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Assessment of the Abuse Liability of Synthetic Cannabinoid Agonists JWH-030, JWH-175, and JWH-176

  • Tampus, Reinholdgher (Uimyung Research Institute for Neuroscience, School of Pharmacy, Sahmyook University) ;
  • Yoon, Seong Shoon (Center for Safety Pharmacology, Korea Institute of Toxicology) ;
  • Pena, June Bryan de la (Uimyung Research Institute for Neuroscience, School of Pharmacy, Sahmyook University) ;
  • Botanas, Chrislean Jun (Uimyung Research Institute for Neuroscience, School of Pharmacy, Sahmyook University) ;
  • Kim, Hee Jin (Uimyung Research Institute for Neuroscience, School of Pharmacy, Sahmyook University) ;
  • Seo, Joung-Wook (Center for Safety Pharmacology, Korea Institute of Toxicology) ;
  • Jeong, Eun Ju (Center for Safety Pharmacology, Korea Institute of Toxicology) ;
  • Jang, Choon Gon (Department of Pharmacology, School of Pharmacy, Sungkyunkwan University) ;
  • Cheong, Jae Hoon (Uimyung Research Institute for Neuroscience, School of Pharmacy, Sahmyook University)
  • Received : 2015.08.07
  • Accepted : 2015.08.25
  • Published : 2015.11.01

Abstract

The emergence and use of synthetic cannabinoids have greatly increased in recent years. These substances are easily dispensed over the internet and on the streets. Some synthetic cannabinoids were shown to have abuse liability and were subsequently regulated by authorities. However, there are compounds that are still not regulated probably due to the lack of abuse liability studies. In the present study, we assessed the abuse liability of three synthetic cannabinoids, namely JWH-030, JWH-175, and JWH-176. The abuse liability of these drugs was evaluated in two of the most widely used animal models for assessing the abuse potential of drugs, the conditioned place preference (CPP) and self-administration (SA) test. In addition, the open-field test was utilized to assess the effects of repeated (7 days) treatment and abrupt cessation of these drugs on the psychomotor activity of animals. Results showed that JWH-175 (0.5 mg/kg), but not JWH-030 or JWH-176 at any dose, significantly decreased the locomotor activity of mice. This alteration in locomotor activity was only evident during acute exposure to the drug and was not observed during repeated treatment and abstinence. Similarly, only JWH-175 (0.1 mg/kg) produced significant CPP in rats. On the other hand, none of the drugs tested was self-administered by rats. Taken together, the present results indicate that JWH-175, but not JWH-030 and JWH-176, may have abuse potential. More importantly, our findings indicate the complex psychopharmacological effects of synthetic cannabinoids and the need to closely monitor the production, dispensation, and use of these substances.

Keywords

References

  1. Auwarter, V., Dresen, S., Weinmann, W., Muller, M., Putz, M. and Ferreiros, N. (2009) 'Spice'and other herbal blends: harmless incense or cannabinoid designer drugs? J. Mass. Spectrom. 44, 832-837. https://doi.org/10.1002/jms.1558
  2. Botanas, C. J., de la Pena, J. B., dela Pena, I. J., Tampus, R., Yoon, R., Kim, H. J., Lee, Y. S., Jang, C. G. and Cheong, J. H. (2015) Methoxetamine, a ketamine derivative, produced conditioned place preference and was self-administered by rats: Evidence of its abuse potential. Pharmacol. Biochem. Behav. 133, 31-36. https://doi.org/10.1016/j.pbb.2015.03.007
  3. Braida, D., Iosue, S., Pegorini, S. and Sala, M. (2004) ${\Delta}$ 9-Tetrahydrocannabinol-induced conditioned place preference and intracerebroventricular self-administration in rats. Eur. J. Pharmacol. 506, 63-69. https://doi.org/10.1016/j.ejphar.2004.10.043
  4. Brents, L. K., Reichard, E. E., Zimmerman, S. M., Moran, J. H., Fantegrossi, W. E. and Prather, P. L. (2011) Phase I hydroxylated metabolites of the K2 synthetic cannabinoid JWH-018 retain in vitro and in vivo cannabinoid 1 receptor affinity and activity. PLoS One 6. e21917 https://doi.org/10.1371/journal.pone.0021917
  5. Chaperon, F., Soubrie, P., Puech, A. J. and Thiebot, M. H. (1998) Involvement of central cannabinoid (CB1) receptors in the establishment of place conditioning in rats. Psychopharmacology 135, 324-332. https://doi.org/10.1007/s002130050518
  6. Cheer, J., Kendall, D. and Marsden, C. (2000) Cannabinoid receptors and reward in the rat: a conditioned place preference study. Psychopharmacology 151, 25-30. https://doi.org/10.1007/s002130000481
  7. Crawley, J. N., Corwin, R. L., Robinson, J. K., Felder, C. C., Devane, W. A. and Axelrod, J. (1993) Anandamide, an endogenous ligand of the cannabinoid receptor, induces hypomotility and hypothermia in vivo in rodents. Pharmacol. Biochem. Behav. 46, 967-972. https://doi.org/10.1016/0091-3057(93)90230-Q
  8. de la Pena, J. B. I., Lee, H. C., Ike, C., Woo, T. S., Yoon, S. Y., Lee, H. L., Han, J. S., Lee, J. I., Cho, Y. J. and Shin, C. Y. (2012) Rewarding and reinforcing effects of the NMDA receptor antagonistbenzodiazepine combination, zoletil(R): Difference between acute and repeated exposure. Behav. Brain Res. 233, 434-442. https://doi.org/10.1016/j.bbr.2012.05.038
  9. Del Arco, I., Marti, J. L., Gorriti, M. A. and Navarro, M. (1998) Role of the endogenous cannabinoid system in the regulation of motor activity. Neurobiol. Dis. 5, 483-501. https://doi.org/10.1006/nbdi.1998.0217
  10. Drews, E., Schneider, M. and Koch, M. (2005) Effects of the cannabinoid receptor agonist WIN 55, 212-2 on operant behavior and locomotor activity in rats. Pharmacol. Biochem. Behav. 80, 145-150. https://doi.org/10.1016/j.pbb.2004.10.023
  11. Fadda, P., Scherma, M., Spano, M. S., Salis, P., Melis, V., Fattore, L. and Fratta, W. (2006) Cannabinoid self-administration increases dopamine release in the nucleus accumbens. Neuroreport 17, 1629-1632. https://doi.org/10.1097/01.wnr.0000236853.40221.8e
  12. Fantegrossi, W. E., Moran, J. H., Radominska-Pandya, A. and Prather, P. L. (2014) Distinct pharmacology and metabolism of K2 synthetic greater toxicity? Life Sci. 97, 45-54. https://doi.org/10.1016/j.lfs.2013.09.017
  13. Fattore, L. and Fratta, W. (2011) Beyond THC: the new generation of cannabinoid designer drugs. Front. Behav. Neurosci. 5. 60
  14. Ghozland, S., Matthes, H. W., Simonin, F., Filliol, D., Kieffer, B. L. and Maldonado, R. (2002) Motivational effects of cannabinoids are mediated by $\mu$-opioid and ${\kappa}$-opioid receptors. J. Neurosci. 22, 1146-1154.
  15. Golovko, A. (2011) Cannabinoids: Neurochemistry and neurobiology. Biol. Bull. Rev. 1, 526-535. https://doi.org/10.1134/S2079086411060028
  16. Gurney, S. M., Scott, K., Kacinko, S., Presley, B. and Logan, B. (2014) Pharmacology, toxicology, and adverse effects of synthetic cannabinoid drugs. Forensic. Sci. Rev. 26, 54-78.
  17. Huestis, M. A. (2002) Cannabis(Marijuana)- effects on human behavior and performance. Forensic Sci. Rev. 14, 15-60.
  18. Huffman, J. W. and Padgett, L. W. (2005) Recent developments in the medicinal chemistry of cannabimimetic indoles, pyrroles and indenes. Curr. Med. Chem. 12, 1395-1411. https://doi.org/10.2174/0929867054020864
  19. Justinova, Z., Tanda, G., Redhi, G. H. and Goldberg, S. R. (2003) Selfadministration of ${\Delta}$9-tetrahydrocannabinol (THC) by drug naive squirrel monkeys. Psychopharmacology 169, 135-140. https://doi.org/10.1007/s00213-003-1484-0
  20. Maldonado, R. (2002) Study of cannabinoid dependence in animals. Pharmacol. Ther. 95, 153-164. https://doi.org/10.1016/S0163-7258(02)00254-1
  21. Maldonado, R. and de Fonseca, F. R. (2002) Cannabinoid addiction: behavioral models and neural correlates. J. Neurosci. 22, 3326-3331.
  22. Martellotta, M., Cossu, G., Fattore, L., Gessa, G. and Fratta, W. (1998) Self-administration of the cannabinoid receptor agonist WIN 55, 212-2 in drug-naive mice. Neuroscience 85, 327-330. https://doi.org/10.1016/S0306-4522(98)00052-9
  23. McGregor, I. S., Issakidis, C. N. and Prior, G. (1996) Aversive effects of the synthetic cannabinoid CP 55,940 in rats. Pharmacol. Biochem. Behav. 53, 657-664. https://doi.org/10.1016/0091-3057(95)02066-7
  24. Presley, B., Jansen-Varnum, S. and Logan, B. (2013) Analysis of synthetic cannabinoids in botanical material: a review of analytical methods and findings. Forensic Sci. Rev. 25, 27-46.
  25. Rey, A. A., Purrio, M., Viveros, M. P. and Lutz, B. (2012) Biphasic effects of cannabinoids in anxiety responses: CB1 and GABAB receptors in the balance of GABAergic and glutamatergic neurotransmission. Neuropsychopharmacology 37, 2624-2634. https://doi.org/10.1038/npp.2012.123
  26. Sanudo-Pena, M. C., Romero, J., Seale, G. E., Fernandez-Ruiz, J. J. and Walker, J. M. (2000) Activational role of cannabinoids on movement. Eur. J. Pharmacol. 391, 269-274. https://doi.org/10.1016/S0014-2999(00)00044-3
  27. Schramm-Sapyta, N. L., Cha, Y. M., Chaudhry, S., Wilson, W. A., Swartzwelder, H. S. and Kuhn, C. M. (2007) Differential anxiogenic, aversive, and locomotor effects of THC in adolescent and adult rats. Psychopharmacology 191, 867-877. https://doi.org/10.1007/s00213-006-0676-9
  28. Solinas, M., Yasar, S. and Goldberg, S. R. (2007) Endocannabinoid system involvement in brain reward processes related to drug abuse. Pharmacol. Res. 56, 393-405. https://doi.org/10.1016/j.phrs.2007.09.005
  29. Tai, S. and Fantegrossi, W. E. (2014) Synthetic cannabinoids: pharmacology, behavioral effects, and abuse potential. Curr. Addict. Rep. 1, 129-136. https://doi.org/10.1007/s40429-014-0014-y
  30. Tanda, G., Munzar, P. and Goldberg, S. R. (2000) Self-administration behavior is maintained by the psychoactive ingredient of marijuana in squirrel monkeys. Nat. Neurosci. 3, 1073-1074. https://doi.org/10.1038/80577
  31. Tzschentke, T. M. (2007) Review on CPP: Measuring reward with the conditioned place preference (CPP) paradigm: update of the last decade. Addict. Biol. 12, 227-462. https://doi.org/10.1111/j.1369-1600.2007.00070.x
  32. Uchiyama, N., Kikura-Hanajiri, R., Matsumoto, N., Huang, Z.-L., Goda, Y. and Urade, Y. (2012) Effects of synthetic cannabinoids on electroencephalogram power spectra in rats. Forensic Sci. Int. 215, 179-183. https://doi.org/10.1016/j.forsciint.2011.05.005
  33. Valjent, E., Bertran-Gonzalez, J., Aubier, B., Greengard, P., Herve, D. and Girault, J.-A. (2010) Mechanisms of locomotor sensitization to drugs of abuse in a two-injection protocol. Neuropsychopharmacology 35, 401-415 https://doi.org/10.1038/npp.2009.143
  34. Valjent, E. and Maldonado, R. (2000) A behavioural model to reveal place preference to ${\Delta}$9-tetrahydrocannabinol in mice. Psychopharmacology 147, 436-438. https://doi.org/10.1007/s002130050013

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