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

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), 9 beta-(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), Delta(9)-tetra-hydrocannabinol (Delta(9)-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, Delta(9)-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 D-2 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 D-2 signaling mechanisms.