538–544

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Supported by a grant to KG from the Office of Research and Development, Medical Research Service, Department of Veterans Affairs. The authors would like to thank the Midwest Biomedical Research Foundation of Kansas City Missouri for administrative support. In addition, the excellent technical assistance provided by Robert Moreno is greatly appreciated.

Author information

Authors and Affiliations

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

    Kenneth Grasing, Shuangteng He & Yungao Yang

  2. Kansas City VA Medical Center, Research Service, 151, 4801 Linwood Boulevard, Kansas City, MO, 64128, USA

    Kenneth Grasing

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

    Kenneth Grasing

Authors
  1. Kenneth Grasing
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shuangteng He
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yungao Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kenneth Grasing.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Grasing, K., He, S. & Yang, Y. Dose-related effects of the acetylcholinesterase inhibitor tacrine on cocaine and food self-administration in rats. Psychopharmacology 196, 133–142 (2008). https://doi.org/10.1007/s00213-007-0944-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-007-0944-3

Keywords

Search

Navigation