TY - JOUR
T1 - Apparent affinity estimates of rimonabant in combination with anandamide and chemical analogs of anandamide in rhesus monkeys discriminating Δ9-tetrahydrocannabinol
AU - McMahon, Lance R.
N1 - Funding Information:
Acknowledgments Supported by the U.S. Public Health Service Grant DA19222. The author thanks Drs. A. Giuffrida and M. Morgese for assistance with synthesis and GC/MS analysis of anandamide, Drs. L. Gerak and W. Koek for assistance with data analysis, and V. Carlton, L. Hargrove, and J. Usrey for technical assistance.
PY - 2009/4
Y1 - 2009/4
N2 - Rationale: Anandamide and Δ9-tetrahydrocannabinol (Δ9-THC) sometimes produce different discriminative stimulus effects and, therefore, appear to differ in their mechanism of action. In order to understand the widespread use of cannabis and the therapeutic potential of cannabinoids, mechanisms responsible for behavioral effects need to be identified. Objective: Drug discrimination was used to compare the mechanism of action of Δ9-THC, anandamide, and two structural analogs of anandamide in rhesus monkeys. Materials and methods: Monkeys discriminated Δ9-THC (0.1 mg/kg i.v.) from vehicle. Δ9-THC, anandamide, methanandamide, and arachidonylcyclopropylamide (ACPA) were administered i.v. alone and in combination with at least one dose of rimonabant. Schild analysis and single-dose apparent affinity estimates were used to estimate the potency of rimonabant as an antagonist of each cannabinoid; these values were compared to examine whether the same receptors mediated discriminative stimulus effects. Results: Δ9-THC, ACPA, methanandamide, and anandamide produced greater than 96% of responses on the Δ9-THC lever. The ED50 values were 0.024 mg/kg for Δ9-THC, 0.14 mg/kg for ACPA, 0.28 mg/kg for methanandamide, and 1.7 mg/kg for anandamide. The duration of action of Δ9-THC was 4-6 h and longer than the duration of action ACPA, methanandamide, and anandamide (i.e., each less than 50 min). Rimonabant surmountably antagonized the discriminative stimulus effects of each agonist, and the apparent affinity estimates (pA 2 and pK B values) were 6.24-6.83. Conclusions: Rimonabant can produce surmountable antagonism of the behavioral effects of not only Δ9-THC but also anandamide, methanandamide, and ACPA, and the interactions appear simple, competitive, and reversible. These cannabinoid agonists act at the same receptors to produce discriminative stimulus effects.
AB - Rationale: Anandamide and Δ9-tetrahydrocannabinol (Δ9-THC) sometimes produce different discriminative stimulus effects and, therefore, appear to differ in their mechanism of action. In order to understand the widespread use of cannabis and the therapeutic potential of cannabinoids, mechanisms responsible for behavioral effects need to be identified. Objective: Drug discrimination was used to compare the mechanism of action of Δ9-THC, anandamide, and two structural analogs of anandamide in rhesus monkeys. Materials and methods: Monkeys discriminated Δ9-THC (0.1 mg/kg i.v.) from vehicle. Δ9-THC, anandamide, methanandamide, and arachidonylcyclopropylamide (ACPA) were administered i.v. alone and in combination with at least one dose of rimonabant. Schild analysis and single-dose apparent affinity estimates were used to estimate the potency of rimonabant as an antagonist of each cannabinoid; these values were compared to examine whether the same receptors mediated discriminative stimulus effects. Results: Δ9-THC, ACPA, methanandamide, and anandamide produced greater than 96% of responses on the Δ9-THC lever. The ED50 values were 0.024 mg/kg for Δ9-THC, 0.14 mg/kg for ACPA, 0.28 mg/kg for methanandamide, and 1.7 mg/kg for anandamide. The duration of action of Δ9-THC was 4-6 h and longer than the duration of action ACPA, methanandamide, and anandamide (i.e., each less than 50 min). Rimonabant surmountably antagonized the discriminative stimulus effects of each agonist, and the apparent affinity estimates (pA 2 and pK B values) were 6.24-6.83. Conclusions: Rimonabant can produce surmountable antagonism of the behavioral effects of not only Δ9-THC but also anandamide, methanandamide, and ACPA, and the interactions appear simple, competitive, and reversible. These cannabinoid agonists act at the same receptors to produce discriminative stimulus effects.
KW - Anandamide
KW - Arachidonylcyclopropylamide
KW - Cannabinoid
KW - Drug discrimination
KW - Methanandamide
KW - Rhesus monkey
KW - Rimonabant
KW - SR 141716A
KW - Schild analysis
KW - Δ- tetrahydrocannabinol
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U2 - 10.1007/s00213-008-1230-8
DO - 10.1007/s00213-008-1230-8
M3 - Article
C2 - 18592221
AN - SCOPUS:62449087101
VL - 203
SP - 219
EP - 228
JO - Psychopharmacology
JF - Psychopharmacology
SN - 0033-3158
IS - 2
ER -