RT Journal Article
SR Electronic
T1 Analysis of Tolerance and Behavioral/Physical Dependence during Chronic CB<sub>1</sub> Agonist Treatment: Effects of CB<sub>1</sub> Agonists, Antagonists, and Noncannabinoid Drugs
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 319
OP 328
DO 10.1124/jpet.112.198374
VO 344
IS 2
A1 Rajeev I. Desai
A1 Ganesh A. Thakur
A1 V. Kiran Vemuri
A1 Shama Bajaj
A1 Alexandros Makriyannis
A1 Jack Bergman
YR 2013
UL http://jpet.aspetjournals.org/content/344/2/319.abstract
AB 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) &gt;250-fold (AM411, methanandamide) and &gt;45-fold (AM4054, WIN55,212.2, Δ9-THC) rightward shifts in the ED50 values for CB1 agonists; 2) &gt;100-fold and &gt;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.