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.