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Abstract: The endogenous cannabinoid system has been noted for its therapeutic potential, as well as the psychoactivity of cannabinoids such as Δ9-tetrahydrocannabinol (THC). However, less is known about the psychoactivity of anandamide (AEA), an endocannabinoid ligand. Thus, the goals of this study were to establish AEA as a discriminative stimulus in transgenic mice lacking fatty acid amide hydrolase (i.e., FAAH −/− mice unable to rapidly metabolize AEA), evaluate whether THC or oleamide, a fatty acid amide, produced AEA-like responding, and assess for CB1 mediation of AEA''s discriminative stimulus. Mice readily discriminated between 6mg/kg AEA and vehicle in a two-lever drug discrimination task. AEA dose-dependently generalized to itself. THC elicited full AEA-like responding, whereas oleamide failed to substitute. The CB1 antagonist rimonabant attenuated AEA- and THC-induced AEA-appropriate responding, demonstrating CB1 mediation of AEA''s discriminative stimulus. These findings suggest that, in the absence of FAAH, AEA produces intoxication comparable to THC, and consequently to marijuana. [Copyright &y& Elsevier]

Synthetic cannabinoid receptor agonists (SCRAs) possess high abuse liability and complex toxicological profiles, making them serious threats to public health. EG-018 is a SCRA that has been detected in both illicit products and human samples, but it has received little attention to date. The current studies investigated EG-018 at human CB 1 and CB 2 receptors expressed in HEK293 cells in 3H]CP55,940 competition binding, 35S]GTPγS binding and forskolin-stimulated cAMP production. EG-018 was also tested in vivo for its ability to produce cannabimimetic and abuse-related effects in the cannabinoid tetrad and THC drug discrimination, respectively. EG-018 exhibited high affinity at CB 1 (21 nM) and at CB 2 (7 nM), but in contrast to typical SCRAs, behaved as a weak partial agonist in 35S]GTPγS binding, exhibiting lower efficacy but greater potency, than that of THC at CB 1 and similar potency and efficacy at CB 2. EG-018 inhibited forskolin-stimulated cAMP with similar efficacy but lower potency, compared to THC, which was likely due to high receptor density facilitating saturation of this signaling pathway. In mice, EG-018 (100 mg/kg, 30 min) administered intraperitoneally (i.p.) did not produce effects in the tetrad or drug discrimination nor did it shift THC's ED 50 value in drug discrimination when administered before THC, suggesting EG-018 has negligible occupancy of brain CB 1 receptors following i.p. administration. Following intravenous (i.v.) administration, EG-018 (56 mg/kg) produced hypomotility, catalepsy, and hypothermia, but only catalepsy was blocked by the selective CB 1 antagonist rimonabant (3 mg/kg, i.v.). Additional studies of EG-018 and its structural analogues could provide further insight into how cannabinoids exert efficacy through the cannabinoid receptors. • EG-018 binds to human cannabinoid type-1 and type-2 receptors with high affinity. • EG-018 acts as a very weak partial agonist of both cannabinoid receptors in vitro. • Intraperitoneal EG-018 treatment did not produce cannabinoid-like effects in mice. • Intravenous EG-018 treatment caused hypomotility, catalepsy, and hypothermia in mice. • Further study of EG-018 analogues might reveal insight into cannabinoid efficacy. [ABSTRACT FROM AUTHOR]

Background: The recent NIH mandate to consider sex as a biological variable in preclinical research has focused attention on delineation of sex differences in behavior. To investigate mechanisms underlying sex differences in Δ9-tetrahydrocannabinol (THC) effects, we examined the effects of sex and gonadal hormones on CB1 receptors in cerebellum, hippocampus, prefrontal cortex, and striatum.Methods: Adult Sprague-Dawley rats underwent gonadectomy (GDX) or sham-GDX. Half of the GDX females and males received estradiol or testosterone replacement (GDX+H), respectively. All rats were injected with vehicle or 30 mg/kg THC twice daily for 1 week before brain collection. CP55,940-stimulated [35S]GTPγS and [3H]SR141716A saturation binding assays were performed.Results: With exception of enhanced receptor activation in the hippocampi of female rats compared to males, vehicle-treated rats exhibited minimal sex differences in CB1 receptor densities or G-protein coupling. Repeated treatment with THC resulted in pronounced CB1 receptor desensitization and downregulation in both sexes in all brain regions with a greater magnitude of change in females.Conclusions: These results suggest that sex differences in the density and G-protein coupling of brain CB1 receptors may play a limited role in sex differences in acute THC effects not mediated by the hippocampus. In contrast, sex differences after repeated THC were common, with females (intact, GDX, and GDX+H) showing greater downregulation or desensitization in all four brain regions compared to the respective male groups. This result is consistent with a finding that women tend to progress to tolerance and dependence quicker than men after initiation of cannabis use. [ABSTRACT FROM AUTHOR]

The cannabis plant contains several cannabinoids, and many terpenoids that give cannabis its distinctive flavoring and aroma. Δ9-Tetrahydrocannabinol (Δ9-THC) is the plant's primary psychoactive constituent. Given the abuse liability of Δ9-THC, assessment of the psychoactive effects of minor cannabinoids and other plant constituents is important, especially for compounds that may be used medicinally. This study sought to evaluate select minor cannabinoids and terpenes for Δ9-THC-like psychoactivity in mouse Δ9-THC drug discrimination and determine their binding affinities at CB 1 and CB 2 receptors. Δ9-THC, cannabidiol (CBD), cannabinol (CBN), cannabichromene (CBC), cannabichromenevarin (CBCV), Δ8-tetrahydrocannabinol (Δ8-THC), (6aR,9R)-Δ10-tetrahydrocannabinol [(6aR,9R)-Δ10-THC], Δ9-tetrahydrocannabinol varin (THCV), β-caryophyllene (BC), and β-caryophyllene oxide (BCO) were examined. All minor cannabinoids showed measurable cannabinoid 1 (CB 1) and cannabinoid 2 (CB 2) receptor binding, with CBC, CBCV, and CBD, showing the weakest CB 1 receptor binding affinity. BC and BCO exhibited negligible affinity for both CB 1 and CB 2 receptors. In drug discrimination, only Δ8-THC fully substituted for Δ9-THC, while CBN and (6aR,9R)-Δ10-THC partially substituted for Δ9-THC. THCV and BCO did not alter the discriminative stimulus effects of Δ9-THC. In summary, only some of myriad cannabinoids and other chemicals found in the cannabis plant bind potently to the identified cannabinoid receptors. Further, only four of the compounds tested herein [Δ9-THC, Δ8-THC, (6aR,9R)-Δ10-THC, and CBN] produced Δ9-THC-like discriminative stimulus effects, suggesting they may possess cannabimimetic subjective effects. Given that the medicinal properties of phytocannabinoids and terpenoids are being investigated scientifically, delineation of their potential adverse effects, including their ability to produce Δ9-THC-like intoxication, is crucial. • We evaluated minor cannabinoids and terpenes for Δ9-THC-like effects. • Minor cannabinoids bound to CB 1 and CB 2 receptors, whereas terpenes did not. • Δ8-THC was the only compound that produced Δ9-THC-like psychoactive effects. • Few of the minor cannabinoids tested possess cannabimimetic subjective effects. [ABSTRACT FROM AUTHOR]

Cannabis edibles are becoming more common in an increasingly diverse population of users, and the impact of first pass metabolism on cannabis's pharmacological profile across age and sex is not well understood. The present study examined the impact of age, sex and rodent species on the effects of intraperitoneal (i.p.) delta-9-tetrahydrocannabinol (THC) and its primary psychoactive metabolite, 11-OH-THC, in rodent models of psychoactivity and molecular assays of cannabinoid receptor type-1 (CB 1) pharmacology. Like oral THC, i.p. THC also undergoes first pass metabolism. In both species and sexes, 11-OH-THC exhibited marginally higher affinity (~1.5 fold) than THC and both served as partial agonists in [35S]GTPγS binding with equivalent potency; 11-OH-THC exhibited slightly greater efficacy in rat brain tissue. In ICR mice, 11-OH-THC exhibited greater potency than THC in assays of catalepsy (7- to 15-fold) and hypothermia (7- to 31-fold). Further, 11-OH-THC was more potent in THC drug discrimination (7- to 9-fold) in C57Bl/6 J mice, with THC-like discriminative stimulus effects being CB 1 -, but not CB 2 -, mediated. THC's discriminative stimulus also was stable across age in mice, as its potency did not change over the course of the experiment (~17 months). While sex differences in THC's effects were not revealed in mice, THC was significantly more potent in females Sprague-Dawley rats than in males trained to discriminate THC from vehicle. This study demonstrates a cross-species in the psychoactive effects of i.p. THC across sex that may be related to differential metabolism of THC into its psychoactive metabolite 11-OH-THC, suggesting that species is a crucial design consideration in the preclinical study of phytocannabinoids. • Choice of animal model is important in study of THC-containing edibles. • We compared the effects of THC and 11-OH-THC in mice and rats of both sexes. • 11-OH-THC had marginally higher affinity than THC for cerebellar CB 1 receptors. • Sex differences in THC-like in vivo effects occurred in rats, but not in mice. • Results support consideration of sex and species in choice of animal model. [ABSTRACT FROM AUTHOR]