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Daily Synthetic Cannabinoid Agonist (JWH‐018) Treatment: Tolerance to Δ 9 ‐Tetrahydrocannabinol‐Like Discriminative Stimulus Effects in Rhesus Monkeys
Author(s) -
Cocke Morgan L,
McMahon Lance R
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.703.4
Subject(s) - delta 9 tetrahydrocannabinol , potency , cannabinoid , agonist , pharmacology , anesthesia , tetrahydrocannabinol , medicine , synthetic cannabinoids , confidence interval , chemistry , biochemistry , receptor , in vitro
Abused synthetic cannabinoids are used repeatedly, yet the consequences of repeated treatment on sensitivity to abuse‐related effects have not been established. This study assessed sensitivity to the discriminative stimulus effects of JWH‐018 and Δ 9 ‐tetrahydrocannabinol (Δ 9 ‐THC) before and immediately after daily JWH‐018 treatment in rhesus monkeys. Rhesus monkeys discriminated Δ 9 ‐THC (0.1 mg/kg i.v.) under an FR5 schedule of stimulus‐shock termination. Cumulative dose‐response functions for JWH‐018 and Δ 9 ‐THC were determined before and the day after 7 days of twice daily treatment with 0.32 mg/kg of JWH‐018 s.c. 6 h apart. Drug discrimination sessions were suspended during daily JWH‐018 treatment. Δ 9 ‐THC and JWH‐018 dose‐dependently increased Δ 9 ‐THC lever responding; the respective ED 50 values were 0.017 mg/kg and 0.0077 mg/kg. After daily JWH‐018 treatment, the ED 50 values of JWH‐018 and Δ 9 ‐THC were significantly increased, as evidenced by potency ratios (95% confidence limits) of 4.1 (2.1–8.1) and 6.6 (5.0–8.8), respectively. The magnitudes of increases in ED 50 value were not significantly different between JWH‐018 and Δ 9 ‐THC. Twice daily vehicle treatment for 7 days did not significantly alter sensitivity to JWH‐018, i.e., the potency ratio (95% confidence limits) comparing the ED 50 value after vs. before vehicle treatment was 0.4 (0.2–1.2). Full substitution of JWH‐018 for Δ 9 ‐THC, coupled with the similar tolerance to JWH‐018 and cross‐tolerance to Δ 9 ‐THC as a function of daily JWH‐018 treatment, are consistent with a common pharmacological mechanism. Daily synthetic cannabinoid agonist use can result in tolerance and a likely need to increase the frequency and quantity of use to maintain subjective effects. Support or Funding Information USPHS grant R01 DA19222 and T32 NS082145