In a recent study published in the journal Scientific Reports, researchers investigated how cannabinoid-1 receptor (CB1R) expressing neurons in the mediobasal hypothalamus ( MBH) regulate the appetite-stimulating effects of inhaled cannabis in rodents.
Study: Cannabis Sativa targets mediobasal hypothalamic neurons to stimulate appetite. Image Credit: TayHamPhotography / Shutterstock
Background
Cannabis sativa is known to stimulate appetite, influencing the development of treatments for anorexia, but therapies mimicking its effects are often poorly tolerated and inconsistently effective. Consequently, many patients with anorexia turn to cannabis for appetite stimulation, yet the underlying neurobiological mechanisms remain unclear. Previous studies highlight the role of the MBH, specifically the arcuate nucleus, in feeding behavior. Further research is needed to fully understand the neurobiological mechanisms, specifically the role of CB1R in MBH neurons, behind the appetite-stimulating effects of cannabis, which is crucial for its clinical application in treating anorexia.
About the study
In the present study, researchers employed both rats and mice to investigate the neurobiological mechanisms behind the appetite-stimulatory properties of Cannabis sativa. Rats were initially chosen for their simplicity in behavioral assays, but mice were also used for more mechanistic imaging and chemogenetic studies. The animals were housed in a controlled environment with access to food and water, except during specific test conditions. A range of experiments were designed to explore various aspects of the research question.
The cannabis plant matter, containing 7.8% Tetrahydrocannabinol (THC) and 0.5% Cannabidiol (CBD), was sourced in accordance with federal law. Rats were habituated to vapor chambers before being exposed to vaporized cannabis. Meal patterns and locomotor activities were then observed in different settings, including BioDAQ and Sable Promethion metabolic chambers. Additionally, an operant touch screen system was used to evaluate food-reinforced behavior in rats following cannabis exposure.
For the mouse studies, researchers established a behaviorally relevant dose of cannabis vapor. Mice were then exposed to this vapor, and their food intake was measured. In vivo, calcium imaging of MBH neurons was performed to assess neuronal activation in response to a high-fat diet following cannabis exposure. Additionally, electrophysiological recordings were conducted to understand the effects of CB1R activation on Agouti-Related Peptide (AgRP) neuronal GABAergic spontaneous inhibitory postsynaptic currents (sIPSCs).
Chemogenetic inhibition of AgRP neurons was also explored to determine their role in cannabis-induced feeding behavior. This involved injecting a virus targeting AgRP neurons in the MBH and then observing the effects of cannabis exposure on food intake.
All data were analyzed using appropriate statistical methods, including two-way repeated measures analysis of Variance (ANOVA) and paired student's t-tests, to draw conclusions about the impact of cannabis vapor on feeding behavior and the underlying neurobiological mechanisms.
Study results
Exposure to vaporized cannabis significantly influences feeding patterns and associated neurobiological mechanisms in rodents. In free-feeding rats, cannabis vapor exposure resulted in an increase in meal frequency while the size of each meal decreased. These changes were apparent 2 and 3 hours post-exposure, suggesting a temporal pattern in cannabis-induced feeding behavior. The study also found that cannabis exposure did not significantly alter the rats' locomotor activity, countering the notion of THC-induced sedation. Instead, the rats displayed increased movement towards food, particularly around the food hopper, indicating a specific increase in food-motivated behavior.
Regarding metabolic activity, rats exposed to cannabis vapor exhibited no significant difference in respiratory quotient compared to air controls. However, there was a notable increase in oxygen consumption rate in cannabis-exposed rats. The findings suggest that while the macronutrient utilization remained unchanged, there was an increase in energy expenditure, indicating enhanced metabolic activity following cannabis exposure.
Operant behavior studies revealed that cannabis vapor exposure significantly increased rats' operant response to sucrose one hour after exposure. This increase was not observed two hours post-exposure, suggesting a time-dependent effect of cannabis on food-motivated behavior.
In mice, a dose-response relationship was established for cannabis-induced feeding behavior. A 200 mg dose of cannabis significantly increased food intake, whereas a 400 mg dose decreased it. This finding was crucial for subsequent in vivo calcium imaging experiments and chemogenetic manipulations.
Calcium imaging of MBH neurons in mice revealed that cannabis exposure augmented the activity of these neurons during anticipatory and consummatory phases of feeding behavior. Interestingly, a novel population of MBH neurons was activated in response to cannabis, suggesting its role in altering neuronal activity associated with feeding behavior.
Lastly, the study demonstrated that activation of CB1R in AgRP neurons led to disinhibition, as evidenced by reduced frequency of sIPSCs. Additionally, chemogenetic inhibition of AgRP neurons attenuated the appetite-stimulating effects of cannabis, underscoring the functional relevance of these neurons in cannabis-induced feeding behavior. The data suggest that activation of CB1Rs in the MBH contributes to the appetite-stimulatory properties of inhaled cannabis.
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