Vengeliene, V. | Search bioRxiv

bioRxiv2025

Effect of cannabinol, tetrahydrocannabivarin and cannabidiol on voluntary alcohol consumption

Previous studies demonstrated that the endocannabinoid system plays a significant role in the development of the alcohol use disorder (AUD), and CB1 receptor antagonists/inverse agonists showed promise as a novel AUD pharmacotherapy. However, these compounds failed in clinical trials due to the severe psychiatric side effects. It has been suggested that non-psychoactive phytocannabinoids may have a better safety profile and could be used as an alternative approach to treat AUD. Hence, the aim of this study was to test the potential of three phytocannabinoids in reducing alcohol consumption: CB1 receptor partial agonist cannabinol (CBN), neutral antagonist tetrahydrocannabivarin (THCV) and negative allosteric modulator cannabidiol (CBD). For this purpose, male Wistar rats were subjected to a long-term voluntary alcohol drinking procedure that lasted for at least 6 months. Thereafter, rats were given 3 daily administrations of CBN, THCV or CBD. A side-effect profile of all three compounds was measured by recording water consumption, body weight changes and home-cage locomotor activity. Ultrasonic vocalisations were recorded before and after a single administration of CBN, THCV or CBD in alcohol-naive group-housed rats to monitor if these compounds induced discomfort, distress or other changes in emotional states of rats. Our data demonstrated that all phytocannabinoids reduced voluntary alcohol consumption in rats. However, compounds differed in their effectiveness in reducing alcohol consumption and the side-effect profile. Treatment with CBN and THCV reduced alcohol intake and demonstrated a good safety profile. In contrast, CBD only had a minor effect on alcohol consumption, reduced the locomotor activity and lowered the positive emotional states of rats. None of the compounds caused discomfort or distress. We conclude that phytocannabinoids acting as CB1 receptor partial agonists or neutral antagonists may have potential in treatment of AUD.

neuroscience↗

bioRxiv2020

A common molecular mechanism for cognitive deficits and craving in alcoholism

Alcohol-dependent patients commonly show impairments in executive functions that facilitate craving and can lead to relapse. The medial prefrontal cortex, a key brain region for executive control, is prone to alcohol-induced neuroadaptations. However, the molecular mechanisms leading to executive dysfunction in alcoholism are poorly understood. Here using a bi-directional neuromodulation approach we demonstrate a causal link for reduced prefrontal mGluR2 function and both impaired executive control and alcohol craving. By neuron-specific prefrontal knockdown of mGluR2 in rats, we generated a phenotype of reduced cognitive flexibility and excessive alcohol-seeking. Conversely, restoring prefrontal mGluR2 levels in alcohol-dependent rats rescued these pathological behaviors. Also targeting mGluR2 pharmacologically reduced relapse behavior. Finally, we developed a FDG-PET biomarker to identify those individuals that respond to mGluR2-based interventions. In conclusion, we identified a common molecular pathological mechanism for both executive dysfunction and alcohol craving, and provide a personalized mGluR2-mechanism-based intervention strategy for medication development of alcoholism.

neuroscience↗