Antidepressant‐like effects of cannabidiol in mice: possible involvement of 5‐HT<sub>1A</sub>receptors

Zanelati, Tatiane; Biojone, Caroline; Moreira, Fabrício A.; Guimarães, Francisco Silveira; Joca, Sâmia Regiane Lourenço

doi:10.1111/j.1476-5381.2009.00521.x

Cited by 339 publications

(306 citation statements)

References 68 publications

(150 reference statements)

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“…CBD may also act via serotonin (5-HT) receptors [26,[42][43][44][45]. The 5-HT 1A receptor is coupled to G protein G i/o, where it is thought to mediate inhibitory neurotransmission [46].…”

Section: Serotonin Receptorsmentioning

confidence: 99%

Molecular Targets of Cannabidiol in Neurological Disorders

Bih

Chen

Nunn³

et al. 2015

Neurotherapeutics

462

323

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Cannabis has a long history of anecdotal medicinal use and limited licensed medicinal use. Until recently, alleged clinical effects from anecdotal reports and the use of licensed cannabinoid medicines are most likely mediated by tetrahydrocannabinol by virtue of: 1) this cannabinoid being present in the most significant quantities in these preparations; and b) the proportion:potency relationship between tetrahydrocannabinol and other plant cannabinoids derived from cannabis. However, there has recently been considerable interest in the therapeutic potential for the plant cannabinoid, cannabidiol (CBD), in neurological disorders but the current evidence suggests that CBD does not directly interact with the endocannabinoid system except in vitro at supraphysiological concentrations. Thus, as further evidence for CBD's beneficial effects in neurological disease emerges, there remains an urgent need to establish the molecular targets through which it exerts its therapeutic effects. Here, we conducted a systematic search of the extant literature for original articles describing the molecular pharmacology of CBD. We critically appraised the results for the validity of the molecular targets proposed. Thereafter, we considered whether the molecular targets of CBD identified hold therapeutic potential in relevant neurological diseases. The molecular targets identified include numerous classical ion channels, receptors, transporters, and enzymes. Some CBD effects at these targets in in vitro assays only manifest at high concentrations, which may be difficult to achieve in vivo, particularly given CBD's relatively poor bioavailability. Moreover, several targets were asserted through experimental designs that demonstrate only correlation with a given target rather than a causal proof. When the molecular targets of CBD that were physiologically plausible were considered for their potential for exploitation in neurological therapeutics, the results were variable. In some cases, the targets identified had little or no established link to the diseases considered. In others, molecular targets of CBD were entirely consistent with those already actively exploited in relevant, clinically used, neurological treatments. Finally, CBD was found to act upon a number of targets that are linked to neurological therapeutics but that its actions were not consistent withmodulation of such targets that would derive a therapeutically beneficial outcome. Overall, we find that while >65 discrete molecular targets have been reported in the literature for CBD, a relatively limited number represent plausible targets for the drug's action in neurological disorders when judged by the criteria we set. We conclude that CBD is very unlikely to exert effects in neurological diseases through modulation of the endocannabinoid system. Moreover, a number of other molecular targets of CBD reported in the literature are unlikely to be of relevance owing to effects only being observed at supraphysiological concentrations. Of interest and after excludin...

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“…CBD may also act via serotonin (5-HT) receptors [26,[42][43][44][45]. The 5-HT 1A receptor is coupled to G protein G i/o, where it is thought to mediate inhibitory neurotransmission [46].…”

Section: Serotonin Receptorsmentioning

confidence: 99%

Molecular Targets of Cannabidiol in Neurological Disorders

Bih

Chen

Nunn³

et al. 2015

Neurotherapeutics

462

323

View full text Add to dashboard Cite

show abstract

“…In addition, CBD inhibits fatty acid amide hydrolase, a catabolic enzyme that alters the hydrolysis of the endogenous cannabinoid neurotransmitter anandamide [28]. Perhaps the largest body of evidence pertains to the modulation and activation of 5-hydroxytryptamine 1A serotoninergic receptors [29][30][31][32][33][34][35]. CBD also has low potency for inhibiting the uptake of striatal dopamine [36]; it modulates allosterically μ and δ opioid receptors [37] and enhances adenosine signaling through uptake inhibition [36,38].…”

Section: Cbd and Neurobiological Targets/effectsmentioning

confidence: 99%

“…CBD improves performance in numerous animal models of cognitive impairments [30,[46][47][48]. It acts as an antidepressant in animal models of depression and decreases compulsive behaviors in rodents [35,49]. These actions are hypothesized to be linked to CB1-related mechanisms [50,51].…”

Section: Cbd and Neurobiological Targets/effectsmentioning

confidence: 99%

Early Phase in the Development of Cannabidiol as a Treatment for Addiction: Opioid Relapse Takes Initial Center Stage

et al. 2015

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Multiple cannabinoids derived from the marijuana plant have potential therapeutic benefits but most have not been well investigated, despite the widespread legalization of medical marijuana in the USA and other countries. Therapeutic indications will depend on determinations as to which of the multiple cannabinoids, and other biologically active chemicals that are present in the marijuana plant, can be developed to treat specific symptoms and/or diseases. Such insights are particularly critical for addiction disorders, where different phytocannabinoids appear to induce opposing actions that can confound the development of treatment interventions. Whereas Δ 9 -tetracannabinol has been well documented to be rewarding and to enhance sensitivity to other drugs, cannabidiol (CBD), in contrast, appears to have low reinforcing properties with limited abuse potential and to inhibit drug-seeking behavior. Other considerations such as CBD's anxiolytic properties and minimal adverse side effects also support its potential viability as a treatment option for a variety of symptoms associated with drug addiction. However, significant research is still needed as CBD investigations published to date primarily relate to its effects on opioid drugs, and CBD's efficacy at different phases of the abuse cycle for different classes of addictive substances remain largely understudied. Our paper provides an overview of preclinical animal and human clinical investigations, and presents preliminary clinical data that collectively sets a strong foundation in support of the further exploration of CBD as a therapeutic intervention against opioid relapse. As the legal landscape for medical marijuana unfolds, it is important to distinguish it from Bmedical CBD^and other specific cannabinoids, that can more appropriately be used to maximize the medicinal potential of the marijuana plant.

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“…The OFT was used to measure the locomotor activity of the animals (35). Mice were placed individually in a circular open-field arena (40 cm in diameter with a 50 cm high Plexiglas wall) for 6 min.…”

Section: Open Field Test (Oft)mentioning

confidence: 99%

Effects of DNA methylation inhibitors and conventional antidepressants on mice behaviour and brain DNA methylation levels

Sales

Joca

2015

Acta Neuropsychiatr.

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Sales AJ, Joca SRL. Effects of DNA methylation inhibitors and conventional antidepressants on mice behaviour and brain DNA methylation levels.Objective: Stress increases DNA methylation and decreases the expression of genes involved in neural plasticity, while treatment with DNA methyltransferase inhibitors (DNMTi) increases gene expression and induces antidepressant-like effects in preclinical models. Therefore, the aim of the present work was to further investigate the potential antidepressantlike effect induced by DNMTi by evaluating the behavioural effects induced by associating DNMTi treatment with conventional antidepressant drugs in mice submitted to the forced swimming test (FST). In addition, brain levels of DNA methylation were also investigated. Methods: Mice received systemic injections of 5-aza-2'-deoxycytidine (5-AzaD, 0.1, 0.2 mg/kg), RG108 (0.1, 0.2, 0.4 mg/kg), desipramine (DES, 2.5, 5, 10 mg/kg) or fluoxetine (FLX, 5, 10, 20, 30 mg/kg) and were submitted to the FST or to the open field test (OFT). Additional groups received a combination of subeffective doses of 5-AzaD or RG108 (DNMTi) with subeffective doses of DES or FLX (antidepressants). Results: Subeffective doses of RG108 (0.1 mg/kg) or 5-AzaD (0.1mg/kg) in association with subeffective doses of DES (2.5 mg/kg) or FLX (10 mg/ kg) induced significant antidepressant-like effects. Effective doses of RG108 (0.2 mg/kg), 5-AzaD (0.2 mg/kg), DES (10 mg/kg) and FLX (20 mg/kg) atenuated stress-induced changes in DNA methylation levels in the hippocampus and prefrontal cortex. None of the treatments induced locomotor effects in the OFT. Conclusion: These results suggest that DNMTi potentiate the behavioural effects of antidepressant drugs in the FST and that antidepressants, as well as DNMTi, are able to modulate stress-induced changes in DNA methylation in brain regions closely associated with the neurobiology of depression. Significant outcomesThe results as given below further support a possible antidepressant-like profile for drugs that inhibit DNA methyltransferases.• Systemic administration of different classes of DNA methyltransferase inhibitors induces antidepressantlike effects.• The association of subeffective doses of DNA methyltransferase inhibitors with subeffective doses of conventional antidepressant drugs induces antidepressant-like effects.

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Antidepressant‐like effects of cannabidiol in mice: possible involvement of 5‐HT_1Areceptors

Cited by 339 publications

References 68 publications

Molecular Targets of Cannabidiol in Neurological Disorders

Molecular Targets of Cannabidiol in Neurological Disorders

Early Phase in the Development of Cannabidiol as a Treatment for Addiction: Opioid Relapse Takes Initial Center Stage

Effects of DNA methylation inhibitors and conventional antidepressants on mice behaviour and brain DNA methylation levels

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Antidepressant‐like effects of cannabidiol in mice: possible involvement of 5‐HT1Areceptors

Cited by 339 publications

References 68 publications

Molecular Targets of Cannabidiol in Neurological Disorders

Molecular Targets of Cannabidiol in Neurological Disorders

Early Phase in the Development of Cannabidiol as a Treatment for Addiction: Opioid Relapse Takes Initial Center Stage

Effects of DNA methylation inhibitors and conventional antidepressants on mice behaviour and brain DNA methylation levels

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Product

Resources

About

Antidepressant‐like effects of cannabidiol in mice: possible involvement of 5‐HT_1Areceptors