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JWH-018 in rhesus monkeys: differential antagonism of discriminative stimulus, rate-decreasing, and hypothermic effects.
Eur J Pharmacol. 2014 Oct 05; 740:151-9.EJ

Abstract

Several effects of the abused synthetic cannabinoid JWH-018 were compared to those of Δ9-tetrahydrocannabinol (Δ9-THC) in rhesus monkeys. JWH-018 (0.1 mg/kg i.v.) was established as a discriminative stimulus and rimonabant was used to examine mechanisms responsible for discrimination as well as operant response rate-decreasing and hypothermic effects. JWH-018 dose-dependently increased drug-lever responding (ED50=0.01 mg/kg) and decreased response rate (ED50=0.064 mg/kg). Among various cannabinoids, the relative potency for producing discriminative stimulus and rate-decreasing effects was the same: CP-55940=JWH-018>Δ9-THC=WIN-55212-2=JWH-073. The benzodiazepine agonist midazolam and the NMDA antagonist ketamine did not exert JWH-018 like discriminative stimulus effects up to doses that disrupted responding. JWH-018 and Δ9-THC decreased rectal temperature by 2.2 and 2.8°C, respectively; the doses decreasing temperature by 2°C were 0.21 and 1.14 mg/kg, respectively. Antagonism did not differ between JWH-018 and Δ9-THC, but did differ among effects. The apparent affinities of rimonabant calculated in the presence of JWH-018 and Δ9-THC were not different from each other for antagonism of discriminative stimulus effects (6.58 and 6.59, respectively) or hypothermic effects (7.08 and 7.19, respectively). Apparent affinity estimates are consistent with the same receptors mediating the discriminative stimulus and hypothermic effects of both JWH-018 and Δ9-THC. However, there was more limited and less orderly antagonism of rate-decreasing effects, suggesting that an additional receptor mechanism is involved in mediating the effects of cannabinoids on response rate. Overall, these results strongly suggest that JWH-018 and Δ9-THC act at the same receptors to produce several of their shared psychopharmacological effects.

Authors+Show Affiliations

Department of Pharmacology, The University of Texas Health Science Center at San Antonio, USA.Department of Pharmacology, The University of Texas Health Science Center at San Antonio, USA. Electronic address: mcmahonl@uthscsa.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

24972243

Citation

Rodriguez, Jesse S., and Lance R. McMahon. "JWH-018 in Rhesus Monkeys: Differential Antagonism of Discriminative Stimulus, Rate-decreasing, and Hypothermic Effects." European Journal of Pharmacology, vol. 740, 2014, pp. 151-9.
Rodriguez JS, McMahon LR. JWH-018 in rhesus monkeys: differential antagonism of discriminative stimulus, rate-decreasing, and hypothermic effects. Eur J Pharmacol. 2014;740:151-9.
Rodriguez, J. S., & McMahon, L. R. (2014). JWH-018 in rhesus monkeys: differential antagonism of discriminative stimulus, rate-decreasing, and hypothermic effects. European Journal of Pharmacology, 740, 151-9. https://doi.org/10.1016/j.ejphar.2014.06.023
Rodriguez JS, McMahon LR. JWH-018 in Rhesus Monkeys: Differential Antagonism of Discriminative Stimulus, Rate-decreasing, and Hypothermic Effects. Eur J Pharmacol. 2014 Oct 5;740:151-9. PubMed PMID: 24972243.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - JWH-018 in rhesus monkeys: differential antagonism of discriminative stimulus, rate-decreasing, and hypothermic effects. AU - Rodriguez,Jesse S, AU - McMahon,Lance R, Y1 - 2014/06/24/ PY - 2014/04/03/received PY - 2014/06/12/revised PY - 2014/06/17/accepted PY - 2014/6/28/entrez PY - 2014/6/28/pubmed PY - 2015/10/28/medline SP - 151 EP - 9 JF - European journal of pharmacology JO - Eur. J. Pharmacol. VL - 740 N2 - Several effects of the abused synthetic cannabinoid JWH-018 were compared to those of Δ9-tetrahydrocannabinol (Δ9-THC) in rhesus monkeys. JWH-018 (0.1 mg/kg i.v.) was established as a discriminative stimulus and rimonabant was used to examine mechanisms responsible for discrimination as well as operant response rate-decreasing and hypothermic effects. JWH-018 dose-dependently increased drug-lever responding (ED50=0.01 mg/kg) and decreased response rate (ED50=0.064 mg/kg). Among various cannabinoids, the relative potency for producing discriminative stimulus and rate-decreasing effects was the same: CP-55940=JWH-018>Δ9-THC=WIN-55212-2=JWH-073. The benzodiazepine agonist midazolam and the NMDA antagonist ketamine did not exert JWH-018 like discriminative stimulus effects up to doses that disrupted responding. JWH-018 and Δ9-THC decreased rectal temperature by 2.2 and 2.8°C, respectively; the doses decreasing temperature by 2°C were 0.21 and 1.14 mg/kg, respectively. Antagonism did not differ between JWH-018 and Δ9-THC, but did differ among effects. The apparent affinities of rimonabant calculated in the presence of JWH-018 and Δ9-THC were not different from each other for antagonism of discriminative stimulus effects (6.58 and 6.59, respectively) or hypothermic effects (7.08 and 7.19, respectively). Apparent affinity estimates are consistent with the same receptors mediating the discriminative stimulus and hypothermic effects of both JWH-018 and Δ9-THC. However, there was more limited and less orderly antagonism of rate-decreasing effects, suggesting that an additional receptor mechanism is involved in mediating the effects of cannabinoids on response rate. Overall, these results strongly suggest that JWH-018 and Δ9-THC act at the same receptors to produce several of their shared psychopharmacological effects. SN - 1879-0712 UR - https://www.unboundmedicine.com/medline/citation/24972243/JWH_018_in_rhesus_monkeys:_differential_antagonism_of_discriminative_stimulus_rate_decreasing_and_hypothermic_effects_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-2999(14)00465-8 DB - PRIME DP - Unbound Medicine ER -