THC and CBD: Similarities and differences between siblings

Stella, Nephi

doi:10.1016/j.neuron.2022.12.022

Cited by 41 publications

(18 citation statements)

References 320 publications

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“…Cannabidiol presents a wide range of potential therapeutic targets; however, its low oral bioavailability is a limiting factor for its clinical use. Therefore, we have recently started investigating cannabidiol analogs to overcome this limitation (Stella, 2023). Adding a fluorine atom is one of the possible modifications of the cannabidiol molecule.…”

Section: Discussionmentioning

confidence: 99%

Behavioral effects induced by the cannabidiol analogs HU-502 and HU-556

Colodete,

Silva,

Pedrazzi

et al. 2023

Behavioural Pharmacology

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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-inducedprepulse 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 amphetamineinduced 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.

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Section: Discussionmentioning

confidence: 99%

Behavioral effects induced by the cannabidiol analogs HU-502 and HU-556

Colodete,

Silva,

Pedrazzi

et al. 2023

Behavioural Pharmacology

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“…For the precise spatio‐temporal control of such processes, diverse stimuli activate specific signaling pathways that control intracellular and intercellular processes, ultimately promoting and controlling brain functions. One example of such signaling systems is the endocannabinoid system (ECS) (Martinez Ramirez et al, 2023; Zou & Kumar, 2018), which is known for being targeted by Δ 9 ‐tetrahydrocannabinol (THC), the main psychoactive component of the plant Cannabis sativa (Stella, 2023). The molecular target of THC is the G protein‐coupled receptor (GPCR) type‐1 (CB 1 ) and type‐2 (CB 2 ) cannabinoid receptors, that together with their endogenous ligands called endocannabinoids (eCBs), and the enzymatic machinery for eCB synthesis and degradation, are the principal components that conform the ECS (Martinez Ramirez et al, 2023; Zou & Kumar, 2018).…”

Section: Cb1 Receptor Signaling In the Brainmentioning

confidence: 99%

Type‐1 cannabinoid receptors and their ever‐expanding roles in brain energy processes

Fernández‐Moncada

Rodrigues

Fundazuri

et al. 2023

Journal of Neurochemistry

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The brain requires large quantities of energy to sustain its functions. At the same time, the brain is isolated from the rest of the body, forcing this organ to develop strategies to control and fulfill its own energy needs. Likely based on these constraints, several brain‐specific mechanisms emerged during evolution. For example, metabolically specialized cells are present in the brain, where intercellular metabolic cycles are organized to separate workload and optimize the use of energy. To orchestrate these strategies across time and space, several signaling pathways control the metabolism of brain cells. One of such controlling systems is the endocannabinoid system, whose main signaling hub in the brain is the type‐1 cannabinoid (CB1) receptor. CB1 receptors govern a plethora of different processes in the brain, including cognitive function, emotional responses, or feeding behaviors. Classically, the mechanisms of action of CB1 receptors on brain function had been explained by its direct targeting of neuronal synaptic function. However, new discoveries have challenged this view. In this review, we will present and discuss recent data about how a small fraction of CB1 receptors associated to mitochondrial membranes (mtCB1), are able to exert a powerful control on brain functions and behavior. mtCB1 receptors impair mitochondrial functions both in neurons and astrocytes. In the latter cells, this effect is linked to an impairment of astrocyte glycolytic function, resulting in specific behavioral outputs. Finally, we will discuss the potential implications of (mt)CB1 expression on oligodendrocytes and microglia metabolic functions, with the aim to encourage interdisciplinary approaches to better understand the role of (mt)CB1 receptors in brain function and behavior.image

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“…Importantly, CB1 receptors can also be targeted by exogenous cannabinoids, such as Δ 9 -tetrahydrocannabinol (THC), the main psychoactive component of Cannabis sativa . This exogenous, non-physiological activation might bear therapeutic properties, but it can also alter brain activity, impairing, for instance, cognitive, locomotor and perceptive functions 5 . Another remarkable feature of CB1 receptor signaling is its subcellular compartmentalization, which deviates from the strict plasma membrane functional localization of most GPCRs.…”

Section: Mainmentioning

confidence: 99%

A lactate-dependent shift of glycolysis mediates synaptic and cognitive processes

Fernández‐Moncada

Fundazuri

Lavanco

et al. 2023

Preprint

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Control of brain energy metabolism and regulation of synaptic activity through gliotransmission are two important ways, through which astrocytes contribute to mental functions. However, the potential functional and molecular links between these two astrocyte-dependent processes have been scantly explored so far. Here we show that a lactate-dependent shift of glycolysis underlies the production of the gliotransmitter D-serine by acute activation of astrocyte type-1 cannabinoid (CB1) receptors, thereby gating synaptic and cognitive processes. Acute cannabinoid application causes a CB1 receptor-dependent rapid and reversible increase of lactate production and release in primary astrocyte cultures. As shown before, mutant mice lacking the CB1 receptor gene in astrocytes (GFAP-CB1-KO) were impaired in a novel object recognition (NOR) task. Notably, this phenotype was rescued not only by the gliotransmitter D-serine, but also by its precursor L-serine. Surprisingly, the administration of lactate also reverted the memory impairment of GFAP-CB1-KO mice. This rescue effect was abolished by in vivo blockade of the astrocyte-specific phosphorylated pathway (PP), which diverts glycolysis towards L-serine synthesis, suggesting that lactate itself might promote the accumulation of this amino acid. Consistent with this idea, lactate increased the co-agonist occupancy of CA1 post-synaptic hippocampal NMDA receptors in a PP-dependent manner. By establishing a mechanistic link between lactate, serine availability, synaptic activity and behavior, these results reveal an unforeseen functional connection between energy metabolism and gliotransmission to control cognitive processes.

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THC and CBD: Similarities and differences between siblings

Cited by 41 publications

References 320 publications

Behavioral effects induced by the cannabidiol analogs HU-502 and HU-556

Behavioral effects induced by the cannabidiol analogs HU-502 and HU-556

Type‐1 cannabinoid receptors and their ever‐expanding roles in brain energy processes

A lactate-dependent shift of glycolysis mediates synaptic and cognitive processes

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