Antidepressant-like effects of cannabidiol in mice: possible involvement of 5HT 1A receptors (original) (raw)
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European Neuropsychopharmacology, 2005
These experiments aimed to assess whether enhanced activity at the cannabinoid CB 1 receptor elicits antidepressant-like effects. To examine this we administered 1 and 5 mg/kg doses of the endocannabinoid uptake inhibitor AM404; 5 and 25 Ag/kg doses of HU-210, a potent CB 1 receptor agonist; 1, 2.5 and 5 mg/kg of oleamide, which elicits cannabinoidergic actions; 1 and 5 mg/kg doses of AM 251, a selective CB 1 receptor antagonist, as well as 10 mg/kg desipramine (a positive antidepressant control) and measured the duration of immobility, during a 5-min test session of the rat Porsolt forced swim test. Results demonstrated that administration of desipramine reduced immobility duration by about 50% and that all of AM404, oleamide and HU-210 administration induced comparable decreases in immobility that were blocked by pretreatment with AM 251. Administration of the antagonist AM 251 alone had no effect on immobility at either dose. These data suggest that enhancement of CB 1 receptor signaling results in antidepressant effects in the forced swim test similar to that seen following conventional antidepressant administration. D
Journal of Neuroscience, 2007
Preclinical and clinical studies show that cannabis modulates mood and possesses antidepressant-like properties, mediated by the agonistic activity of cannabinoids on central CB 1 receptors (CB 1 Rs). The action of CB 1 R agonists on the serotonin (5-HT) system, the major transmitter system involved in mood control and implicated in the mechanism of action of antidepressants, remains however poorly understood. In this study, we demonstrated that, at low doses, the CB 1 R agonist WIN55,
Antidepressant-like effect induced by Cannabidiol is dependent on brain serotonin levels
Progress in neuro-psychopharmacology & biological psychiatry, 2018
Cannabidiol (CBD) is a compound of Cannabis sativa with relevant therapeutic potential in several neuropsychiatric disorders including depression. CBD treatment has shown significant antidepressant-like effects in different rodent preclinical models. However, the mechanisms involved in CBD-induced antidepressant effects are still poorly understood. Therefore, this work aimed at investigating the participation of serotonin (5-HT) and/or noradrenaline (NA) in CBD-induced antidepressant-like effects in the forced swimming test (FST) by: 1) testing if CBD co-administration with serotonergic (fluoxetine, FLX) or noradrenergic (desipramine, DES) antidepressants would have synergistic effects; and 2) investigating if 5-HT or NA depletion would impair CBD-induced behavioral effects. Results showed that CBD (10 mg/kg), FLX (10 mg/kg) and DES (5 mg/kg) induced antidepressant-like effects in mice submitted to FST. Ineffective doses of CBD (7 mg/kg), when co-administered with ineffective doses ...
Systemic administration of direct cannabinoid CB 1 receptor agonists and inhibitors of the hydrolytic enzyme fatty acid amide hydrolase have been shown to elicit antidepressant effects. Moreover, the endocannabinoid system in the hippocampus is sensitive to both chronic stress and antidepressant administration, suggesting a potential role of this system in emotional changes associated with these regimens. The aim of this study was to determine if cannabinoid CB 1 receptors in the hippocampus modulate emotionality in rats as assessed via the forced swim test. Male Sprague-Dawley rats were bilaterally implanted with cannulae directed at the dentate gyrus of the dorsal hippocampus and subsequently received three infusions of either the cannabinoid CB 1 receptor agonist HU-210 (1 and 2.5 lg), the fatty acid amide hydrolase inhibitor URB597 (0.5 and 1 lg), the cannabinoid CB 1 receptor antagonist AM251 (1 and 2.5 lg), or vehicle (dimethyl sulfoxide) and were assessed in the forced swim test. Infusion of both doses of HU-210 resulted in a dramatic reduction in immobility and increase in swimming behaviour, indicative of an antidepressant response, which was partially reversed by coadministration of AM251. No effect of URB597 administration or any effect following the administration of AM251 alone was, however, observed. These data indicate that activation of CB 1 receptors in the dentate gyrus of the hippocampus results in an antidepressant-like response. Collectively, these data highlight the potential importance of changes in the hippocampal endocannabinoid system following stress or antidepressant treatment with respect to the manifestation and/or treatment of depression.
Molecular neurobiology, 2018
Currently available antidepressants have a substantial time lag to induce therapeutic response and a relatively low efficacy. The development of drugs that addresses these limitations is critical to improving public health. Cannabidiol (CBD), a non-psychotomimetic component of Cannabis sativa, is a promising compound since it shows large-spectrum therapeutic potential in preclinical models and humans. However, its antidepressant properties have not been completely investigated. Therefore, the aims of this study were to investigate in male rodents (i) whether CBD could induce rapid and sustained antidepressant-like effects after a single administration and (ii) whether such effects could be related to changes in synaptic proteins/function. Results showed that a single dose of CBD dose-dependently induced antidepressant-like effect (7-30 mg/kg) in Swiss mice submitted to the forced swim test (FST), 30 min (acute) or 7 days (sustained) following treatment. Similar effects were observed...
Behavioural Brain Research, 2019
Although a lot of information can be found on the specific dual role of the endocannabinoid system in the emotional-related responses, little is known whether stimulation or inhibition of the cannabinoid (CB) receptors may affect the activity of the frequently prescribed antidepressant drugs. Our interests have been particularly focused on the potential influence of the CB 2 receptors, as the ones whose central effects are relatively poorly documented when compared to the central effects of the CB 1 receptors. Therefore, we evaluated the potential interaction between the CB 2 receptor ligands (i.e., JWH133-CB 2 receptor agonist and AM630-CB 2 receptor inverse agonist) and several common antidepressant drugs that influence the monoaminergic system (i.e., imipramine, escitalopram, reboxetine). In order to assess the antidepressant-like effects we used two widely recognized behavioural tests, the mouse forced swim test (FST) and the tail suspension test (TST). Brain concentrations of the tested antidepressants were evaluated by the HPLC method. Intraperitoneal co-administration of per se ineffective doses of JWH133 (0.25 mg/kg) or AM630 (0.25 mg/kg) with imipramine (15 mg/kg), escitalopram (2 mg/kg), and reboxetine (2.5 mg/kg) significantly shortened the immobility time of mice in the FST and the TST, whereas it did not disturb their spontaneous locomotor activity. Furthermore, the brain levels of antidepressants were not changed. Summarizing, the results of the present study revealed that both activation and inhibition of the CB 2 receptor function have a potential to strengthen the antidepressant activity of drugs targeting the monoaminergic system. Most probably, the described interaction has a pharmacodynamic background.
Pharmacology Biochemistry and Behavior, 2020
Available data support the notion that cannabinoids, whose therapeutic value is limited due to severe adverse reactions, could be beneficial as adjunctive agents in the management of mood disorders. Polytherapy, which is superior to monotherapy in the terms of effectiveness, usually requires lower doses of the individual components. Therefore, the main objective of our study was to determine whether administration of cannabinoid (CB) receptor ligands would enhance the antidepressant activity of atypical antidepressant drugs, i.e. agomelatine and tianeptine. To evaluate the antidepressant-like potential of the tested combinations, the mouse forced swim test (FST) and the tail suspension test (TST) were used. The HPLC method was applied to assess the brain levels of agomelatine and tianeptine. Both behavioural tests demonstrated that per se an ineffective intraperitoneal dose of oleamide (CB 1 receptor agonist, 5 mg/kg) potentiated the anti-immobility activity of tianeptine (15 mg/kg), whereas AM251 (CB 1 receptor inverse agonist/antagonist, 0.25 mg/kg) enhanced the antidepressant effects of tianeptine and agomelatine (20 mg/kg). Intraperitoneal co-administration of per se inactive doses of AM630 (CB 2 receptor inverse agonist/antagonist) and agomelatine or tianeptine significantly reduced the immobility time of animals only in the FST. CB receptor ligands did not affect the brain levels of the tested atypical antidepressants. In summary, the outcomes of the present study showed that activation and inhibition of CB 1 receptors as well as inhibition of CB 2 receptors may increase the antidepressant activity of tianeptine, whereas only inhibition of CB 1 and CB 2 receptors has a potential to augment the antidepressant activity of agomelatine.
Philosophical Transactions of the Royal Society B: Biological Sciences, 2012
Cannabidiol (CBD) is a major phytocannabinoid present in the Cannabis sativa plant. It lacks the psychotomimetic and other psychotropic effects that the main plant compound D 9 -tetrahydrocannabinol (THC) being able, on the contrary, to antagonize these effects. This property, together with its safety profile, was an initial stimulus for the investigation of CBD pharmacological properties. It is now clear that CBD has therapeutic potential over a wide range of non-psychiatric and psychiatric disorders such as anxiety, depression and psychosis. Although the pharmacological effects of CBD in different biological systems have been extensively investigated by in vitro studies, the mechanisms responsible for its therapeutic potential are still not clear. Here, we review recent in vivo studies indicating that these mechanisms are not unitary but rather depend on the behavioural response being measured. Acute anxiolytic and antidepressant-like effects seem to rely mainly on facilitation of 5-HT1Amediated neurotransmission in key brain areas related to defensive responses, including the dorsal periaqueductal grey, bed nucleus of the stria terminalis and medial prefrontal cortex. Other effects, such as anti-compulsive, increased extinction and impaired reconsolidation of aversive memories, and facilitation of adult hippocampal neurogenesis could depend on potentiation of anandamidemediated neurotransmission. Finally, activation of TRPV1 channels may help us to explain the antipsychotic effect and the bell-shaped dose-response curves commonly observed with CBD. Considering its safety profile and wide range of therapeutic potential, however, further studies are needed to investigate the involvement of other possible mechanisms (e.g. inhibition of adenosine uptake, inverse agonism at CB2 receptor, CB1 receptor antagonism, GPR55 antagonism, PPARg receptors agonism, intracellular (Ca 2รพ ) increase, etc.), on CBD behavioural effects.