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Cannabidiol is a phytocannabinoid that lacks the psychotomimetic properties of Δ9-tetrahydrocannabinol (THC), the main psychoactive Cannabis sativa component. Cannabidiol has several potential therapeutic properties, including anxiolytic, antidepressant, and antipsychotic; however, cannabidiol has low oral bioavailability, which can limit its clinical use. Here, we investigated if two cannabidiol analogs, HU-502 and HU-556, would be more potent than cannabidiol in behavioral tests predictive of anxiolytic, antidepressant, and antipsychotic effects. Different doses (0.01-3 mg/kg; intraperitoneally) of HU-556 and HU-502 were tested in male Swiss mice submitted to the elevated plus maze (EPM), forced swimming test (FST), and amphetamine-induced-prepulse inhibition (PPI) disruption and hyperlocomotion. Cannabidiol is effective in these tests at a dose range of 15-60 mg/kg in mice. We also investigated if higher doses of HU-556 (3 and 10 mg/kg) and HU-502 (10 mg/kg) produced the cannabinoid tetrad (hypolocomotion, catalepsy, hypothermia, and analgesia), which is induced by THC-like compounds. HU-556 (0.1 and 1 mg/kg) increased the percentage of open arm entries (but not time) in the EPM, decreased immobility time in the FST, and attenuated amphetamine-induced PPI disruption. HU-502 (1 and 3 mg/kg) decreased amphetamine-induced hyperlocomotion and PPI impairment. HU-556, at high doses, caused catalepsy and hypolocomotion, while HU-502 did not. These findings suggest that similar to cannabidiol, HU-556 could induce anxiolytic, antidepressant, and antipsychotic-like effects and that HU-502 has antipsychotic properties. These effects were found at a dose range devoid of cannabinoid tetrad effects., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Despite attenuating the positive symptoms, drugs currently used to treat schizophrenia frequently do not improve the negative symptoms and cognitive impairments. In addition, they show low tolerability, which has been associated with high rates of treatment discontinuation. Recent evidence suggests that the endocannabinoid system may be a target for schizophrenia treatment. The CB2 receptor modulates dopaminergic neurotransmission, which is abnormally enhanced in schizophrenia patients. Here, we aimed to evaluate whether HU-910, a selective CB2 receptor agonist, would reverse schizophrenia-related behavioral changes observed after the acute injections of amphetamine or the N-methyl-d-aspartate receptor (NMDAR) antagonist MK-801. We also investigated the effects of HU-910 in the memory impairment caused by repeated MK-801 administration. Finally, we tested whether HU-910 would produce the cannabinoid tetrad (catalepsy, hypolocomotion, hypothermia, and antinociception). In male C57BL/6 mice, the acute treatment with HU-910 (30 mg/kg) prevented the hyperlocomotion induced by acute MK-801. This effect was blocked by the CB2 receptor antagonist AM630 (1 mg/kg). On the contrary, HU-910 did not prevent the increased locomotor activity caused by acute amphetamine. The acute treatment with HU-910 (3, 10, and 30 mg/kg) also attenuated the impairments in the prepulse inhibition test induced by acute MK-801 and amphetamine. The repeated treatment with HU-910 attenuated the cognitive impairment caused by chronic administration of MK-801 in the novel object recognition test. Furthermore, HU-910 did not produce the cannabinoid tetrad. These results indicate that HU-910 produced antipsychotic-like effects and support further research on the potential therapeutic properties of this compound to treat schizophrenia., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Cannabidiol (CBD) is a phytocannabinoid with multiple pharmacological effects and several potential therapeutic properties. Its low oral bioavailability, however, can limit its clinical use. Preliminary results indicate that fluorination of the CBD molecule increases its pharmacological potency. Here, we investigated whether HUF-101 (3, 10, and 30 mg/kg), a fluorinated CBD analogue, would induce antinociceptive effects. HUF-101 effects were compared to those induced by CBD (10, 30, and 90 mg/kg) and the cannabinoid CB 1/2 receptor agonist WIN55,212-2 (1, 3, and 5 mg/kg). These drugs were tested in male Swiss mice submitted to the following models predictive to antinociceptive drugs: hot plate, acetic acid-induced writhing, and carrageenan-induced inflammatory hyperalgesia. To evaluate the involvement of CB 1 and CB 2 receptors in HUF-101 and CBD effects, mice received the CB 1 receptor antagonist AM251 (1 or 3 mg/kg) or the CB 2 receptor antagonist AM630 (1 or 3 mg/kg) 30 min before HUF-101, CBD, or WIN55,212-2. In the hot plate test, HUF-101 (30 mg/kg) and WIN55,212-2 (5 mg/kg) induced antinociceptive effects, which were attenuated by the pretreatment with AM251 and AM630. In the abdominal writhing test, CBD (30 and 90 mg/kg), HUF-101 (30 mg/kg), and WIN55,212-2 (3 and 5 mg/kg) induced antinociceptive effects indicated by a reduction in the number of writhing. Whereas the pretreatment with AM630 did not mitigate the effects induced by any drug in this test, the pretreatment with AM251 attenuated the effect caused by WIN55,212-2. In the carrageenan-induced hyperalgesia test, CBD (30 and 90 mg/kg), HUF-101 (3, 10 and 30 mg/kg) and WIN55,212-2 (1 mg/kg) decreased the intensity of mechanical hyperalgesia measured by the electronic von Frey method. The effects of all compounds were attenuated by the pretreatment with AM251 and AM630. Additionally, we evaluated whether HUF-101 would induce the classic cannabinoid CB 1 receptor-mediated tetrad (hypolocomotion, catalepsy, hypothermia, and antinociception). Unlike WIN55,212-2, CBD and HUF-101 did not induce the cannabinoid tetrad. These findings show that HUF-101 produced antinociceptive effects at lower doses than CBD, indicating that the addition of fluoride improved its pharmacological profile. Furthermore, some of the antinociceptive effects of CBD and HUF-101 effects seem to involve the activation of CB 1 and CB 2 receptors. [ABSTRACT FROM AUTHOR]