Abstract
Previous studies suggest that cannabinoid CB1 receptors do not appear to be involved in cocaine's rewarding effects, as assessed by the use of SR141716A, a prototypic CB1 receptor antagonist and CB1-knockout mice. In the present study, we found that blockade of CB1 receptors by AM 251 (1–10 mg/kg), a novel CB1 receptor antagonist, dose-dependently lowered (by 30–70%) the break point for cocaine self-administration under a progressive-ratio (PR) reinforcement schedule in rats. The same doses of SR141716 (freebase form) maximally lowered the break point by 35%, which did not reach statistical significance. Neither AM 251 nor SR141716 altered cocaine self-administration under a fixed-ratio (FR2) reinforcement schedule. AM 251 (0.1–3 mg/kg) also significantly and dose-dependently inhibited (by 25–90%) cocaine-enhanced brain stimulation reward (BSR), while SR141716 attenuated cocaine's BSR-enhancing effect only at 3 mg/kg (by 40%). When the dose was increased to 10 or 20 mg/kg, both AM 251 and SR141716 became less effective, with AM 251 only partially inhibiting cocaine-enhanced BSR and PR cocaine self-administration, and SR141716 having no effect. AM 251 alone, at all doses tested, had no effect on BSR, while high doses of SR141716 alone significantly inhibited BSR. These data suggest that blockade of CB1 receptors by relatively low doses of AM 251 dose-dependently inhibits cocaine's rewarding effects, whereas SR141716 is largely ineffective, as assessed by both PR cocaine self-administration and BSR. Thus, AM 251 or other more potent CB1 receptor antagonists deserve further study as potentially effective anti-cocaine medications.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Arnold JC (2005). The role of endocannabinoid transmission in cocaine addiction. Pharmacol Biochem Behav 81: 396–406.
Arnold JC, Hunt GE, McGregor IS (2001). Effects of the cannabinoid receptor agonist CP 55,940 and the cannabinoid receptor antagonist SR141716 on intracranial self-stimulation in Lewis rats. Life Sci 70: 97–108.
Arnold JM, Roberts DCS (1997). A critique of fixed and progressive ratio schedules used to examine the neural substrates of drug reinforcement. Pharmacol Biochem Behav 57: 441–447.
Bass CE, Griffin G, Grier M, Mahadevan A, Razdan RK, Martin BR (2002). SR-141716A-induced stimulation of locomotor activity. A structure-activity relationship study. Pharmacol Biochem Behav 74: 31–40.
Bauco P, Wise RA (1997). Synergistic effects of cocaine with lateral hypothalamic brain stimulation reward: lack of tolerance or sensitization. J Pharmacol Exp Ther 283: 1160–1167.
Beardsley PM, Thomas BF (2005). Current evidence supporting a role of cannabinoid CB1 receptor (CB1R) antagonists as potential pharmacotherapies for drug abuse disorders. Behav Pharmacol 16: 275–296.
Caillé S, Parsons LH (2006). Cannabinoid modulation of opiate reinforcement through the ventral striatopallidal pathway. Neuropsychopharmacology 31: 804–813.
Carlezon Jr WA, Wise RA (1996). Microinjections of phencyclidine (PCP) and related drugs into nucleus accumbens shell potentiate medial forebrain bundle brain stimulation reward. Psychopharmacology 128: 413–420.
Centonze D, Battista N, Rossi S, Mercuri NB, Finazzi-Agró A, Bernardi G et al (2004). A critical interaction between dopamine D2 receptors and endocannabinoids mediates the effects of cocaine on striatal GABAergic transmission. Neuropsychopharmacology 29: 1488–1497.
Centonze D, Picconi B, Baunez C, Borrelli E, Pisani A, Bernardi G et al (2002). Cocaine and amphetamine depress striatal GABAergic synaptic transmission through D2 dopamine receptors. Neuropsychopharmacology 26: 164–175.
Chaperon F, Soubrié P, Puech AJ, Thiébot M-H (1998). Involvement of central cannabinoid (CB1) receptors in the establishment of place conditioning in rats. Psychopharmacology 135: 324–332.
Chen J, Paredes W, Li J, Smith D, Lowinson J, Gardner EL (1990). Δ9-tetrahydrocannabinol produces naloxone-blockable enhancement of presynaptic basal dopamine efflux in nucleus accumbens of conscious, freely-moving rats as measured by intracerebral microdialysis. Psychopharmacology 102: 156–162.
Cohen C, Kodas E, Griebel G (2005). CB1 receptor antagonists for the treatment of nicotine addiction. Pharmacol Biochem Behav 81: 387–395.
Corbillé AG, Valjent E, Marsicano G, Ledent C, Lutz B, Herve D et al (2007). Role of cannabinoid type 1 receptors in locomotor activity and striatal signaling in response to psychostimulants. J Neurosci 27: 6937–6947.
Cossu G, Ledent C, Fattore L, Imperato A, Bohme GA, Parmentier M et al (2001). Cannabinoid CB1 receptor knockout mice fail to self-administer morphine but not other drugs of abuse. Behav Brain Res 118: 61–65.
Coulombe D, Miliaressis E (1987). Fitting intracranial self-stimulation data with growth models. Behav Neurosci 101: 209–214.
Crawley JN (1999). Behavioral phenotyping of transgenic and knockout mice: experimental design and evaluation of general health, sensory functions, motor abilities, and specific behavioral tests. Brain Res 835: 18–26.
De Vries TJ, Shaham Y, Homberg JR, Crombag H, Schuurman K, Dieben J et al (2001). A cannabinoid mechanism in relapse to cocaine seeking. Nat Med 7: 1151–1154.
Deroche-Gamonet V, Le Moal M, Piazza PV, Soubrié P (2001). SR141716, a CB1 receptor antagonist, decreases the sensitivity to the reinforcing effects of electrical brain stimulation in rats. Psychopharmacology 157: 254–259.
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.
Fattore L, Cossu G, Spano MS, Deiana S, Fadda P, Scherma M et al (2004). Cannabinoids and reward: interactions with the opioid system. Crit Rev Neurobiol 16: 147–158.
Fattore L, Martellotta MC, Cossu G, Mascia MS, Fratta W (1999). CB1 cannabinoid receptor agonist WIN 55,212-2 decreases intravenous cocaine self-administration in rats. Behav Brain Res 104: 141–146.
Foltin RW, Fischman MW, Pippen PA, Kelly TH (1993). Behavioral effects of cocaine alone and in combination with ethanol or marijuana in humans. Drug Alcohol Depend 32: 93–106.
Freund TF, Katona I, Piomelli D (2003). Role of endogenous cannabinoids in synaptic signaling. Physiol Rev 83: 1017–1066.
Gardner EL (2000). What we have learned about addiction from animal models of drug self-administration. Am J Addict 9: 285–313.
Gardner EL, Paredes W, Smith D, Donner A, Milling C, Cohen D et al (1988). Facilitation of brain stimulation reward by Δ9-tetrahydrocannabinol. Psychopharmacology 96: 142–144.
Giuffrida A, Parsons LH, Kerr TM, Rodriguez de Fonseca F, Navarro M, Piomelli D (1999). Dopamine activation of endogenous cannabinoid signaling in dorsal striatum. Nat Neurosci 2: 358–363.
Hajos N, Ledent C, Freund TF (2001). Novel cannabinoid-sensitive receptor mediates inhibition of glutamatergic synaptic transmission in the hippocampus. Neuroscience 106: 1–4.
Herkenham M, Lynn AB, de Costa BR, Richfield EK (1991). Neuronal localization of cannabinoid receptors in the basal ganglia of the rat. Brain Res 547: 267–274.
Krishnamurthy M, Li W, Moore II BM (2004). Synthesis, biological evaluation, and structural studies on N1 and C5 substituted cycloalkyl analogues of the pyrazole class of CB1 and CB2 ligands. Bioorg Med Chem 12: 393–404.
Lan R, Liu Q, Fan P, Lin S, Fernando SR, McCallion D et al (1999). Structure-activity relationships of pyrazole derivatives as cannabinoid receptor antagonists. J Med Chem 42: 769–776.
Le Foll B, Goldberg SR (2005). Cannabinoid CB1 receptor antagonists as promising new medications for drug dependence. J Pharmacol Exp Ther 312: 875–883.
Ledent C, Valverde O, Cossu G, Petitet F, Aubert J-F, Beslot F et al (1999). Unresponsiveness to cannabinoids and reduced addictive effects of opiates in CB1 receptor knockout mice. Science 283: 401–404.
Lesscher HMB, Hoogveld E, Burbach PH, van Ree JM, Gerrits MAFM (2005). Endogenous cannabinoids are not involved in cocaine reinforcement and development of cocaine-induced behavioural sensitization. Eur Neuropsychopharm 15: 31–37.
Lukas SE, Sholar M, Kouri E, Fukuzako H, Mendelson JH (1994). Marihuana smoking increases plasma cocaine levels and subjective reports of euphoria in male volunteers. Pharmacol Biochem Behav 48: 715–721.
Lupica CR, Riegel AC, Hoffman AF (2004). Marijuana and cannabinoid regulation of brain reward circuits. Br J Pharmacol 143: 227–234.
Mailleux P, Vanderhaeghen JJ (1992). Distribution of neuronal cannabinoid receptor in the adult rat brain: a comparative receptor binding radioautography and in situ hybridization histochemistry. Neuroscience 48: 655–668.
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 M, Ledent C, Parmentier M, Maldonado R, Valverde O (2000). Cocaine, but not morphine, induces conditioned place preference and sensitization to locomotor responses in CB1 knockout mice. Eur J Neurosci 12: 4038–4046.
Matyas F, Yanovsky Y, Mackie K, Kelsch W, Misgeld U, Freund TF (2006). Subcellular localization of type 1 cannabinoid receptors in the rat basal ganglia. Neuroscience 137: 337–361.
Nicola SM, Malenka RC (1997). Dopamine depresses excitatory and inhibitory synaptic transmission by distinct mechanisms in the nucleus accumbens. J Neurosci 17: 5697–5710.
O’Brien CP, Gardner EL (2005). Critical assessment of how to study addiction and its treatment: human and non-human animal models. Pharmacol Ther 108: 18–58.
Patel S, Rademacher DJ, Hillard CJ (2003). Differential regulation of the endocannabinoids anandamide and 2-arachidonylglycerol within the limbic forebrain by dopamine receptor activity. J Pharmacol Exp Ther 306: 880–888.
Paxinos G, Watson C (1998). The Rat Brain in Stereotaxic Coordinates, 4th edn. Academic Press: San Diego, CA.
Pertwee RG (2005). Inverse agonism and neutral antagonism at cannabinoid CB1 receptors. Life Sci 76: 1307–1324.
Phillips TJ, Hen R, Crabbe JC (1999). Complications associated with genetic background effects in research using knockout mice. Psychopharmacology 147: 5–7.
Richardson NR, Roberts DCS (1996). Progressive ratio schedules in drug self-administration studies in rats: a method to evaluate reinforcing efficacy. J Neurosci Methods 66: 1–11.
Rinaldi-Carmona M, Barth F, Héaulme M, Shire D, Calandra B, Congy C et al (1994). SR141716A, a potent and selective antagonist of the brain cannabinoid receptor. FEBS Lett 350: 240–244.
Robbe D, Alonso G, Duchamp F, Bockaert J, Manzoni OJ (2001). Localization and mechanisms of action of cannabinoid receptors at the glutamatergic synapses of the mouse nucleus accumbens. J Neurosci 21: 109–116.
Rowlett JK (2000). A labor-supply analysis of cocaine self-administration under progressive-ratio schedules: antecedents, methodologies, and perspectives. Psychopharmacology 153: 1–16.
Rubino T, Patrini G, Massi P, Fuzio D, Vigano D, Giagnoni G et al (1998). Cannabinoid-precipitated withdrawal: a time-course study of the behavioral aspect and its correlation with cannabinoid receptors and G protein expression. J Pharmacol Exp Ther 285: 813–819.
Rubino T, Vigano D, Zagato E, Sala M, Parolaro D (2000). In vivo characterization of the specific cannabinoid receptor antagonist, SR141716A: behavioral and cellular responses after acute and chronic treatments. Synapse 35: 8–14.
Soria G, Mendizábal V, Tourio C, Robledo P, Ledent C, Parmentier M et al (2005). Lack of CB1 cannabinoid receptor impairs cocaine self-administration. Neuropsychopharmacology 30: 1670–1680.
Tanda G, Goldberg SR (2003). Cannabinoids: reward, dependence, and underlying neurochemical mechanisms—a review of recent preclinical data. Psychopharmacology 169: 115–134.
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.
Tanda G, Pontieri FE, Di Chiara G (1997). Cannabinoid and heroin activation of mesolimbic dopamine transmission by a common μ1 opioid receptor mechanism. Science 276: 2048–2050.
Vinklerova J, Novakova J, Sulcova A (2002). Inhibition of methamphetamine self-administration in rats by cannabinoid receptor antagonist AM 251. J Psychopharmacol 16: 139–143.
Vinod KY, Hungund BL (2005). Endocannabinoid lipids and mediated system: implications for alcoholism and neuropsychiatric disorders. Life Sci 77: 1569–1583.
Vlachou S, Nomikos GG, Panagis G (2003). WIN 55,212-2 decreases the reinforcing actions of cocaine through CB1 cannabinoid receptor stimulation. Behav Brain Res 141: 215–222.
Vlachou S, Nomikos GG, Panagis G (2005). CB1 cannabinoid receptor agonists increase intracranial self-stimulation thresholds in the rat. Psychopharmacology 179: 498–508.
Wenger T, Moldrich G, Furst S (2003). Neuromorphological background of cannabis addiction. Brain Res Bull 61: 125–128.
White FJ, Hu X-T, Henry DJ (1993). Electrophysiological effects of cocaine in the rat nucleus accumbens: microiontophoretic studies. J Pharmacol Exp Ther 266: 1075–1084.
Wiley JL, Martin BR (2002). Cannabinoid pharmacology: implications for additional cannabinoid receptor subtypes. Chem Phys Lipids 121: 57–63.
Wise RA (1996). Addictive drugs and brain stimulation reward. Annu Rev Neurosci 19: 319–340.
Xi Z-X, Gardner EL (2007). Pharmacological actions of NGB 2904, a novel dopamine D3 receptor antagonist, in animal models of drug addiction. CNS Drug Rev 13: 240–259.
Xi Z-X, Gilbert JG, Pak AC, Ashby Jr CR, Heidbreder CA, Gardner EL (2005). Selective dopamine D3 receptor antagonism by SB-277011A attenuates cocaine reinforcement as assessed by progressive-ratio and variable-cost-variable-payoff fixed-ratio cocaine self-administration in rats. Eur J Neurosci 21: 3427–3438.
Xi Z-X, Gilbert JG, Peng X-Q, Pak AC, Li X, Gardner EL (2006a). Cannabinoid CB1 receptor antagonist AM 251 inhibits cocaine-primed relapse in rats: role of glutamate in the nucleus accumbens. J Neurosci 26: 8531–8536.
Xi Z-X, Newman AH, Gilbert JG, Pak AC, Peng X-Q, Ashby Jr CR et al (2006b). The novel dopamine D3 receptor antagonist NGB 2904 inhibits cocaine's rewarding effects and cocaine-induced reinstatement of drug-seeking behavior in rats. Neuropsychopharmacology 31: 1393–1405.
Xi Z-X, Peng X-Q, Li X, Gilbert J, Pak AC, Gardner EL (2006c). Δ9-Tetrahydrocannabinol (Δ9-THC) inhibits glutamate release in the nucleus accumbens via a non-CB1 receptor-mediated mechanism. Abstracts of 35th Annual Meeting of Society for Neuroscience, Abstract 766.9.
Acknowledgements
This research was supported by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services.
Author information
Authors and Affiliations
Corresponding author
Additional information
DISCLOSURE/CONFLICT OF INTEREST
We hereby declare that, except for income received from their respective primary employers, no financial support or compensation has been received from any individual or corporate entity over the past 3 years for research or professional services. There are no personal financial holdings that could be perceived as constituting a potential conflict of interest.
Rights and permissions
About this article
Cite this article
Xi, ZX., Spiller, K., Pak, A. et al. Cannabinoid CB1 Receptor Antagonists Attenuate Cocaine's Rewarding Effects: Experiments with Self-Administration and Brain-Stimulation Reward in Rats. Neuropsychopharmacol 33, 1735–1745 (2008). https://doi.org/10.1038/sj.npp.1301552
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/sj.npp.1301552
Keywords
This article is cited by
-
AM6527, a neutral CB1 receptor antagonist, suppresses opioid taking and seeking, as well as cocaine seeking in rodents without aversive effects
Neuropsychopharmacology (2024)
-
Therapeutic potential of PIMSR, a novel CB1 receptor neutral antagonist, for cocaine use disorder: evidence from preclinical research
Translational Psychiatry (2022)
-
Beta-caryophyllene inhibits cocaine addiction-related behavior by activation of PPARα and PPARγ: repurposing a FDA-approved food additive for cocaine use disorder
Neuropsychopharmacology (2021)
-
Restoring glutamate homeostasis in the nucleus accumbens via endocannabinoid-mimetic drug prevents relapse to cocaine seeking behavior in rats
Neuropsychopharmacology (2021)
-
Cannabinoid type 1 receptors in A2a neurons contribute to cocaine-environment association
Psychopharmacology (2021)
