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Discriminative stimulus effects of the cannabinoid CB1 antagonist SR 141716A in rhesus monkeys pretreated with Delta9-tetrahydrocannabinol.
Psychopharmacology (Berl) 2006; 188(3):306-14P

Abstract

RATIONALE

Drug discrimination can be used to examine tolerance and dependence in agonist-treated animals by establishing an appropriate antagonist as a discriminative stimulus.

OBJECTIVE

Establish intravenous SR 141716A as a discriminative stimulus in four rhesus monkeys pretreated with a relatively small dose of Delta9-tetrahydrocannabinol (Delta9-THC).

METHODS

Rhesus monkeys received i.v. Delta9-THC (0.32 mg/kg) and discriminated i.v. SR 141716A (1 mg/kg) from vehicle while responding under a fixed ratio (FR) 5 schedule of stimulus-shock termination.

RESULTS

The discriminative stimulus effects of SR 141716A were dose-dependent (ED50=0.33 mg/kg) and were mimicked by the CB1 antagonist AM 251 (ED50=0.98 mg/kg), but not by a benzodiazepine (midazolam) or an N-methyl-D-aspartate antagonist (ketamine). An additional dose (0.32 mg/kg in addition to 0.32 mg/kg administered before the session) of Delta9-THC shifted the SR 141716A dose-effect curve 3-fold rightward. Omitting Delta9-THC before test sessions resulted in responding on the SR 141716A lever that was attenuated by subsequent administration of Delta9-THC (ED50=0.13 mg/kg), CP 55940 (ED50=0.013 mg/kg), and WIN 55212-2 (ED50=0.35 mg/kg); midazolam and ketamine did not attenuate responding on the SR 141716A lever. SR 141716A (1 mg/kg) shifted the Delta9-THC and CP 55940 dose-effect curves 3.4-fold rightward; the WIN 55212-2 dose-effect curve was not significantly modified by a dose of 1 mg/kg of SR 141716A.

CONCLUSIONS

SR 141716A can be established as a discriminative stimulus in animals pretreated with Delta9-THC, and this assay is selective for cannabinoid activity. Differential antagonism of cannabinoids by SR 141716A might indicate that the mechanism of action of WIN 55212-2 is not identical to other cannabinoids. This study demonstrates that, under the appropriate conditions, drug discrimination has utility for examining cannabinoid dependence and withdrawal.

Authors+Show Affiliations

Department of Pharmacology, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX, 78229-3900, USA. mcmahonl@uthscsa.edu

Pub Type(s)

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

Language

eng

PubMed ID

16953389

Citation

McMahon, Lance R.. "Discriminative Stimulus Effects of the Cannabinoid CB1 Antagonist SR 141716A in Rhesus Monkeys Pretreated With Delta9-tetrahydrocannabinol." Psychopharmacology, vol. 188, no. 3, 2006, pp. 306-14.
McMahon LR. Discriminative stimulus effects of the cannabinoid CB1 antagonist SR 141716A in rhesus monkeys pretreated with Delta9-tetrahydrocannabinol. Psychopharmacology (Berl). 2006;188(3):306-14.
McMahon, L. R. (2006). Discriminative stimulus effects of the cannabinoid CB1 antagonist SR 141716A in rhesus monkeys pretreated with Delta9-tetrahydrocannabinol. Psychopharmacology, 188(3), pp. 306-14.
McMahon LR. Discriminative Stimulus Effects of the Cannabinoid CB1 Antagonist SR 141716A in Rhesus Monkeys Pretreated With Delta9-tetrahydrocannabinol. Psychopharmacology (Berl). 2006;188(3):306-14. PubMed PMID: 16953389.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Discriminative stimulus effects of the cannabinoid CB1 antagonist SR 141716A in rhesus monkeys pretreated with Delta9-tetrahydrocannabinol. A1 - McMahon,Lance R, Y1 - 2006/09/05/ PY - 2006/02/22/received PY - 2006/06/29/accepted PY - 2006/9/6/pubmed PY - 2007/3/14/medline PY - 2006/9/6/entrez SP - 306 EP - 14 JF - Psychopharmacology JO - Psychopharmacology (Berl.) VL - 188 IS - 3 N2 - RATIONALE: Drug discrimination can be used to examine tolerance and dependence in agonist-treated animals by establishing an appropriate antagonist as a discriminative stimulus. OBJECTIVE: Establish intravenous SR 141716A as a discriminative stimulus in four rhesus monkeys pretreated with a relatively small dose of Delta9-tetrahydrocannabinol (Delta9-THC). METHODS: Rhesus monkeys received i.v. Delta9-THC (0.32 mg/kg) and discriminated i.v. SR 141716A (1 mg/kg) from vehicle while responding under a fixed ratio (FR) 5 schedule of stimulus-shock termination. RESULTS: The discriminative stimulus effects of SR 141716A were dose-dependent (ED50=0.33 mg/kg) and were mimicked by the CB1 antagonist AM 251 (ED50=0.98 mg/kg), but not by a benzodiazepine (midazolam) or an N-methyl-D-aspartate antagonist (ketamine). An additional dose (0.32 mg/kg in addition to 0.32 mg/kg administered before the session) of Delta9-THC shifted the SR 141716A dose-effect curve 3-fold rightward. Omitting Delta9-THC before test sessions resulted in responding on the SR 141716A lever that was attenuated by subsequent administration of Delta9-THC (ED50=0.13 mg/kg), CP 55940 (ED50=0.013 mg/kg), and WIN 55212-2 (ED50=0.35 mg/kg); midazolam and ketamine did not attenuate responding on the SR 141716A lever. SR 141716A (1 mg/kg) shifted the Delta9-THC and CP 55940 dose-effect curves 3.4-fold rightward; the WIN 55212-2 dose-effect curve was not significantly modified by a dose of 1 mg/kg of SR 141716A. CONCLUSIONS: SR 141716A can be established as a discriminative stimulus in animals pretreated with Delta9-THC, and this assay is selective for cannabinoid activity. Differential antagonism of cannabinoids by SR 141716A might indicate that the mechanism of action of WIN 55212-2 is not identical to other cannabinoids. This study demonstrates that, under the appropriate conditions, drug discrimination has utility for examining cannabinoid dependence and withdrawal. SN - 0033-3158 UR - https://www.unboundmedicine.com/medline/citation/16953389/Discriminative_stimulus_effects_of_the_cannabinoid_CB1_antagonist_SR_141716A_in_rhesus_monkeys_pretreated_with_Delta9_tetrahydrocannabinol_ L2 - https://dx.doi.org/10.1007/s00213-006-0500-6 DB - PRIME DP - Unbound Medicine ER -