Abstract
Rationale
Despite the high prevalence of nicotine use in humans, robust nicotine self-administration has been difficult to demonstrate in laboratory animals.
Objectives
A parametric analysis of nicotine self-administration was conducted to study its reinforcing effects in nonhuman primates.
Methods
Adult rhesus macaques (N = 6) self-administered intravenous (IV) nicotine (0.001–0.1 mg/kg) under a fixed-ratio (FR)1 schedule of reinforcement during daily 90-min sessions. Next, the demand function relating drug intake and response cost was determined by increasing the FR across sessions during the availability of each of several unit doses of nicotine (0.0032–0.032 mg/kg/inj). The reinforcing effects of 0.01 mg/kg/inj cocaine and 1 g banana-flavored food pellets were also determined under similar testing conditions. Finally, the nicotine demand function was re-determined after approximately 8 months of daily IV nicotine self-administration.
Results
IV nicotine self-administration followed an inverted U-shaped pattern, with the peak number of injections maintained by 0.0032 mg/kg/inj. Self-administration of each reinforcer (food pellets, IV cocaine, and IV nicotine) decreased as FR size increased. Application of the exponential model of demand showed that demand elasticity for nicotine was (1) dose-dependent and lowest for 0.0032 mg/kg/inj; (2) for 0.0032 mg/kg/inj, similar to that of food pellets and significantly higher than cocaine; and (3) decreased after 8 months of daily nicotine self-administration.
Conclusions
These data show that, though high levels of nicotine self-administration can be achieved under simple FR schedules in nonhuman primates, its reinforcing effectiveness is dose-related but limited and may increase over time.
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References
Ator NA, Griffiths RR (1983) Nicotine self-administration in baboons. Pharmacol Biochem Behav 19:993–1003
Benowitz NL, Jacob P 3rd (1984) Daily intake of nicotine during cigarette smoking. Clin Pharmacol Ther 35:499–504
Bergman J, Roof RA, Furman CA et al (2012) Modification of cocaine self-administration by buspirone (Buspar®): potential involvement of D3 and D4 dopamine receptors. Int J Neuropsychopharmacol 16:445–458. doi:10.1017/S1461145712000661
Bickel WK, DeGrandpre RJ, Higgins ST, Hughes JR (1990) Behavioral economics of drug self-administration. I. Functional equivalence of response requirement and drug dose. Life Sci 47:1501–1510. doi:10.1016/0024-3205(90)90178-T
Bickel WK, DeGrandpre RJ, Hughes JR, Higgins ST (1991) Behavioral economics of drug self-administration. II. A unit-price analysis of cigarette smoking. J Exp Anal Behav 55:145–154. doi:10.1901/jeab.1991.55-145
Caggiula A, Donny E, Chaudhri N et al (2002a) Importance of nonpharmacological factors in nicotine self-administration. Physiol Behav 77:683–687. doi:10.1016/S0031-9384(02)00918-6
Caggiula A, Donny E, White A et al (2002b) Environmental stimuli promote the acquisition of nicotine self-administration in rats. Psychopharmacology 163:230–237. doi:10.1007/s00213-002-1156-5
Chase HW, MacKillop J, Hogarth L (2013) Isolating behavioural economic indices of demand in relation to nicotine dependence. Psychopharmacology 226:371–380. doi:10.1007/s00213-012-2911
Christensen CJ, Silberberg A, Hursh SR et al (2008a) Essential value of cocaine and food in rats: tests of the exponential model of demand. Psychopharmacology 198:221–229. doi:10.1007/s00213-008-1120-0
Christensen CJ, Silberberg A, Hursh SR et al (2008b) Demand for cocaine and food over time. Pharmacol Biochem Behav 91:209–216. doi:10.1016/j.pbb.2008.07.009
de La Garza DR, Johanson CE (1987) The effects of food deprivation on the self-administration of psychoactive drugs. Drug Alcohol Depend 19:17–27
DeGrandpre RJ, Bickel WK, Hughes JR, Higgins ST (1992) Behavioral economics of drug self-administration. III. A reanalysis of the nicotine regulation hypothesis. Psychopharmacology 108:1–10. doi:10.1007/BF02245277
Deneau GA, Inoki R (1967) Nicotine self-administration in monkeys. Ann N Y Acad Sci 142:277–279
Donny EC, Caggiula AR, Mielke MM et al (1998) Acquisition of nicotine self-administration in rats: the effects of dose, feeding schedule, and drug contingency. Psychopharmacology 136:83–90
Donny EC, Caggiula AR, Rowell PP et al (2000) Nicotine self-administration in rats: estrous cycle effects, sex differences and nicotinic receptor binding. Psychopharmacology 151:392–405. doi:10.1007/s002130000497
Dougherty J, Miller D, Todd G, Kostenbauder HB (1981) Reinforcing and other behavioral effects of nicotine. Neurosci Biobehav Rev 5:487–495
Fowler CD, Kenny PJ (2014) Nicotine aversion: neurobiological mechanisms and relevance to tobacco dependence vulnerability. Neuropharmacology 76:533–544. doi:10.1016/j.neuropharm.2013.09.008
Goldberg SR, Spealman RD, Goldberg DM (1981) Persistent behavior at high rates maintained by intravenous self-administration of nicotine. Science 214:573–575. doi:10.1126/science.7291998
Goldberg SR, Spealman RD (1983) Suppression of behavior by intravenous injections of nicotine or by electric shocks in squirrel monkeys: effects of chlordiazepoxide and mecamylamine. J Pharmacol Exp Ther 224:334–340
Goldberg SR, Spealman RD, Risner ME, Henningfield JE (1983) Control of behavior by intravenous nicotine injections in laboratory animals. Pharmacol Biochem Behav 19:1011–1020
Goodwin AK, Hiranita T, Paule MG (2015) The reinforcing effects of nicotine in humans and nonhuman primates: a review of intravenous self-administration evidence and future directions for research. Nicotin Tob Res. doi:10.1093/ntr/ntv002
Gould RW, Czoty PW, Nader SH, Nader MA (2011) Effects of varenicline on the reinforcing and discriminative stimulus effects of cocaine in rhesus monkeys. J Pharmacol Exp Ther 339:678–686. doi:10.1124/jpet.111.185538
Harvey DM, Yasar S, Heishman SJ et al (2004) Nicotine serves as an effective reinforcer of intravenous drug-taking behavior in human cigarette smokers. Psychopharmacology 175:134–142
Hursh SR (2014) Behavioral economics and the analysis of consumption and choice. In: McSweeney FK, Murphy ES (eds) The Wiley Blackwell handbook of operant and classical conditioning. Wiley, Oxford. doi:10.1002/9781118468135.ch12
Hursh SR, Roma PG (2013) Behavioral economics and empirical public policy. J Exp Anal Behav 99:98–124
Hursh SR, Silberberg A (2008) Economic demand and essential value. Psychol Rev 115:186–198. doi:10.1037/0033-295X.115.1.186
Hursh SR, Winger G (1995) Normalized demand for drugs and other reinforcers. J Exp Anal Behav 64:373–384. doi:10.1901/jeab.1995.64-373
Hursh SR, Raslear TG, Shurtleff D et al (1988) A cost-benefit analysis of demand for food. J Exp Anal Behav 50:419–440
ILAR-NRC (2010) Guide for the care and use of laboratory animals. Washington, DC: National Academy Press
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
Justinova Z, Panlilio LV, Moreno-Sanz G, Redhi GH, Auber A, Secci ME et al (2015) Effects of fatty acid amide hydrolase (FAAH) inhibitors in non-human primate models of nicotine reward and relapse. Neuropsychopharmacology 40:2185–2197. doi:10.1038./npp.2015.62
Koffarnus MN, Winger G (2015) Individual differences in the reinforcing and punishing effects of nicotine in rhesus monkeys. Psychopharmacology 232:2393–2403. doi:10.1007/s00213-015-3871-8
Koffarnus MN, Hall A, Winger G (2011) Individual differences in rhesus monkeys’ demand for drugs of abuse. Addict Biol 17:887–896. doi:10.1111/j.1369-1600.2011.00335.x
Kohut SJ, Fivel PA, Mello NK (2013) Differential effects of acute and chronic treatment with the α2-adrenergic agonist, lofexidine, on cocaine self-administration in rhesus monkeys. Drug Alcohol Depend 133:593–599. doi:10.1016/j.drugalcdep.2013.07.032
Le Foll B, Wertheim C, Goldberg SR (2007) High reinforcing efficacy of nicotine in non-human primates. PLoS ONE 2:e230. doi:10.1371/journal.pone.0000230.t001
Le Foll B, Chefer SI, Kimes AS, Stein EA, Goldberg SR, Mukhin AG (2016) Impact of short access nicotine self-administration of alpha4beta2 nicotinic acetylcholine receptors in non-human primates. Psychopharmacology. doi:10.1007/s00213-016-4250-9
Manzardo AM, Stein L, Belluzzi JD (2002) Rats prefer cocaine over nicotine in a two-lever self-administration choice test. Brain Res 924:10–19. doi:10.1016/S0006-8993(01)03215-2
Marquis KL, Webb MG, Moreton JE (1989) Effects of fixed ratio size and dose on phencyclidine self-administration by rats. Psychopharmacology 97:179–182. doi:10.1007/BF00442246
Mello NK, Newman JL (2011) Discriminative and reinforcing stimulus effects of nicotine, cocaine, and cocaine + nicotine combinations in rhesus monkeys. Exp Clin Psychopharmacol 19:203–214. doi:10.1037/a0023373
Moreton JE, Meisch RA, Stark L, Thompson T (1977) Ketamine self-administration by the rhesus monkey. J Pharmacol Exp Ther 203:303–309
National Center for Chronic Disease Prevention and Health Promotion (US) Office of Smoking and Health (2014) The health consequences of smoking—50 years of progress: a report of the surgeon general. Centers for Disease Control and Prevention (US), Atlanta
Risner ME, Goldberg SR (1983) A comparison of nicotine and cocaine self-administration in the dog: fixed-ratio and progressive-ratio schedules of intravenous drug infusion. J Pharmacol Exp Ther 224:319–326
Schuster CR, Thompson T (1969) Self administration of and behavioral dependence on drugs. Annu Rev Pharmacol 9:483–502. doi:10.1146/annurev.pa.09.040169.002411
Slifer BL, Balster RL (1985) Intravenous self-administration of nicotine: with and without schedule-induction. Pharmacol Biochem Behav 22:61–69
Sofuoglu M, Yoo S, Hill KP, Mooney M (2007) Self-administration of intravenous nicotine in male and female cigarette smokers. Neuropsychopharmacology 33:715–720. doi:10.1038/sj.npp.1301460
Spealman RD (1983) Maintenance of behavior by postponement of schedule injections of nicotine in squirrel monkeys. J Pharmacol Exp Ther 227:154–159
Spealman RD, Goldberg SR (1982) Maintenance of schedule-controlled behavior by intravenous injections of nicotine in squirrel monkeys. J Pharmacol Exp Ther 223:402–408
Wade-Galuska T, Galuska CM, Winger G (2011) Effects of daily morphine administration and deprivation on choice and demand for remifentanil and cocaine in rhesus monkeys. J Exp Anal Behav 95:75–89. doi:10.1901/jeab.2011.95-75
Wing VC, Shoaib M (2013) Effect of infusion rate on intravenous nicotine self-administration in rats. Behav Pharmacol 24:517–522. doi:10.1097/FBP.0b013e3283644d58
Winger G (1993) Fixed-ratio and time-out changes on behavior maintained by cocaine or methohexital in rhesus monkeys: I. Comparison of reinforcing strength. Exp Clin Psychopharmacol 1:142
Acknowledgments
This work was supported by grants K01-DA039306 and R01-DA026892 from the National Institute on Drug Abuse, National Institute of Health. We thank Claire Barkin and George Anderson for the excellent technical assistance. We also thank Dr. Peter G. Roma for the helpful discussions regarding the demand analysis.
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The protocol used in this study was fully approved by the Institutional Animal Care and Use Committee at McLean Hospital.
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The authors declare that they have no conflicts of interest.
Funding
This work was funded by NIH grants DA039306 and DA026892.
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Kohut, S.J., Bergman, J. Reinforcing effectiveness of nicotine in nonhuman primates: effects of nicotine dose and history of nicotine self-administration. Psychopharmacology 233, 2451–2458 (2016). https://doi.org/10.1007/s00213-016-4293-y
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DOI: https://doi.org/10.1007/s00213-016-4293-y