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Research ArticleBehavioral Pharmacology

Analysis of Tolerance and Behavioral/Physical Dependence during Chronic CB1 Agonist Treatment: Effects of CB1 Agonists, Antagonists, and Noncannabinoid Drugs

Rajeev I. Desai, Ganesh A. Thakur, V. Kiran Vemuri, Shama Bajaj, Alexandros Makriyannis and Jack Bergman
Journal of Pharmacology and Experimental Therapeutics February 2013, 344 (2) 319-328; DOI: https://doi.org/10.1124/jpet.112.198374
Rajeev I. Desai
Preclinical Pharmacology Laboratory, Department of Psychiatry, McLean Hospital/Harvard Medical School, Belmont, Massachusetts (R.I.D., J.B.); and Center for Drug Discovery, Northeastern University, Boston, Massachusetts (G.A.T., V.K.V., S.B., A.M.)
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Ganesh A. Thakur
Preclinical Pharmacology Laboratory, Department of Psychiatry, McLean Hospital/Harvard Medical School, Belmont, Massachusetts (R.I.D., J.B.); and Center for Drug Discovery, Northeastern University, Boston, Massachusetts (G.A.T., V.K.V., S.B., A.M.)
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V. Kiran Vemuri
Preclinical Pharmacology Laboratory, Department of Psychiatry, McLean Hospital/Harvard Medical School, Belmont, Massachusetts (R.I.D., J.B.); and Center for Drug Discovery, Northeastern University, Boston, Massachusetts (G.A.T., V.K.V., S.B., A.M.)
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Shama Bajaj
Preclinical Pharmacology Laboratory, Department of Psychiatry, McLean Hospital/Harvard Medical School, Belmont, Massachusetts (R.I.D., J.B.); and Center for Drug Discovery, Northeastern University, Boston, Massachusetts (G.A.T., V.K.V., S.B., A.M.)
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Alexandros Makriyannis
Preclinical Pharmacology Laboratory, Department of Psychiatry, McLean Hospital/Harvard Medical School, Belmont, Massachusetts (R.I.D., J.B.); and Center for Drug Discovery, Northeastern University, Boston, Massachusetts (G.A.T., V.K.V., S.B., A.M.)
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Jack Bergman
Preclinical Pharmacology Laboratory, Department of Psychiatry, McLean Hospital/Harvard Medical School, Belmont, Massachusetts (R.I.D., J.B.); and Center for Drug Discovery, Northeastern University, Boston, Massachusetts (G.A.T., V.K.V., S.B., A.M.)
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Abstract

Behavioral studies of chronic CB1 receptor activation may provide a pharmacological approach to understanding efficacy-related differences among CB1 ligands as well as mechanistic commonalities between cannabinoid and noncannabinoid drugs. In the present studies, the effects of CB1 agonists [(6aR,10aR)-3-(1-adamantyl)-6,6,9-trimethyl-6a,7,10,10a-tetrahydrobenzo[c]chromen-1-ol (AM411), 9β-(hydroxymethyl)-3-(1-adamantyl)-hexahydrocannabinol (AM4054), R-(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone mesylate (WIN55,212.2), Δ9-tetrahydrocannabinol (Δ9-THC), (R)-(+)-arachidonyl-1'-hydroxy-2'-propylamide (methanandamide)], CB1 antagonists [5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide (SR141716A), 5-(4-alkylphenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide (AM4113)], and dopamine (DA)–related [methamphetamine, (±)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (SKF82958), (R)-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH23390), (6aR)-5,6,6a,7-tetrahydro-6-propyl-4H-dibenzo[de,g]quinoline-10,11-diol (R-(−)-NPA), haloperidol] and opioid (morphine, naltrexone) drugs on scheduled-controlled responding under a 30-response fixed ratio schedule of stimulus-shock termination in squirrel monkeys were compared before and during chronic treatment with the long-acting CB1 agonist AM411 (1.0 mg/kg per day, i.m.). Prechronic treatment with all drugs except naltrexone (1–10 mg/kg) produced dose-related decreases in responses rates. Dose-response re-determinations during chronic treatment revealed the following: 1) >250-fold (AM411, methanandamide) and >45-fold (AM4054, WIN55,212.2, Δ9-THC) rightward shifts in the ED50 values for CB1 agonists; 2) >100-fold and >20-fold leftward shifts in the ED50 values for SR141716A and AM4113, respectively; and 3) approximately 4.8-fold and 10-fold rightward shifts in the ED50 values for methamphetamine and the DA D2 agonist R-(−)-NPA, respectively. Dose-response relationships for other DA-related and opioid drugs were unchanged by chronic CB1 agonist treatment. Differences in the magnitude of tolerance among CB1 agonists during chronic treatment may be indicative of differences in their pharmacological efficacy, whereas the enhanced sensitivity to behaviorally disruptive effects of CB1 antagonists may provide evidence for CB1-related behavioral and/or physical dependence. Finally, the development of cross-tolerance to methamphetamine and R-(−)-NPA bolsters previous evidence of interplay between CB1 and DA D2 signaling mechanisms.

Footnotes

  • This research was supported by grants from National Institutes of Health National Institute on Drug Abuse [Grants DA19205 (J.B., principal investigator) and DA26795 (A.M., principal investigator)], as well as a Ruth L. Kirschstein National Service Award [awarded to R.I.D. (N.K. Mello, principal investigator).

  • dx.doi.org/10.1124/jpet.112.198374

  • Received July 11, 2012.
  • Accepted November 29, 2012.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 344 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 344, Issue 2
1 Feb 2013
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Research ArticleBehavioral Pharmacology

Cannabinoid Tolerance and Dependence

Rajeev I. Desai, Ganesh A. Thakur, V. Kiran Vemuri, Shama Bajaj, Alexandros Makriyannis and Jack Bergman
Journal of Pharmacology and Experimental Therapeutics February 1, 2013, 344 (2) 319-328; DOI: https://doi.org/10.1124/jpet.112.198374

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Research ArticleBehavioral Pharmacology

Cannabinoid Tolerance and Dependence

Rajeev I. Desai, Ganesh A. Thakur, V. Kiran Vemuri, Shama Bajaj, Alexandros Makriyannis and Jack Bergman
Journal of Pharmacology and Experimental Therapeutics February 1, 2013, 344 (2) 319-328; DOI: https://doi.org/10.1124/jpet.112.198374
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