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Antagonism of discriminative stimulus effects of delta(9)-THC and (R)-methanandamide in rats.
Psychopharmacology (Berl). 2006 Jan; 184(1):36-45.P

Abstract

RATIONALE

In previous drug discrimination studies we observed surmountable antagonism by Delta(9)-tetrahydrocannabinol (THC) in the presence of constant doses of SR-141716 [N-(piperidin-1-yl)-5-(4-chloro-phenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide] (0.3 and 1 mg/kg), but there was only marginal evidence for surmountable antagonism with combinations of SR-141716 and (R)-methanandamide, a chiral analog of the endocannabioid anandamide.

OBJECTIVE

Here we examine antagonism where the cannabinoid CB1 receptor agonist [Delta(9)-THC and (R)-methanandamide] dose is held constant (i.e., the training dose) and the antagonist {i.e., SR-141716 and AM-251 [N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide; 2 ml/kg]} dose varied. We also tested the cannabinoid CB2 receptor antagonist SR-144528 {N-[(1S)-endo-1,3,3-trimethylbicyclo(2.2.1)heptan-2-yl]5-(4-chloro-3-methyl-phenyl)-1-(4-methylbenzyl)pyrazole-3-carboxamide}.

METHODS

Different groups of rats were trained to discriminate between vehicle and three different doses of Delta(9)-THC (1.8, 3, and 5.6 mg/kg, presumably reflecting different efficacy demands) as well as 10 mg/kg (R)-methanandamide. Dose-generalization tests involved different doses of the cannabinoid CB1 receptor agonists. Antagonist tests varied the dose of the antagonist (range: 0.1 and 3 mg/kg for SR-141716 and AM-251, and 1 to 10 mg/kg for SR-144528).

RESULTS

SR-141716 and AM-251 doses dependently blocked the agonist-induced discriminative stimulus effects. SR-141716 tended to be slightly more potent than AM-251. The effective dose 50 (ED(50)) of SR-141716 was higher in the 5.6 mg/kg Delta(9)-THC-trained group relative to the two other Delta(9)-THC-trained groups. The cannabinoid CB2 receptor antagonist SR-144528 combined with the training dose of 1.8 mg/kg Delta(9)-THC, as well as when combined with the training dose of 10 mg/kg (R)-methanandamide, did not markedly change drug-appropriate (agonist) responses.

CONCLUSION

Data support that the discriminative stimulus effects of (R)-methanandamide and its overlap with the Delta(9)-THC cue are, indeed, CB1 receptor mediated events as revealed in antagonism tests with the selective central CB1 receptor antagonists SR-141716 and AM-251. The activation of cannabinoid CB2 receptors appears to be insignificant for these discriminations.

Authors+Show Affiliations

Department of Psychology, Temple University, 265-67 Weiss Hall, 1701 North 13th Street, Philadelphia, PA 19122, USA. tjarbe@excite.comNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

16307294

Citation

Järbe, Torbjörn U C., et al. "Antagonism of Discriminative Stimulus Effects of delta(9)-THC and (R)-methanandamide in Rats." Psychopharmacology, vol. 184, no. 1, 2006, pp. 36-45.
Järbe TU, Liu Q, Makriyannis A. Antagonism of discriminative stimulus effects of delta(9)-THC and (R)-methanandamide in rats. Psychopharmacology (Berl). 2006;184(1):36-45.
Järbe, T. U., Liu, Q., & Makriyannis, A. (2006). Antagonism of discriminative stimulus effects of delta(9)-THC and (R)-methanandamide in rats. Psychopharmacology, 184(1), 36-45.
Järbe TU, Liu Q, Makriyannis A. Antagonism of Discriminative Stimulus Effects of delta(9)-THC and (R)-methanandamide in Rats. Psychopharmacology (Berl). 2006;184(1):36-45. PubMed PMID: 16307294.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Antagonism of discriminative stimulus effects of delta(9)-THC and (R)-methanandamide in rats. AU - Järbe,Torbjörn U C, AU - Liu,Quian, AU - Makriyannis,Alexandros, Y1 - 2005/11/24/ PY - 2005/04/29/received PY - 2005/09/22/accepted PY - 2005/11/25/pubmed PY - 2006/4/29/medline PY - 2005/11/25/entrez SP - 36 EP - 45 JF - Psychopharmacology JO - Psychopharmacology (Berl.) VL - 184 IS - 1 N2 - RATIONALE: In previous drug discrimination studies we observed surmountable antagonism by Delta(9)-tetrahydrocannabinol (THC) in the presence of constant doses of SR-141716 [N-(piperidin-1-yl)-5-(4-chloro-phenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide] (0.3 and 1 mg/kg), but there was only marginal evidence for surmountable antagonism with combinations of SR-141716 and (R)-methanandamide, a chiral analog of the endocannabioid anandamide. OBJECTIVE: Here we examine antagonism where the cannabinoid CB1 receptor agonist [Delta(9)-THC and (R)-methanandamide] dose is held constant (i.e., the training dose) and the antagonist {i.e., SR-141716 and AM-251 [N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide; 2 ml/kg]} dose varied. We also tested the cannabinoid CB2 receptor antagonist SR-144528 {N-[(1S)-endo-1,3,3-trimethylbicyclo(2.2.1)heptan-2-yl]5-(4-chloro-3-methyl-phenyl)-1-(4-methylbenzyl)pyrazole-3-carboxamide}. METHODS: Different groups of rats were trained to discriminate between vehicle and three different doses of Delta(9)-THC (1.8, 3, and 5.6 mg/kg, presumably reflecting different efficacy demands) as well as 10 mg/kg (R)-methanandamide. Dose-generalization tests involved different doses of the cannabinoid CB1 receptor agonists. Antagonist tests varied the dose of the antagonist (range: 0.1 and 3 mg/kg for SR-141716 and AM-251, and 1 to 10 mg/kg for SR-144528). RESULTS: SR-141716 and AM-251 doses dependently blocked the agonist-induced discriminative stimulus effects. SR-141716 tended to be slightly more potent than AM-251. The effective dose 50 (ED(50)) of SR-141716 was higher in the 5.6 mg/kg Delta(9)-THC-trained group relative to the two other Delta(9)-THC-trained groups. The cannabinoid CB2 receptor antagonist SR-144528 combined with the training dose of 1.8 mg/kg Delta(9)-THC, as well as when combined with the training dose of 10 mg/kg (R)-methanandamide, did not markedly change drug-appropriate (agonist) responses. CONCLUSION: Data support that the discriminative stimulus effects of (R)-methanandamide and its overlap with the Delta(9)-THC cue are, indeed, CB1 receptor mediated events as revealed in antagonism tests with the selective central CB1 receptor antagonists SR-141716 and AM-251. The activation of cannabinoid CB2 receptors appears to be insignificant for these discriminations. SN - 0033-3158 UR - https://www.unboundmedicine.com/medline/citation/16307294/Antagonism_of_discriminative_stimulus_effects_of_delta_9__THC_and__R__methanandamide_in_rats_ L2 - https://dx.doi.org/10.1007/s00213-005-0225-y DB - PRIME DP - Unbound Medicine ER -