Abstract
Rationale
Interest in therapeutic activities of cannabinoids has been restrained by the fact that they are most often mediated through activation of cannabinoid CB1 receptors, the same receptors that mediate the effects of Δ9-tetrahydrocannabinol (THC) and are responsible for the abuse liability of marijuana. Persistent intravenous self-administration of THC by animals was first demonstrated in squirrel monkeys and shown to be mediated by CB1 receptors, but monkeys in the study had a history of cocaine self-administration, raising the possibility that persistent neurobiological adaptations might subsequently predispose animals to self-administer THC.
Objectives
To demonstrate persistent intravenous self-administration of THC in drug-naive squirrel monkeys.
Methods
Monkeys with no history of exposure to other drugs learned to press a lever for intravenous injections (0.2 ml in 0.2 s) of THC under a 10-response, fixed-ratio schedule with a 60-s time-out after each injection. Acquisition of THC self-administration was rapid and the final schedule was reached in 11–34 sessions. Dose of THC was then varied from 1 to 16 µg/kg per injection with vehicle extinction following each dose of THC.
Results
THC maintained significantly higher numbers of self-administered injections per session and higher rates of responding than vehicle at doses of 2, 4 and 8 µg/kg per injection, with maximal rates of responding at 4 µg/kg per injection. Response rates, injections per session and total THC intake per session were two- to three-fold greater in monkeys with no history of exposure to other drugs compared to previous findings in monkeys with a history of cocaine self-administration.
Conclusions
THC can act as an effective reinforcer of drug-taking behavior in monkeys with no history of exposure to other drugs, suggesting that self-administration of THC by monkeys provides a reliable animal model of human marijuana abuse.
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References
Agurell S, Halldin M, Lindgren JE, Ohlsson A, Widman M, Gillespie H, Hollister L (1986) Pharmacokinetics and metabolism of delta 1-tetrahydrocannabinol and other cannabinoids with emphasis on man. Pharmacol Rev 38:21–43
Balster RL (1991) Drug abuse potential evaluation in animals. Br J Addict 86:1549–1558
Bergman J, Johanson CE (1985) The reinforcing properties of diazepam under several conditions in the rhesus monkey. Psychopharmacology 86:108–113
Carroll ME, Meisch RA (1984) Increased drug-reinforced behavior due to food deprivation. In: Thompson T, Dews PB, Barrett JE (eds) Advances in behavioral pharmacology. Academic Press, New York, pp 47–88
Cheer JF, Kendall DA, Marsden CA (2000) Cannabinoid receptors and reward in the rat: a conditioned place preference study. Psychopharmacology 151:25–30
Colpaert FC, Desmedt LK, Janssen PA (1976) Discriminative stimulus properties of benzodiazepines, barbiturates and pharmacologically related drugs; relation to some intrinsic and anticonvulsant effects. Eur J Pharmacol 37:113–123
Devane WA, Dysarz FA III, Johnson MR, Melvin LS, Howlett AC (1988) Determination and characterization of a cannabinoid receptor in rat brain. Mol Pharmacol 34:605–613
Fattore L, Cossu G, Martellotta CM, Fratta W (2001) Intravenous self-administration of the cannabinoid CB1 receptor agonist WIN 55,212-2 in rats. Psychopharmacology 156:410–416
Gaoni Y, Mechoulam R (1964) Isolation, structure, and partial synthesis of an active constituent of hashish. J Am Chem Soc 86:1646–1647
Goldberg SR (1973) Comparable behavior maintained under fixed-ratio and second-order schedules of food presentation, cocaine injection or d-amphetamine injection in the squirrel monkey. J Pharmacol Exp Ther 186:18–30
Harris RT, Waters W, McLendon D (1974) Evaluation of reinforcing capability of delta-9-tetrahydrocannabinol in rhesus monkeys. Psychopharmacologia 37:23–29
Herling S, Coale EH Jr, Hein DW, Winger G, Woods JH (1981) Similarity of the discriminative stimulus effects of ketamine, cyclazocine, and dextrorphan in the pigeon. Psychopharmacology 73:286–291
Hoffmeister F, Goldberg SR (1973) A comparison of chlorpromazine, imipramine, morphine and d-amphetamine self-administration in cocaine-dependent rhesus monkeys. J Pharmacol Exp Ther 187:8–14
Holtzman SG (1980) Phencyclidine-like discriminative effects of opioids in the rat. J Pharmacol Exp Ther 214:614–619
Kathuria S, Gaetani S, Fegley D, Valino F, Duranti A, Tontini A, Mor M, Tarzia G, Rana GL, Calignano A, Giustino A, Tattoli M, Palmery M, Cuomo V, Piomelli D (2003) Modulation of anxiety through blockade of anandamide hydrolysis. Nat Med 9:76–81
Ledent C, Valverde O, Cossu G, Petitet F, Aubert JF, Beslot F, Bohme GA, Imperato A, Pedrazzini T, Roques BP, Vassart G, Fratta W, Parmentier M (1999) Unresponsiveness to cannabinoids and reduced addictive effects of opiates in CB1 receptor knockout mice. Science 283:401–404
Lepore M, Vorel SR, Lowinson J, Gardner EL (1995) Conditioned place preference induced by delta 9-tetrahydrocannabinol: comparison with cocaine, morphine, and food reward. Life Sci 56:2073–2080
Maldonado R (2002) Study of cannabinoid dependence in animals. Pharmacol Ther 95:153–164
Mansbach RS, Nicholson KL, Martin BR, Balster RL (1994) Failure of delta(9)-tetrahydrocannabinol and CP 55,940 to maintain intravenous self-administration under a fixed-interval schedule in rhesus monkeys. Behav Pharmacol 5:219–225
Martellotta MC, Cossu G, Fattore L, Gessa GL, Fratta W (1998) Self-administration of the cannabinoid receptor agonist WIN 55,212-2 in drug-naive mice. Neuroscience 85:327–330
Martin BR, Lichtman AH (1998) Cannabinoid transmission and pain perception. Neurobiol Dis 5:447–461
Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI (1990) Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346:561–564
Munzar P, Yasar S, Redhi GH, Justinova Z, Goldberg SR (2001) High rates of midazolam self-administration in squirrel monkeys. Behav Pharmacol 12:257–265
Navarro M, Carrera MR, Fratta W, Valverde O, Cossu G, Fattore L, Chowen JA, Gomez R, del A, I, Villanua MA, Maldonado R, Koob GF, Rodriguez de Fonseca F (2001) Functional interaction between opioid and cannabinoid receptors in drug self-administration. J Neurosci 21:5344–5350
Olsen JL, Makhani M, Davis KH, Wall ME (1973) Preparation of 9-tetrahydrocannabinol for intravenous injection. J Pharm Pharmacol 25:344
Piomelli D, Giuffrida A, Calignano A, Rodriguez de Fonseca F (2000) The endocannabinoid system as a target for therapeutic drugs. Trends Pharmacol Sci 21:218–224
Sannerud CA, Prada J, Goldberg DM, Goldberg SR (1994) The effects of sertraline on nicotine self-administration and food-maintained responding in squirrel monkeys. Eur J Pharmacol 271:461–469
Sanudo-Pena MC, Tsou K, Delay ER, Hohman AG, Force M, Walker JM (1997) Endogenous cannabinoids as an aversive or counter-rewarding system in the rat. Neurosci Lett 223:125–128
Shannon HE, Herling S (1983) Discriminative stimulus effects of diazepam in rats: evidence for a maximal effect. J Pharmacol Exp Ther 227:160–166
Sidman M, Stebbins WC (1954) Satiation effects under fixed-ratio schedules of reinforcement. Comp Physiol Psychol 47:114–116
Spear DJ, Muntaner C, Goldberg SR, Katz JL (1991) Methohexital and cocaine self-administration under fixed-ratio and second-order schedules. Pharmacol Biochem Behav 38:411–416
Takahashi RN, Singer G (1979) Self-administration of delta 9-tetrahydrocannabinol by rats. Pharmacol Biochem Behav 11:737–740
Takahashi RN, Singer G (1980) Effects of body weight levels on cannabis self-injection. Pharmacol Biochem Behav 13:877–881
Tanda G, Goldberg SR (2003) Cannabinoids: reward, dependence and underlying neurochemical mechanisms. A review of recent preclinical data. Psychopharmacology DOI 10.1007/s00213-003-1485-7
Tanda G, Pontieri FE, Di Chiara G (1997) Cannabinoid and heroin activation of mesolimbic dopamine transmission by a common mu1 opioid receptor mechanism. Science 276:2048–2050
Tanda G, Munzar P, Goldberg SR (2000) Self-administration behavior is maintained by the psychoactive ingredient of marijuana in squirrel monkeys. Nat Neurosci 3:1073–1074
Valjent E, Maldonado R (2000) A behavioural model to reveal place preference to delta 9-tetrahydrocannabinol in mice. Psychopharmacology 147:436–438
Wilson RI, Nicoll RA (2002) Endocannabinoid signaling in the brain. Science 296:678–682
Young AM, Herling S (1986) Drugs as reinforcers: studies in laboratory animals. In: Goldberg SR, Stolerman IP (eds) Behavioral analysis of drug dependence. Academic Press, Orlando, pp 9–67
Young AM, Woods JH (1981) Maintenance of behavior by ketamine and related compounds in rhesus monkeys with different self-administration histories. J Pharmacol Exp Ther 218:720–727
Acknowledgements
This work was supported by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services.
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Justinova, Z., Tanda, G., Redhi, G.H. et al. Self-administration of Δ9-tetrahydrocannabinol (THC) by drug naive squirrel monkeys. Psychopharmacology 169, 135–140 (2003). https://doi.org/10.1007/s00213-003-1484-0
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DOI: https://doi.org/10.1007/s00213-003-1484-0