Abstract
Rationale
Previous work has demonstrated asymmetrical cross-generalization between the discriminative stimulus effects of nicotine and cocaine: nicotine fully substitutes for cocaine, whereas cocaine only partially substitutes for nicotine. The factors responsible for the similarities and differences between the two drugs remain unclear.
Objective
The study tested the involvement of dopaminergic and/or cholinergic mechanisms in the discriminative stimulus effects of nicotine and cocaine.
Methods
One set of rats was trained to discriminate cocaine (8.9 mg/kg) from saline, and two other sets of rats were trained to discriminate nicotine (0.1 mg/kg) from saline.
Results
In cocaine-trained rats, among the cholinergic agonists studied only nicotine (0.01–0.56 mg/kg) produced full, dose-related substitution; nornicotine (1–5.6 mg/kg) substituted only partially, and lobeline (2.71–15.34 mg/kg) and pilocarpine (0.26–2.55 mg/kg) failed to engender any cocaine-appropriate responding. The nicotinic antagonist mecamylamine (1–5.6 mg/kg) failed to block cocaine's discriminative stimulus effects. The dopamine antagonist cis-flupentixol (0.48 mg/kg) blocked the substitution of nicotine for cocaine. In nicotine-trained rats, the dopamine uptake blockers cocaine, bupropion and nomifensine (0.2–26.1 mg/kg) each substituted only partially for nicotine, and cis-flupentixol (0.48–0.86 mg/kg) antagonized the discriminative stimulus effects of nicotine.
Conclusions
Nicotine fully substitutes for cocaine because of its effects on dopamine transmission, and not because the discriminative stimulus effects of cocaine incorporate a cholinergic component. Substitution of nicotine for cocaine may depend more on nicotine-induced dopamine release than does the nicotine-trained discriminative stimulus; there may be differential dopaminergic involvement after acute and repeated treatment with nicotine or cocaine.
Similar content being viewed by others
References
Anderson DJ, Arneric SP (1994) Nicotine receptor-binding of [H-3] cytisine, [H-3]nicotine and [H-3]methylcarbamylcholine in rat brain. Eur J Pharmacol 253:261–267
Ando K, Yanagita T (1978) The discriminative stimulus properties of intravenously administered cocaine in rhesus monkeys. In: Colpaert FC, Rosecrans JA (eds) Stimulus properties of drugs: ten years of progress. Elsevier/North-Holland Biomedical Press, Amsterdam, pp 125–136
Baker LE, Riddle EE, Saunders RB, Appel JB (1993) The role of monoamine uptake in the discriminative stimulus effects of cocaine and related compounds. Behav Pharmacol 4:69–79
Bardo MT, Green TA, Crooks PA, Dwoskin LP (1999) Nornicotine is self-administered intravenously by rats. Psychopharmacology 146:290–296
Brioni JD, Kim DJB, O'Neill AB, Williams JEG, Decker MW (1994) Clozapine attenuates the discriminative stimulus properties of (–)-nicotine. Brain Res 643:1–9
Broadbent J, Michael EK, Riddle EE, Appel JB (1991) Involvement of dopamine uptake in the discriminative stimulus effects of cocaine. Behav Pharmacol 2:187–197
Budney AJ, Higgins ST, Bickel W, Kent L (1993) Relationship between intravenous use and achieving initial cocaine abstinence. Drug Alcohol Depend 32:133–142
Callahan PM, De La Garza R, Cunningham KA (1997) Mediation of the discriminative stimulus properties of cocaine by mesocorticolimbic dopamine systems. Pharmacol Biochem Behav 57:601–607
Clarke PBS, Reuben M (1996) Release of [H-3]-noradrenaline from rat hippocampal synaptosomes by nicotine: mediation by different nicotinic receptor subtypes from striatal [H-3]-dopamine release. Br J Pharmacol 117:595–606
Corrigall WA, Coen KM (1994) Dopamine mechanisms play at best a small role in the nicotine discriminative stimulus. Pharmacol Biochem Behav 48:817–820
Damaj MI, Patrick GS, Creasy KR, Martin BR (1997) Pharmacology of lobeline, a nicotinic receptor ligand. J Pharmacol Exp Ther 282:410–419
Damaj MI, Slemmer JE, Carroll FI, Martin BR (1999) Pharmacological characterization of nicotine's interaction with cocaine and cocaine analogs. J Pharmacol Exp Ther 289:1229–1236
De La Garza R, Johanson CE (1983) The discriminative stimulus properties of cocaine in the rhesus monkey. Pharmacol Biochem Behav19:145–148
De La Garza R, Johanson CE (1985) Discriminative stimulus properties of cocaine in pigeons. Psychopharmacology 85:23–30
Desai RI, Barber DJ, Terry P (1999) Asymmetric generalization between the discriminative stimulus effects of nicotine and cocaine. Behav Pharmacol 10:647–656
Di Chiara G (1999) Drug addiction as dopamine-dependent associative learning disorder. Eur J Pharmacol 375:13–30
Di Chiara G (2000a) Behavioural pharmacology and neurobiology of nicotine reward and dependence. In: Clementi et al. (eds) Handbook of experimental pharmacology, vol 144. Springer, Heidelberg, pp 603–750
Di Chiara G (2000b) Role of dopamine in the behavioural actions of nicotine related to addiction. Eur J Pharmacol 393:295–314
Dwoskin LP, Buxton ST, Jewell AL, Crooks PA (1993) S(–)-nornicotine increases dopamine release in a calcium-dependent manner from superfused rat striatal slices. J Neurochem 60:2167–2174
Dwoskin LP, Crooks PA, Teng LH, Green TA, Bardo MT (1999) Acute and chronic effects of nornicotine on locomotor activity in rats: altered response to nicotine. Psychopharmacology 145:442–451
Finney DJ (1964) Statistical methods in biological assay, 2nd edn. Hafner, New York
Foltin RW, Fischman MW (1991) Smoked and intravenous cocaine in humans, acute tolerance, cardiovascular and subjective effects. J Pharmacol Exp Ther 257:247–261
Garrett BE, Griffiths RR (1997) Comparison of intravenous caffeine and nicotine in cocaine abusers. In: Harris LS (eds) Problems of drug dependence. The College on Problems of Drug Dependence, NIDA Research Monograph no. 178. USDHHS, Rockville, Md., p 285
Gasior M, Shoaib M, Yasar S, Jaszyna M, Goldberg SR (1999) Acquisition of nicotine discrimination and discriminative stimulus effects of nicotine in rats chronically exposed to caffeine. J Pharmacol Exp Ther 288:1053–1073
Gerasimov MR, Franceschi M, Volkow ND, Rice O, Schiffer WK, Dewey SL (2000) Synergistic interactions between nicotine and cocaine or methylphenidate depend on the dose of dopamine transporter inhibitor. Synapse 38:432–437
Goldberg SR, Risner ME, Stolerman IP, Reavill C, Garcha HS (1989) Nicotine and some related compounds—effects on schedule-controlled behavior and discriminative properties in rats. Psychopharmacology 97:295–302
Grady S, Marks MJ, Wonnacott S, Collins AC (1992) Characterization of nicotinic receptor-mediated [H-3] dopamine release from synaptosomes prepared from mouse striatum. J Neurochem 59:848–856
Henningfield JE, London ED, Benowitz NL (1990) Arterial-venous differences in plasma concentrations of nicotine after cigarette smoking. JAMA 263:2049–2050
Higgins ST, Bickel WK, Hughes JR, Lynn M, Caples MA, Fenwick JW (1990) Effects of intranasal cocaine on human learning, performance and physiology. Psychopharmacology 102:115–125
Higgins ST, Budney AJ, Hughes JR, Bickel WK, Lynn M, Mortensen A (1994) Influence of cocaine use on cigarette smoking. JAMA 272:1724
Horger BA, Giles MK, Schenk S (1992) Preexposure to amphetamine and nicotine predisposes rats to self-administer a low dose of cocaine. Psychopharmacology 107:271–276
Johanson CE, Barrett JE (1993) The discriminative stimulus effects of cocaine in pigeons. J Pharmacol Exp Ther 267:1–8
Jones HE, Garrett BE, Griffiths RR (1999) Subjective and physiological effects of intravenous nicotine and cocaine in cigarette smoking cocaine abusers. J Pharmacol Exp Ther 288:188–197
Karler R, Calder LD, Bedingfield JB (1996) A novel nicotinic-cholinergic role in behavioral sensitization to amphetamine-induced stereotypy in mice. Brain Res 725:192–198
Katz JL, Kopajtic TA, Myers KA, Mitkus RJ, Chider M (1999a) Behavioural effects of cocaine: interactions with D1 dopaminergic antagonists and agonists in mice and squirrel monkeys. J Pharmacol Exp Ther 291:265–279
Katz JL, Izenwasser S, Kline RH, Allen AC, Newman AH (1999b) Novel 3 alpha-diphenylmethoxytropane analogs: selective dopamine uptake inhibitors with behavioral effects distinct from those of cocaine. J Pharmacol Exp Ther 288:302–315
Kenakin TP (1993) Pharmacological analysis of drug-receptor interaction, 2nd edn. Raven Press, New York
Konings E, Dubois-Arber F, Narring F, Michaud PA (1995) Identifying adolescent drug users: results of a national survey on adolescent health in Switzerland. J Adolesc Health 16:240–251
Levin ED (1995) Pergolide interactions with nicotine and pilocarpine in rats on the radial-arm maze. Pharmacol Biochem Behav 52:837–840
Levin ED, Mead T, Rezvani AH, Rose JE, Gallivan C, Gross R (2000) The nicotinic antagonist mecamylamine preferentially inhibits cocaine vs. food self-administration in rats. Physiol Behav 71:565–570
Mansbach RS, Rovetti CC, Freedland CS (1998) The role of monoamine neurotransmitter systems in the nicotine discriminative stimulus. Drug Alcohol Depend 52:125–134
Pich EM, Pagliusi SR, Tessari M, TalabotAyer D, VanHuijsduijnen RH, Chiamulera C (1997) Common neural substrates for the addictive properties of nicotine and cocaine. Science 275:83–86
Pontieri FE, Tanda G, Orzi F, Di Chiara G (1996) Effects of nicotine on the nucleus accumbens and similarity to those of addictive drugs. Nature 382:255–257
Pratt JA, Stolerman IP, Garcha HS, Giardini V, Feyerabend C (1983) Discriminative stimulus properties of nicotine—further evidence for mediation at a cholinergic receptor. Psychopharmacology 81:54–60
Reavill C, Stolerman IP (1987) Interaction of nicotine with dopaminergic mechanisms assessed through drug discrimination and rotational behaviour in rats. J Psychopharmacol 1:264–273
Reavill C, Walther B, Stolerman IP, Testa B (1990) Behavioral and pharmacokinetic studies on nicotine, cytisine and lobeline. Neuropharmacology 29:619–624
Roll JM, Higgins ST, Budney AJ, Bickel WK, Badger GJ (1996) A comparison of cocaine-dependent cigarette smokers and non-smokers on demographics, drug use and other characteristics. Drug Alcohol Depend 40:195–201
Romano C, Goldstein A, Jewell NP (1981) Characterization of the receptor mediating the nicotine discriminative stimulus. Psychopharmacology 74:310–315
Schechter MD, Meehan SM (1992) Further evidence for the mechanisms that may mediate nicotine discrimination. Pharmacol Biochem Behav 41:807–812
Schorling JB, Gutgesell M, Klas P, Smith D, Keller A (1994) Tobacco, alcohol and other drug use among college students. J Subst Abuse 6:105–111
Slemmer JE., Martin BR, Damaj MI (2000) Bupropion is a nicotinic antagonist. J Pharmacol Exp Ther 295:321–327
Snedecor GW, Cochran WG (1967) Statistical methods, 6th edn. Iowa State University Press, Ames, Iowa
Stolerman IP, Garcha HS, Pratt JA, Kumar R (1984) Role of training dose in discrimination of nicotine and related compounds by rats. Psychopharmacology 84:413–419
Stolerman IP, Garcha HS, Mirza NR (1995) Dissociations between the locomotor stimulant and depressant effects of nicotinic agonists in rats. Psychopharmacology 117:430–437
Sziraki I, Sershen H, Benuck M, Hashim A, Lajtha A (1998) Receptor systems participating in nicotine-specific effects. Neurochem Int 33:445–457
Takada K, Hagen TJ, Cook JM, Goldberg SR, Katz JL (1988) Discriminative stimulus effects of intravenous nicotine in squirrel monkeys. Pharmacol Biochem Behav 30:243–247
Tani Y, Saito K, Tsuneyoshi A, Imoto M, Ohno T (1997) Nicotinic acetylcholine receptor (nACh-R) agonist-induced changes in brain monoamine turnover in mice. Psychopharmacology 129:225–232
Teng LH, Crooks PA, Buxton ST, Dwoskin LP (1997) Nicotinic-receptor mediation of S (–) nornicotine-evoked [H-3]overflow from rat striatal slices preloaded with [H-3]dopamine. J Pharmacol Exp Ther 283:778–787
Terry AV, Williamson R, Gattu M, Beach JW, McCurdy CR, Sparks JA, Pauly JR (1998) Lobeline and structurally simplified analogs exhibit differential agonist activity and sensitivity to antagonist blockade when compared to nicotine. Neuropharmacology 37:93–102
Terry P, Katz JL (1997) Dopaminergic mediation of the discriminative stimulus effects of bupropion in rats. Psychopharmacology 134:201–212
Volkow ND (1997) The role of dopamine system in addiction. In: New understanding of drug addiction—a special report. McGraw-Hill, New York, pp 22–26
Wiley JL, LaVecchia KL, Martin BR, Damaj MI (2002) Nicotine-like discriminative stimulus effects of bupropion in rats. Exp Clin Psychopharmacol 10:129–135
Witkin JM, Nichols DE, Terry P, Katz JL (1991) Behavioral effects of selective dopaminergic compounds in rats discriminating cocaine injections. J Pharmacol Exp Ther 257:706–713
Zernig G, O'Laughlin IA, Fibiger HC (1997) Nicotine and heroin augment cocaine-induced dopamine overflow in nucleus accumbens. Eur J Pharmacol 337:1–10
Acknowledgements
The authors thank the staff at BMSU for technical support, and Dr. Jonathan Katz (NIDA) and Dr Matthew O'Callaghan (NIDA) for comments on the manuscript.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Desai, R.I., Barber, D.J. & Terry, P. Dopaminergic and cholinergic involvement in the discriminative stimulus effects of nicotine and cocaine in rats. Psychopharmacology 167, 335–343 (2003). https://doi.org/10.1007/s00213-003-1426-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-003-1426-x