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Background and Purpose: To follow up in vitro evidence that Delta(9)-tetrahydrocannabivarin extracted from cannabis (eDelta(9)-THCV) is a CB(1) receptor antagonist by establishing whether synthetic Delta(9)-tetrahydrocannabivarin (O-4394) and Delta(8)-tetrahydrocannabivarin (O-4395) behave as CB(1) antagonists in vivo.Experimental Approach: O-4394 and O-4395 were compared with eDelta(9)-THCV as displacers of [(3)H]-CP55940 from specific CB(1) binding sites on mouse brain membranes and as antagonists of CP55940 in [(35)S]GTPgammaS binding assays performed with mouse brain membranes and of R-(+)-WIN55212 in mouse isolated vasa deferentia. Their ability to antagonize in vivo effects of 3 or 10 mg kg(-1) (i.v.) Delta(9)-tetrahydrocannabinol in mice was then investigated.Key Results: O-4394 and O-4395 exhibited similar potencies to eDelta(9)-THCV as displacers of [(3)H]-CP55940 (K (i)=46.6 and 64.4 nM, respectively) and as antagonists of CP55940 in the [(35)S]GTPgammaS binding assay (apparent K (B)=82.1 and 125.9 nM, respectively) and R-(+)-WIN55212 in the vas deferens (apparent K (B)=4.8 and 3.9 nM respectively). At i.v. doses of 0.1, 0.3, 1.0 and/or 3 mg kg(-1) O-4394 and O-4395 attenuated Delta(9)-tetrahydrocannabinol-induced anti-nociception (tail-flick test) and hypothermia (rectal temperature). O-4395 but not O-4394 also antagonized Delta(9)-tetrahydrocannabinol-induced ring immobility. By themselves, O-4395 and O-4394 induced ring immobility at 3 or 10 mg kg(-1) (i.v.) and antinociception at doses above 10 mg kg(-1) (i.v.). O-4395 also induced hypothermia at 3 mg kg(-1) (i.v.) and above.Conclusions and Implications: O-4394 and O-4395 exhibit similar in vitro potencies to eDelta(9)-THCV as CB(1) receptor ligands and as antagonists of cannabinoid receptor agonists and can antagonize Delta(9)-tetrahydrocannabinol in vivo. [ABSTRACT FROM AUTHOR]

Background and purpose:To follow up in vitro evidence that Δ9-tetrahydrocannabivarin extracted from cannabis (eΔ9-THCV) is a CB1 receptor antagonist by establishing whether synthetic Δ9-tetrahydrocannabivarin (O-4394) and Δ8-tetrahydrocannabivarin (O-4395) behave as CB1 antagonists in vivo.Experimental approach:O-4394 and O-4395 were compared with eΔ9-THCV as displacers of [3H]-CP55940 from specific CB1 binding sites on mouse brain membranes and as antagonists of CP55940 in [35S]GTPγS binding assays performed with mouse brain membranes and of R-(+)-WIN55212 in mouse isolated vasa deferentia. Their ability to antagonize in vivo effects of 3 or 10 mg kg−1 (i.v.) Δ9-tetrahydrocannabinol in mice was then investigated.Key results:O-4394 and O-4395 exhibited similar potencies to eΔ9-THCV as displacers of [3H]-CP55940 (K i=46.6 and 64.4 nM, respectively) and as antagonists of CP55940 in the [35S]GTPγS binding assay (apparent K B=82.1 and 125.9 nM, respectively) and R-(+)-WIN55212 in the vas deferens (apparent K B=4.8 and 3.9 nM respectively). At i.v. doses of 0.1, 0.3, 1.0 and/or 3 mg kg−1 O-4394 and O-4395 attenuated Δ9-tetrahydrocannabinol-induced anti-nociception (tail-flick test) and hypothermia (rectal temperature). O-4395 but not O-4394 also antagonized Δ9-tetrahydrocannabinol-induced ring immobility. By themselves, O-4395 and O-4394 induced ring immobility at 3 or 10 mg kg−1 (i.v.) and antinociception at doses above 10 mg kg−1 (i.v.). O-4395 also induced hypothermia at 3 mg kg−1 (i.v.) and above.Conclusions and implications:O-4394 and O-4395 exhibit similar in vitro potencies to eΔ9-THCV as CB1 receptor ligands and as antagonists of cannabinoid receptor agonists and can antagonize Δ9-tetrahydrocannabinol in vivo.British Journal of Pharmacology (2007) 150, 586–594. doi:10.1038/sj.bjp.0707124; published online 22 January 2007 [ABSTRACT FROM AUTHOR]

Presents a study that evaluated whether the endocannabinoid system also plays a role in extinguishing learned escape behavior and spatial memory of mice in a Morris water maze task.

Presents information on a study which investigated the effect of the γ-aminobutyric acid antagonist bicuculline on the Δ9-tetrahydrocannabinol-induced cognitive deficits in mice. Assessment of the disruptive effects of marijuana consumption on learning and memory; Details of statistical analysis; Results.

Rationale: Marijuana remains the most widely used illicit drug in the U.S., and recent attention has been given to putative therapeutic uses of marijuana and cannabinoid derivatives. Thus, developing a better understanding of Δ[sup 9] -THC (tetrahydrocannabinol)-induced mnemonic deficits is of critical importance. Objectives: These experiments were conducted to determine whether Δ[sup 9] -THC has differential effects on spatial reference and working memory tasks, to investigate its receptor mechanism of action, and to compare these effects with those produced by two other compounds – scopolamine and phencyclidine – known to produce mnemonic deficits. In addition, the potency of Δ[sup 9] -THC in these memory tasks was compared with its potency in other pharmacological effects traditionally associated with cannabinoid activity. Methods: Two different versions of the Morris water maze were employed: a working memory task and a reference memory task. Other effects of Δ[sup 9] -THC were assessed using standard tests of hypomotility, antinociception, catalepsy, and hypothermia. Results: Δ[sup 9] -THC disrupted performance of the working memory task (3.0 mg/kg) at doses lower than those required to disrupt performance of the reference memory task (100 mg/kg), or elicit hypomotility, antinociception, catalepsy, and hypothermia. These performance deficits were reversed by SR 141716A. The effects of Δ[sup 9] -THC resembled those of scopolamine, which also selectively disrupted the working maze task. Conversely, phencyclidine disrupted both tasks only at a dose that also produced motor deficits. Conclusions: These data indicate that Δ[sup 9] -THC selectively impairs performance of a working memory task through a CB[sub 1] receptor mechanism of action and that these memory disruptions are more sensitive than other pharmacological effects of Δ[sup 9] -THC. [ABSTRACT FROM AUTHOR]

The present study was conducted to determine if the tetracyclic antidepressant mianserin could be established as a discrminative stimulus in rats. One group of rats was trained to discriminate mianserin (4.0 mg/kg, IP) from saline in a two-lever drug discrimination procedure, and a second group of rats was trained to discriminate the muscarinic cholinergic antagonist scopolamine (0.25 mg/kg, IP) from saline. Generalization testing with the training drugs yielded an ED of 0.502 mg/kg for the mianserin-trained rats and an ED of 0.048 mg/kg for the scopolamine-trained rats. Asymmetrical cross-generalization between mianserin and scopolamine was observed, because scopolamine produced mianserin-appropriate responding, but mianserin did not produce scopolamine-appropriate responding. This study is the first demonstration that rats can be trained to discriminate mianserin from saline and that antagonism of muscarinic cholinergic receptors is sufficient to produce mianserin-appropriate responding. [ABSTRACT FROM AUTHOR]