Abstract
The presence and function of cannabinoid CB2 receptors in the brain have been the subjects of much debate. We found that systemic, intranasal or intra-accumbens local administration of JWH133, a selective CB2 receptor agonist, dose-dependently inhibited intravenous cocaine self-administration, cocaine-enhanced locomotion, and cocaine-enhanced accumbens extracellular dopamine in wild-type and CB1 receptor knockout (CB1−/−, also known as Cnr1−/−) mice, but not in CB2−/− (Cnr2−/−) mice. This inhibition was mimicked by GW405833, another CB2 receptor agonist with a different chemical structure, and was blocked by AM630, a selective CB2 receptor antagonist. Intra-accumbens administration of JWH133 alone dose-dependently decreased, whereas intra-accumbens administration of AM630 elevated, extracellular dopamine and locomotion in wild-type and CB1−/− mice, but not in CB2−/− mice. Intra-accumbens administration of AM630 also blocked the reduction in cocaine self-administration and extracellular dopamine produced by systemic administration of JWH133. These findings suggest that brain CB2 receptors modulate cocaine's rewarding and locomotor-stimulating effects, likely by a dopamine-dependent mechanism.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Parolaro, D. & Rubino, T. The role of the endogenous cannabinoid system in drug addiction. Drug News Perspect. 21, 149–157 (2008).
Mackie, K. Cannabinoid receptors: where they are and what they do. J. Neuroendocrinol. 20 (suppl. 1), 10–14 (2008).
Glass, M., Dragunow, M. & Faull, R.L. Cannabinoid receptors in the human brain: a detailed anatomical and quantitative autoradiographic study in the fetal, neonatal and adult human brain. Neuroscience 77, 299–318 (1997).
Griffin, G., Tao, Q. & Abood, M.E. Cloning and pharmacological characterization of the rat CB2 cannabinoid receptor. J. Pharmacol. Exp. Ther. 292, 886–894 (2000).
Munro, S., Thomas, K.L. & Abu-Shaar, M. Molecular characterization of a peripheral receptor for cannabinoids. Nature 365, 61–65 (1993).
Malan, T.P. Jr. et al. CB2 cannabinoid receptor agonists: pain relief without psychoactive effects? Curr. Opin. Pharmacol. 3, 62–67 (2003).
Stella, N. Cannabinoid and cannabinoid-like receptors in microglia, astrocytes, and astrocytomas. Glia 58, 1017–1030 (2010).
Baek, J.H., Zheng, Y., Darlington, C.L. & Smith, P.F. Cannabinoid CB2 receptor expression in the rat brainstem cochlear and vestibular nuclei. Acta Otolaryngol. (Stockh.) 128, 1–7 (2008).
Gong, J.-P. Cannabinoid CB2 receptors: immunohistochemical localization in rat brain. Brain Res. 1071, 10–23 (2006).
Onaivi, E.S. et al. Discovery of the presence and functional expression of cannabinoid CB2 receptors in brain. Ann. NY Acad. Sci. 1074, 514–536 (2006).
Van Sickle, M.D. et al. Identification and functional characterization of brainstem cannabinoid CB2 receptors. Science 310, 329–332 (2005).
Guindon, J. & Hohmann, A.G. Cannabinoid CB2 receptors: a therapeutic target for the treatment of inflammatory and neuropathic pain. Br. J. Pharmacol. 153, 319–334 (2008).
Jhaveri, M.D. et al. Evidence for a novel functional role of cannabinoid CB2 receptors in the thalamus of neuropathic rats. Eur. J. Neurosci. 27, 1722–1730 (2008).
Goncalves, M.B. et al. A diacylglycerol lipase-CB2 cannabinoid pathway regulates adult subventricular zone neurogenesis in an age-dependent manner. Mol. Cell. Neurosci. 38, 526–536 (2008).
Viscomi, M.T. et al. Selective CB2 receptor agonism protects central neurons from remote axotomy-induced apoptosis through the PI3K/Akt pathway. J. Neurosci. 29, 4564–4570 (2009).
Sagredo, O. et al. Cannabinoid CB2 receptor agonists protect the striatum against malonate toxicity: relevance for Huntington's disease. Glia 57, 1154–1167 (2009).
Elmes, S.J.R., Jhaveri, M.D., Smart, D., Kendall, D.A. & Chapman, V. Cannabinoid CB2 receptor activation inhibits mechanically evoked responses of wide dynamic range dorsal horn neurons in naive rats and in rat models of inflammatory and neuropathic pain. Eur. J. Neurosci. 20, 2311–2320 (2004).
Sagar, D.R. et al. Inhibitory effects of CB1 and CB2 receptor agonists on responses of DRG neurons and dorsal horn neurons in neuropathic rats. Eur. J. Neurosci. 22, 371–379 (2005).
Morgan, N.H., Stanford, I.M. & Woodhall, G.L. Functional CB2 type cannabinoid receptors at CNS synapses. Neuropharmacology 57, 356–368 (2009).
Ashton, J.C., Wright, J.L., McPartland, J.M. & Tyndall, J.D.A. Cannabinoid CB1 and CB2 receptor ligand specificity and the development of CB2-selective agonists. Curr. Med. Chem. 15, 1428–1443 (2008).
Huffman, J.W. CB2 receptor ligands. Mini Rev. Med. Chem. 5, 641–649 (2005).
Richardson, N.R. & Roberts, D.C.S. Progressive ratio schedules in drug self-administration studies in rats: a method to evaluate reinforcing efficacy. J. Neurosci. Methods 66, 1–11 (1996).
Soria, G. et al. Lack of CB1 cannabinoid receptor impairs cocaine self-administration. Neuropsychopharmacology 30, 1670–1680 (2005).
Li, X. et al. Attenuation of basal and cocaine-enhanced locomotion and nucleus accumbens dopamine in cannabinoid CB1 receptor knockout mice. Psychopharmacology (Berl.) 204, 1–11 (2009).
Thakur, G.A., Nikas, S.P. & Makriyannis, A. CB1 cannabinoid receptor ligands. Mini Rev. Med. Chem. 5, 631–640 (2005).
Valenzano, K.J. et al. Pharmacological and pharmacokinetic characterization of the cannabinoid receptor 2 agonist, GW405833, utilizing rodent models of acute and chronic pain, anxiety, ataxia and catalepsy. Neuropharmacology 48, 658–672 (2005).
Xi, Z.-X. Cannabinoid CB1 receptor antagonists attenuate cocaine's rewarding effects: experiments with self-administration and brain-stimulation reward in rats. Neuropsychopharmacology 33, 1735–1745 (2008).
Costantino, H.R., Illum, L., Brandt, G., Johnson, P.H. & Quay, S.C. Intranasal delivery: physicochemical and therapeutic aspects. Int. J. Pharm. 337, 1–24 (2007).
Wise, R.A. Dopamine, learning and motivation. Nat. Rev. Neurosci. 5, 483–494 (2004).
Schwarting, R.K.W. & Huston, J.P. Behavioral and neurochemical dynamics of neurotoxic meso-striatal dopamine lesions. Neurotoxicology 18, 689–708 (1997).
Bardo, M.T. Neuropharmacological mechanisms of drug reward: beyond dopamine in the nucleus accumbens. Crit. Rev. Neurobiol. 12, 37–67 (1998).
Malan, T.P. Jr. et al. CB2 cannabinoid receptor–mediated peripheral antinociception. Pain 93, 239–245 (2001).
Chin, C.-L. et al. Differential effects of cannabinoid receptor agonists on regional brain activity using pharmacological MRI. Br. J. Pharmacol. 153, 367–379 (2008).
Mukherjee, S. et al. Species comparison and pharmacological characterization of rat and human CB2 cannabinoid receptors. Eur. J. Pharmacol. 505, 1–9 (2004).
Yao, B.B. et al. In vitro pharmacological characterization of AM1241: a protean agonist at the cannabinoid CB2 receptor? Br. J. Pharmacol. 149, 145–154 (2006).
Bingham, B. et al. Species-specific in vitro pharmacological effects of the cannabinoid receptor 2 (CB2) selective ligand AM1241 and its resolved enantiomers. Br. J. Pharmacol. 151, 1061–1070 (2007).
Ibrahim, M.M. et al. CB2 cannabinoid receptor activation produces antinociception by stimulating peripheral release of endogenous opioids. Proc. Natl. Acad. Sci. USA 102, 3093–3098 (2005).
Atwood, B.K. & Mackie, K. CB2: a cannabinoid receptor with an identity crisis. Br. J. Pharmacol. 160, 467–479 (2010).
Brown, S.M., Wager-Miller, J. & Mackie, K. Cloning and molecular characterization of the rat CB2 cannabinoid receptor. Biochim. Biophys. Acta 1576, 255–264 (2002).
Schatz, A.R., Lee, M., Condie, R.B., Pulaski, J.T. & Kaminski, N.E. Cannabinoid receptors CB1 and CB2: a characterization of expression and adenylate cyclase modulation within the immune system. Toxicol. Appl. Pharmacol. 142, 278–287 (1997).
Liu, Q.-R. et al. Species differences in cannabinoid receptor 2 (CNR2 gene): identification of novel human and rodent CB2 isoforms, differential tissue expression and regulation by cannabinoid receptor ligands. Genes Brain Behav. 8, 519–530 (2009).
Bayewitch, M. et al. The peripheral cannabinoid receptor: adenylate cyclase inhibition and G protein coupling. FEBS Lett. 375, 143–147 (1995).
Lanciego, J.L. et al. Expression of the mRNA coding the cannabinoid receptor 2 in the pallidal complex of Macaca fascicularis. J. Psychopharmacol. 25, 97–104 (2010).
Zhang, J. et al. Induction of CB2 receptor expression in the rat spinal cord of neuropathic but not inflammatory chronic pain models. Eur. J. Neurosci. 17, 2750–2754 (2003).
Anand, U. et al. Cannabinoid receptor CB2 localization and agonist-mediated inhibition of capsaicin responses in human sensory neurons. Pain 138, 667–680 (2008).
Ross, R.A. et al. Actions of cannabinoid receptor ligands on rat cultured sensory neurones: implications for antinociception. Neuropharmacology 40, 221–232 (2001).
Beltramo, M. et al. CB2 receptor-mediated antihyperalgesia: possible direct involvement of neural mechanisms. Eur. J. Neurosci. 23, 1530–1538 (2006).
Haydon, P.G., Blendy, J., Moss, S.J. & Rob Jackson, F. Astrocytic control of synaptic transmission and plasticity: a target for drugs of abuse? Neuropharmacology 56 (suppl. 1), 83–90 (2009).
Zimmer, A., Zimmer, A.M., Hohmann, A.G., Herkenham, M. & Bonner, T.I. Increased mortality, hypoactivity, and hypoalgesia in cannabinoid CB1 receptor knockout mice. Proc. Natl. Acad. Sci. USA 96, 5780–5785 (1999).
Buckley, N.E. et al. Immunomodulation by cannabinoids is absent in mice deficient for the cannabinoid CB2 receptor. Eur. J. Pharmacol. 396, 141–149 (2000).
Acknowledgements
We thank Y. Shaham and E.A. Stein of the Intramural Research Program of the National Institute on Drug Abuse, and K. Mackie of Indiana University for their helpful comments on this manuscript. This research was supported by the Intramural Research Program of the National Institute on Drug Abuse.
Author information
Authors and Affiliations
Contributions
Z.-X.X. developed the original research proposal, designed and supervised all of the experiments, analyzed all of the data and wrote the manuscript. X.-Q.P., X.L. and R.S. conducted the cocaine self-administration experiments. X.L., G.-H.B. and H.-Y.Z. conducted the in vivo microdialysis experiments. X.L., H.-J.Y., R.S. and J.L. conducted the locomotor behavioral experiments. X.-Q.P., R.S. and H.-J.Y. conducted the conditioned place preference/aversion experiments. Q.-R.L. contributed to the original research proposal. E.L.G. contributed to the original idea of this work and was responsible for overall supervision of the research and for revisions and modifications to the manuscript.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Supplementary Text and Figures
Supplementary Figures 1–5 (PDF 270 kb)
Rights and permissions
About this article
Cite this article
Xi, ZX., Peng, XQ., Li, X. et al. Brain cannabinoid CB2 receptors modulate cocaine's actions in mice. Nat Neurosci 14, 1160–1166 (2011). https://doi.org/10.1038/nn.2874
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nn.2874
This article is cited by
-
PPARα and PPARγ are expressed in midbrain dopamine neurons and modulate dopamine- and cannabinoid-mediated behavior in mice
Molecular Psychiatry (2023)
-
Repeated cocaine administration upregulates CB2 receptor expression in striatal medium-spiny neurons that express dopamine D1 receptors in mice
Acta Pharmacologica Sinica (2022)
-
Therapeutic potential of PIMSR, a novel CB1 receptor neutral antagonist, for cocaine use disorder: evidence from preclinical research
Translational Psychiatry (2022)
-
Cannabinoids, reward processing, and psychosis
Psychopharmacology (2022)
-
Hippocampal Cannabinoid 1 Receptors Are Modulated Following Cocaine Self-administration in Male Rats
Molecular Neurobiology (2022)