Discriminative stimulus effects of the cannabinoid CB1 receptor antagonist rimonabant in rats

Järbe, Torbjörn U. C.; Li, Chen; Vadivel, Subramanian K.; Makriyannis, Alexandros

doi:10.1007/s00213-008-1076-0

Cited by 18 publications

(17 citation statements)

References 51 publications

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“…As before (Järbe et al 2001), surmountable antagonism for mAEA/rimonabant combinations did not occur. Such tests were accompanied by reduced rates of responding (see also Järbe et al 2003bJärbe et al , 2008. It is possible that route of administration may play a role as Solinas et al (2007a) observed a limited shift to the right of the mAEA generalization curve when increasing doses of the drug were administered intravenously following pre-treatment with i.p.-administered rimonabant (3 mg/kg).…”

Section: Discussionmentioning

confidence: 99%

Discriminative stimulus functions in rats of AM1346, a high-affinity CB1R selective anandamide analog

Järbe

Liu

et al. 2008

Psychopharmacology

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Objective To characterize in vivo the high-affinity CB 1 cannabinoid receptor (CB 1 R) selective anandamide analog AM1346 [alkoxyacid amide of N-eicosa-tetraenylamine] using drug discrimination. Substitution tests involved Δ 9 -tetrahydrocannabinol (Δ 9 -THC) and R-(+)-methanandamide (mAEA), a metabolically stable analog of anandamide (AEA), as well as the CB 1 R antagonist/inverse agonist rimonabant; D-amphetamine and morphine were also examined to assess pharmacological specificity. Materials and methods Rats were initially trained to discriminate between i.p.-injected vehicle and 3 mg/kg AM1346 (group 3 mg/kg; t′=20 min); subsequently, the rats were retrained with 5.6 mg/kg AM1346 (group 5.6 mg/kg; t′= 20 min). Results Dose-generalization curves of AM1346, Δ 9 -THC, and mAEA suggested the following order of potency: Δ 9 -THC > AM1346 > mAEA both for rats discriminating between 3 and 5.6 mg/kg AM1346 from vehicle. In group 3 mg/kg, challenge by 1 mg/kg rimonabant resulted in parallel shifts to the right of the dose-generalization curves for Δ 9 -THC and AM1346, suggesting surmountable antagonism. Surmountable antagonism was not demonstrated with rimonabant-mAEA combinations. A long duration of effect was indicated when 3 mg/kg AM1346 was examined after different time intervals following i.p. administration (group 3 mg/kg). The in vivo half-life was close to 5 h. Neither Damphetamine nor morphine generalized in either of groups 3 mg/kg and 5.6 mg/kg, suggesting pharmacological specificity. Conclusion Unlike mAEA, the surmountable antagonism between rimonabant and AM1346 showed that the structural features of AEA can be modified to produce novel ligands that reduce the dissociation between the discriminative stimulus and rate decreasing effects of CB 1 R agonists derived from an AEA template.

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Section: Discussionmentioning

confidence: 99%

Discriminative stimulus functions in rats of AM1346, a high-affinity CB1R selective anandamide analog

Järbe

Liu

et al. 2008

Psychopharmacology

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“…Acquisition was demonstrated by consistently low levels of drinking in the presence of rimonabant and high levels of drinking in its absence (as compared to rats that received the same schedule of rimonabant and vehicle injections, but did not receive lithium chloride). Results of substitution tests in the discriminating rats showed that rimonabant and its diarylpyrazole analog AM-251 substituted whereas CB 2 receptor antagonists, SR144528 and AM630, did not [115]. Δ 9 -THC also failed to substitute for rimonabant when administered alone; however, when administered in combination with rimonabant, it attenuated rimonabant's suppression of drinking, suggesting opposing actions at the CB 1 receptor [115,116].…”

Section: Cannabinoid Antagonist Discriminationmentioning

confidence: 90%

“…Results of substitution tests in the discriminating rats showed that rimonabant and its diarylpyrazole analog AM-251 substituted whereas CB 2 receptor antagonists, SR144528 and AM630, did not [115]. Δ 9 -THC also failed to substitute for rimonabant when administered alone; however, when administered in combination with rimonabant, it attenuated rimonabant's suppression of drinking, suggesting opposing actions at the CB 1 receptor [115,116]. Hence, rimonabant appears to be discriminable, but only under modified experimental conditions.…”

Section: Cannabinoid Antagonist Discriminationmentioning

confidence: 95%

“…After early studies failed to establish a discrimination with rimonabant using food reinforcement [113,114], Järbe et al [115,116] reported successful training of a rimonabant discrimination in rats using a taste aversion paradigm. In this paradigm, injection with the toxin lithium chloride was systematically paired with rimonabant administration to induce discriminated aversion to a drinking solution.…”

Section: Cannabinoid Antagonist Discriminationmentioning

confidence: 99%

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Discriminative Stimulus Properties of Phytocannabinoids, Endocannabinoids, and Synthetic Cannabinoids

Wiley

Owens

Lichtman

2016

Current Topics in Behavioral Neurosciences

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Psychoactive cannabinoids from the marijuana plant (phytocannabinoids), from the body (endocannabinoids), and from the research lab (synthetic cannabinoids) produce their discriminative stimulus effects by stimulation of CB receptors in the brain. Early discrimination work with phytocannabinoids confirmed that Δ-tetrahydrocannabinol (Δ-THC) is the primary psychoactive constituent of the marijuana plant, with more recent work focusing on characterization of the contribution of the major endocannabinoids, anandamide and 2-arachidonoylglycerol (2-AG), to Δ-THC-like internal states. Collectively, these latter studies suggest that endogenous increases in both anandamide and 2-AG seem to be optimal for mimicking Δ-THC's discriminative stimulus effects, although suprathreshold concentrations of anandamide also appear to be Δ-THC-like in discrimination assays. Recently, increased abuse of synthetic cannabinoids (e.g., "fake marijuana") has spurred discrimination studies to inform regulatory authorities by predicting which of the many synthetic compounds on the illicit market are most likely to share Δ-THC's abuse liability. In the absence of a reliable model of cannabinoid self-administration (specifically, Δ-THC self-administration), cannabinoid discrimination represents the most validated and pharmacologically selective animal model of an abuse-related property of cannabinoids - i.e., marijuana's subjective effects. The influx of recent papers in which cannabinoid discrimination is highlighted attests to its continued relevance as a valuable method for scientific study of cannabinoid use and abuse.

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“…As was found with sibutramine, rimonabant produced an average placebo-subtracted weight loss of less than 5% (Pi-Sunyer et al 2006). Rimonabant has been shown to produce discriminative stimulus effects using a discriminated taste avoidance procedure (Järbe et al 2004(Järbe et al , 2008, and rimonabant antagonizes the discriminative stimulus effects of THC and other CB 1 agonists (Järbe et al 2001;Mansbach et al 1996;Wiley et al 1995a, b).…”

Section: Introductionmentioning

confidence: 91%

Effects of sibutramine and rimonabant in rats trained to discriminate between 22- and 2-h food deprivation

et al. 2008

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Objective The objective of the study was to evaluate whether sibutramine and rimonabant, drugs that decrease food intake in human and non-human animals, affect the discriminative stimulus effects associated with acute food deprivation ("hunger"). Materials and methods Rats were trained to discriminate between 22-and 2-h food deprivation in a two-lever choice procedure. After rats acquired the discrimination, subjects were food-restricted for 22 h and administered with sibutramine (0.32-10 mg/kg, p.o.) or rimonabant (0.32-10 mg/kg, s.c.) before a generalization test session. Results Sibutramine (3.2 mg/kg) produced significant decreases in 22-h deprivation-appropriate responding, response rates (resulting in lever pressing rates similar to those following 2-h food deprivation), and food intake measured 1 h after the generalization test. A larger sibutramine dose eliminated responding and significantly reduced food intake. Rimonabant did not alter the discriminative stimulus effects of 22-h food deprivation, but rimonabant did significantly reduce both response rates and food intake. Conclusion Sibutramine appears to decrease food intake by reducing hunger sensations associated with food deprivation. In contrast, rimonabant does not alter the discrimination of acute food deprivation. The use of food-deprivation discrimination techniques may be useful in identifying the role of specific neuroactive compounds in eating stimulated by a sense of hunger and may aid in medication development for more effective treatments for obesity and other eating-related conditions.

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Discriminative stimulus effects of the cannabinoid CB1 receptor antagonist rimonabant in rats

Cited by 18 publications

References 51 publications

Discriminative stimulus functions in rats of AM1346, a high-affinity CB1R selective anandamide analog

Discriminative stimulus functions in rats of AM1346, a high-affinity CB1R selective anandamide analog

Discriminative Stimulus Properties of Phytocannabinoids, Endocannabinoids, and Synthetic Cannabinoids

Effects of sibutramine and rimonabant in rats trained to discriminate between 22- and 2-h food deprivation

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