Brain’s cannabinoid system links persistent anxiety to stronger alcohol reward learning

Mice with more persistent anxiety-like behaviour showed stronger learning about alcohol-related rewards, while disrupting a cannabinoid receptor in the brain weakened that learning, according to a study published in Translational Psychiatry.

Anxiety is not always the same. Some anxiety is a short-term response to an immediate threat, while trait anxiety describes a more stable tendency to respond anxiously across different situations. People with long-lasting anxiety can also experience problems with mood, motivation and reward, including an increased risk of alcohol-related difficulties.

The researchers focused on the endocannabinoid system, a network of chemical signals that helps regulate stress, emotion and reward. One of its main receptors, called CB1, is found in a brain pathway connecting the ventral tegmental area (VTA) with the nucleus accumbens—two deep brain regions responsible for processing motivation and reward. This pathway uses dopamine and helps the brain learn which experiences and cues are rewarding.

Led by corresponding authors Bo Tian and Pei Zhang, researchers from Wuhan University of Science and Technology and Huazhong University of Science and Technology studied male mice aged six to eight weeks. The mice completed several behavioural tests. An elevated platform and an open-field test were used to identify animals showing relatively high or low levels of trait anxiety.

The mice were then tested using a method called conditioned place preference. In this experiment, the animals learned to associate one environment with alcohol. Spending more time in that environment indicated stronger alcohol-related reward learning.

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The researchers found that mice showing more anxiety-like behaviour also developed a stronger preference for the alcohol-paired environment. When the animals were grouped according to their behaviour, the more anxious group showed greater reward-seeking behaviour.

The team then changed CB1 receptor activity in the nucleus accumbens. Blocking the receptor reduced the mice’s ability to learn the alcohol-related association. Activating it improved reward learning in highly anxious mice. In a separate experiment, the researchers genetically removed CB1 receptors from dopamine-producing nerve cells in the VTA. These mice showed more anxiety-like behaviour and weaker reward learning.

The results suggest that CB1 receptors may help regulate how anxiety and reward learning interact. The authors emphasized the importance of their study and how it translates to broader society: “Alcohol use disorder is a major global public health problem, and it often coexists with anxiety disorders. This makes the study of their comorbidity [co-occurrence] crucial.”

The study has important limitations. For instance, the genetic manipulation affected VTA dopamine nerve cells that project to several brain regions, so the effects may not have come exclusively from the VTA-to-nucleus accumbens connection. In addition, drugs injected into the nucleus accumbens may have influenced other types of nerve cells.

The study, “Cannabinoid CB1 receptor in dopaminergic circuit from ventral tegmental area to nucleus accumbens links trait anxiety with reward learning,” was authored by Chi Cui, Gangan Luo, Jie Lei, Yulong Shi, Yibo Yao, Kun Ren, Jian Yang, Tongxia Li, Ming Li, Xiang Peng, Xueke Yang, Junsong Du, Sitong Chen, Bo Tian and Pei Zhang.