Skip to main content

Advertisement

SpringerLink
Log in

The nicotinic acetylcholine receptor antagonist mecamylamine prevents escalation of cocaine self-administration in rats with extended daily access

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

Abstract

Rationale

Escalation from moderate to excessive drug intake is a hallmark of human addiction that can be modeled in rats by giving them longer daily access time to self-administer cocaine. Nicotine and cocaine are commonly coabused drugs in humans and recent work in animals suggests that activation of nicotinic acetylcholine receptors (nAChR) can increase cocaine self-administration.

Objectives

Determine the role of nAChR in the escalation of cocaine self-administration.

Methods

Control rats self-administered cocaine (0.75 mg/kg/infusion) for either 1 or 6 h per day. Experimental groups had the nAChR antagonist mecamylamine (MEC) added to the cocaine solution for 5 days after the transition from short (1 h per day) to long access (6 h per day) for cocaine self-administration. After 5 days, MEC was removed from the cocaine solution.

Results

Control rats and rats that received a low dose of MEC (7 μg/infusion) with cocaine increased their average hourly intake over 5 days of 6 h per day cocaine access. Rats that received a higher dose of MEC (70 μg/infusion) did not increase their intake of cocaine during 6 h access but continued to self-administer cocaine. When MEC was removed, this group showed an escalation in cocaine self-administration. MEC did not alter cocaine intake in a group that had continuous 1 h access.

Conclusions

Antagonism of nAChRs during the initial exposure to extended cocaine self-administration access time prevented escalation of, but did not eliminate, drug intake. These findings indicate that MEC-sensitive nAChRs are critical for determining cocaine intake as a function of longer access time.

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

  • Ahmed SH, Cador M (2006) Dissociation of psychomotor sensitization from compulsive cocaine consumption. Neuropsychopharmacology 31:563–571

    Article  PubMed  CAS  Google Scholar 

  • Ahmed SH, Koob GF (1998) Transition from moderate to excessive drug intake: change in hedonic set point. Science 282:298–300

    Article  PubMed  CAS  Google Scholar 

  • Ahmed SH, Koob GF (1999) Long-lasting increase in the set point for cocaine self-administration after escalation in rats. Psychopharmacology 146:303–312

    Article  PubMed  CAS  Google Scholar 

  • Ahmed SH, Walker JR, Koob GF (2000) Persistent increase in the motivation to take heroin in rats with a history of drug escalation. Neuropsychopharmacology 22:413–421

    Article  PubMed  CAS  Google Scholar 

  • Balfour DJ, Benwell ME, Birrell CE, Kelly RJ, Al-Aloul M (1998) Sensitization of the mesoaccumbens dopamine response to nicotine. Pharmacol Biochem Behav 59:1021–1030

    Article  PubMed  CAS  Google Scholar 

  • Bardo MT (1998) Neuropharmacological mechanisms of drug reward: beyond dopamine in the nucleus accumbens. Crit Rev Neurobiol 12:37–67

    PubMed  CAS  Google Scholar 

  • Bechtholt AJ, Mark GP (2002) Enhancement of cocaine-seeking behavior by repeated nicotine exposure in rats. Psychopharmacology 162:178–185

    Article  PubMed  CAS  Google Scholar 

  • Bello NT, Sweigart KL, Lakoski JM, Norgren R, Hajnal A (2003) Restricted feeding with scheduled sucrose access results in an upregulation of the rat dopamine transporter. Am J Physiol Regul Integr Comp Physiol 284:R1260–R1268

    PubMed  CAS  Google Scholar 

  • Ben-Shahar O, Ahmed SH, Koob GF, Ettenberg A (2004) The transition from controlled to compulsive drug use is associated with a loss of sensitization. Brain Res 995:46–54

    Article  PubMed  CAS  Google Scholar 

  • Berlanga ML, Olsen CM, Chen V, Ikegami A, Herring BE, Duvauchelle CL, Alcantara AA (2003) Cholinergic interneurons of the nucleus accumbens and dorsal striatum are activated by the self-administration of cocaine. Neuroscience 120:1149–1156

    Article  PubMed  CAS  Google Scholar 

  • Berridge KC, Robinson TE (1998) What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience? Brain Res Rev 28:309–369

    Article  PubMed  CAS  Google Scholar 

  • Caggiula AR, Donny EC, Chaudhri N, Perkins KA, Evans-Martin FF, Sved AF (2002) Importance of nonpharmacological factors in nicotine self-administration. Physiol Behav 77:683–687

    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, New York, pp 117–143

    Google Scholar 

  • Carlezon WA Jr, Nestler EJ (2002) Elevated levels of GluR1 in the midbrain: a trigger for sensitization to drugs of abuse? Trends Neurosci 25:610–615

    Article  PubMed  CAS  Google Scholar 

  • Carroll ME, Batulis DK, Landry KL, Morgan AD (2005) Sex differences in the escalation of oral phencyclidine (PCP) self-administration under FR and PR schedules in rhesus monkeys. Psychopharmacology (Berl) 180:414–426

    Article  CAS  Google Scholar 

  • Collins SL, Izenwasser S (2004) Chronic nicotine differentially alters cocaine-induced locomotor activity in adolescent vs adult male and female rats. Neuropharmacology 46:349–362

    Article  PubMed  CAS  Google Scholar 

  • Corrigall WA, Coen KM (1989) Nicotine maintains robust self-administration in rats on a limited-access schedule. Psychopharmacology (Berl) 99:473–478

    Article  CAS  Google Scholar 

  • Corrigall WA, Coen KM, Adamson KL (1994) Self-administered nicotine activates the mesolimbic dopamine system through the ventral tegmental area. Brain Res 653:278–284

    Article  PubMed  CAS  Google Scholar 

  • Dadmarz M, Vogel WH (2003) Individual self-administration of nicotine by rats. Pharmacol Biochem Behav 76:425–432

    Article  PubMed  CAS  Google Scholar 

  • Deroche-Gamonet V, Belin D, Piazza PV (2004) Evidence for addiction-like behavior in the rat. Science 305:1014–1017

    Article  PubMed  CAS  Google Scholar 

  • Desai RI, Terry P (2003) Evidence of cross-tolerance between behavioural effects of nicotine and cocaine in mice. 166:111–119

  • Di Chiara G, Imperato A (1988) Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci USA 85:5274–5278

    Article  PubMed  Google Scholar 

  • Di Chiara G, Bassareo V, Fenu S, De Luca MA, Spina L, Cadoni C, Acquas E, Carboni E, Valentini V, Lecca D (2004) Dopamine and drug addiction: the nucleus accumbens shell connection. Neuropharmacology 47(Suppl 1):227–241

    PubMed  Google Scholar 

  • Donny EC, Chaudhri N, Caggiula AR, Evans-Martin FF, Booth S, Gharib MA, Clements LA, Sved AF (2003) Operant responding for a visual reinforcer in rats is enhanced by noncontingent nicotine: implications for nicotine self-administration and reinforcement. Psychopharmacology 169:68–76

    Article  PubMed  CAS  Google Scholar 

  • DSMIV (1994) Diagnostic and statistical manual of mental disorders, 4th edn. American Psychiatric Association, Washington, DC

    Google Scholar 

  • Haile CN, Kosten TR, Kosten TA (2006) Genetics of dopamine and its contribution to cocaine addiction. Behav Genet 37:119–145

    Article  PubMed  Google Scholar 

  • Henningfield JE, Clayton R, Pollin W (1990) Involvement of tobacco in alcoholism and illicit drug use. Br J Addict 85:279–291

    Article  PubMed  CAS  Google Scholar 

  • Ikemoto S, Glazier BS, Murphy JM, McBride WJ (1998) Rats self-administer carbachol directly into the nucleus accumbens. Physiol Behav 63:811–814

    Article  PubMed  CAS  Google Scholar 

  • Karler R, Calder LD, Bedingfield JB (1994) Cocaine behavioral sensitization and the excitatory amino acids. Psychopharmacology 115:305–310

    Article  PubMed  CAS  Google Scholar 

  • Kempsill FE, Pratt JA (2000) Mecamylamine but not the alpha7 receptor antagonist alpha-bungarotoxin blocks sensitization to the locomotor stimulant effects of nicotine. Br J Pharmacol 131:997–1003

    Article  PubMed  CAS  Google Scholar 

  • Kenny PJ, Markou A (2006) Nicotine self-administration acutely activates brain reward systems and induces a long-lasting increase in reward sensitivity. Neuropsychopharmacology 31:1203–1211

    PubMed  CAS  Google Scholar 

  • Kitabatake Y, Hikida T, Watanabe D, Pastan I, Nakanishi S (2003) Impairment of reward-related learning by cholinergic cell ablation in the striatum. Proc Natl Acad Sci USA 100:7965–7970

    Article  PubMed  CAS  Google Scholar 

  • Kitamura O, Wee S, Specio SE, Koob GF, Pulvirenti L (2006) Escalation of methamphetamine self-administration in rats: a dose-effect function. Psychopharmacology (Berl) 186:48–53

    Article  CAS  Google Scholar 

  • Koob GF (2000) Neurobiology of addiction: toward the development of new therapies. Ann N Y Acad Sci 909:170–185

    Article  PubMed  CAS  Google Scholar 

  • Koob GF, Ahmed SH, Boutrel B, Chen SA, Kenny PJ, Markou A, O’Dell LE, Parsons LH, Sanna PP (2004) Neurobiological mechanisms in the transition from drug use to drug dependence. Neurosci Biobehav Rev 27:739–749

    Article  PubMed  CAS  Google Scholar 

  • Liu X, Caggiula AR, Yee SK, Nobuta H, Sved AF, Pechnick RN, Poland RE (2006) Mecamylamine attenuates cue-induced reinstatement of nicotine-seeking behavior in rats. Neuropsychopharmacology 32:710

    Article  PubMed  CAS  Google Scholar 

  • Mansvelder HD, De Rover M, McGehee DS, Brussaard AB (2003) Cholinergic modulation of dopaminergic reward areas: upstream and downstream targets of nicotine addiction. Eur J Pharmacol 480:117–123

    Article  PubMed  CAS  Google Scholar 

  • Mantsch JR, Ho A, Schlussman SD, Kreek MJ (2001) Predictable individual differences in the initiation of cocaine self-administration by rats under extended-access conditions are dose-dependent. Psychopharmacology (Berl) 157:31–39

    Article  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 (Berl) 143:47–53

    Article  CAS  Google Scholar 

  • McLellan AT, Lewis DC, O’Brien CP, Kleber HD (2000) Drug dependence, a chronic medical illness: implications for treatment, insurance, and outcomes evaluation. JAMA 284:1689–1695

    Article  PubMed  CAS  Google Scholar 

  • Miller DK, Wilkins LH, Bardo MT, Crooks PA, Dwoskin LP (2001) Once weekly administration of nicotine produces long-lasting locomotor sensitization in rats via a nicotinic receptor-mediated mechanism. Psychopharmacology (Berl) 156:469–476

    Article  CAS  Google Scholar 

  • National Research Council of the National Academies (2003) Guidelines for the care and use of mammals in neuroscience research. The National Academies Press, Washington, DC

  • Nauta WJH, Smith GP, Faull RLM, Domesick VB (1978) Efferent connections and nigral afferents of the nucleus accumbens septi in the rat. Neuroscience 3:385–401

    Article  PubMed  CAS  Google Scholar 

  • O’Dell TJ, Christensen BN (1988) Mecamylamine is a selective non-competitive antagonist of N-methyl-d-aspartate- and aspartate-induced currents in horizontal cells dissociated from the catfish retina. Neurosci Lett 94:93–98

    Article  PubMed  CAS  Google Scholar 

  • Paterson NE, Markou A (2003) Increased motivation for self-administered cocaine after escalated cocaine intake. Neuroreport 14:2229–2232

    Article  PubMed  CAS  Google Scholar 

  • Picciotto MR, Corrigall WA (2002) Neuronal systems underlying behaviors related to nicotine addiction: neural circuits and molecular genetics. 22:3338–3341

  • Pidoplichko VI, Noguchi J, Areola OO, Liang Y, Peterson J, Zhang T, Dani JA (2004) Nicotinic cholinergic synaptic mechanisms in the ventral tegmental area contribute to nicotine addiction. Learn Mem 11:60–69

    Article  PubMed  Google Scholar 

  • Pothos EN, Creese I, Hoebel BG (1995) Restricted eating with weight loss selectively decreases extracellular dopamine in the nucleus accumbens and alters dopamine response to amphetamine, morphine, and food intake. J Neurosci 15:6640–6650

    PubMed  CAS  Google Scholar 

  • Reid MS, Mickalian JD, Delucchi KL, Hall SM, Berger SP (1998) An acute dose of nicotine enhances cue-induced cocaine craving. Drug Alcohol Depend 49:95–104

    Article  PubMed  CAS  Google Scholar 

  • Robinson TE, Berridge KC (1993) The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res Brain Res Rev 18:247–291

    Article  PubMed  CAS  Google Scholar 

  • Salamone JD, Correa M (2002) Motivational views of reinforcement: implications for understanding the behavioral functions of nucleus accumbens dopamine. Behav Brain Res 137:3–25

    Article  PubMed  CAS  Google Scholar 

  • Schenk S, Valadez A, McNamara C, House DT, Higley D, Bankson MG, Gibbs S, Horger BA (1993) Development and expression of sensitization to cocaine’s reinforcing properties: role of NMDA receptors. Psychopharmacology 111:332–338

    Article  PubMed  CAS  Google Scholar 

  • Schoffelmeer AN, De Vries TJ, Wardeh G, van de Ven HW, Vanderschuren LJ (2002) Psychostimulant-induced behavioral sensitization depends on nicotinic receptor activation. J Neurosci 22:3269–3276

    PubMed  CAS  Google Scholar 

  • Shoaib M, Stolerman IP (1992) MK801 attenuates behavioural adaptation to chronic nicotine administration in rats. Br J Pharmacol 105:514–515

    PubMed  CAS  Google Scholar 

  • Smith JE, Co C, Yin X, Sizemore GM, Liguori A, Johnson WE 3rd, Martin TJ (2004) Involvement of cholinergic neuronal systems in intravenous cocaine self-administration. Neurosci Biobehav Rev 27:841–850

    Article  PubMed  CAS  Google Scholar 

  • Wise RA, Rompre P-P (1989) Brain dopamine and reward. Annu Rev Psychol 40:191–225

    Article  PubMed  CAS  Google Scholar 

  • Wong EH, Kemp JA, Priestley T, Knight AR, Woodruff GN, Iversen LL (1986) The anticonvulsant MK-801 is a potent N-methyl-d-aspartate antagonist. Proc Natl Acad Sci USA 83:7104–7108

    Article  PubMed  CAS  Google Scholar 

  • Yeomans J, Baptista M (1997) Both nicotinic and muscarinic receptors in ventral tegmental area contribute to brain-stimulation reward. Pharmacol Biochem Behav 57:915–921

    Article  PubMed  CAS  Google Scholar 

  • Young JM, Shytle RD, Sanberg PR, George TP (2001) Mecamylamine: new therapeutic uses and toxicity/risk profile. Clin Ther 23:532–565

    Article  PubMed  CAS  Google Scholar 

  • Zernig G, Wakonigg G, Madlung E, Haring C, Saria A (2004) Do vertical shifts in dose-response rate-relationships in operant conditioning procedures indicate “sensitization” to “drug wanting”? Psychopharmacology (Berl) 171:349–351

    Article  CAS  Google Scholar 

Download references

Acknowledgement

This research was funded by US PHS grants DA11203 and DA14639. S.T.H. was supported by predoctoral fellowship DA019730.

Author information

Authors and Affiliations

  1. Department of Behavioral Neuroscience, L470, Oregon Health & Science University, 3181 S.W. Sam Jackson Park Road, Portland, OR, 97239-3098, USA

    Stephen T. Hansen & Gregory P. Mark

Authors
  1. Stephen T. Hansen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gregory P. Mark
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gregory P. Mark.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hansen, S.T., Mark, G.P. The nicotinic acetylcholine receptor antagonist mecamylamine prevents escalation of cocaine self-administration in rats with extended daily access. Psychopharmacology 194, 53–61 (2007). https://doi.org/10.1007/s00213-007-0822-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-007-0822-z

Keywords

Search

Navigation