CB1 and CB2 receptors in a brain anxiety region had opposite effects on anxiety in rats | Research

The takeaway

In the bed nucleus of the stria terminalis (BNST), blocking CB1 receptors reduced anxiety while blocking CB2 receptors increased it, with stress exposure modifying these effects.

Anxiety neuroscience researchers, cannabinoid pharmacologists, anxiety treatment developers

CB1 and CB2 receptors had opposite effects on anxiety in the same brain region

What the researchers found

Both CB1 and CB2 receptor gene expression were confirmed in the anterior and posterior BNST. CB1 antagonist AM251 increased open arm exploration (reduced anxiety) in unstressed rats and blocked stress-evoked anxiety. Conversely, CB2 antagonist JTE907 decreased open arm exploration (increased anxiety) and also blocked restraint-evoked behavioral changes. These opposite roles suggest CB1 and CB2 receptors differentially regulate anxiety through this brain region.

Why it matters

The BNST is a key brain structure for sustained anxiety states. Discovering that CB1 and CB2 receptors have opposing roles in this region helps explain why cannabis can both increase and decrease anxiety, and identifies specific receptor targets for anxiety treatment.

The numbers in context

CB1 and CB2 gene expression confirmed in anterior and posterior BNST; AM251 (CB1 antagonist) dose-dependently increased EPM open arm exploration; JTE907 (CB2 antagonist) dose-dependently decreased open arm exploration; both blocked restraint-evoked anxiety changes

How the study worked

Gene expression of CB1 and CB2 receptors confirmed in anterior and posterior BNST by RT-PCR. Behavioral effects tested in elevated plus maze (EPM) in unstressed rats and after restraint stress, with bilateral microinjection of CB1 antagonist AM251 or CB2 antagonist JTE907 into the anterior BNST.

What this study cannot tell us

Male rats only. Pharmacological blockade does not perfectly mimic natural cannabinoid signaling. Elevated plus maze is one measure of anxiety. BNST is one of many anxiety-relevant brain regions. Single stress paradigm used.

How to read the evidence

Novel finding confirming CB2 presence in BNST for the first time with clear functional dissociation, but limited to male rats.

When this study was published

Published in 2021.

The bigger picture

The opposing anxiety effects of CB1 and CB2 in the same brain region may explain the paradoxical anxiety responses people have to cannabis. Selective targeting of one receptor type in the BNST could offer more predictable anxiety treatment than whole-plant cannabis.

Questions still open

Would CB2-selective agonists reduce anxiety without the CB1-related side effects of cannabis? Do these opposite CB1/CB2 effects in the BNST extend to other anxiety-related brain regions?

Common questions

Why does cannabis sometimes increase and sometimes decrease anxiety?

This study suggests one reason: CB1 and CB2 receptors in the BNST (a brain region important for anxiety) have opposite effects. CB1 activation may promote anxiety while CB2 activation may reduce it. Cannabis activates both, so the net effect depends on the balance.

What is the BNST?

The bed nucleus of the stria terminalis is a brain structure involved in sustained anxiety and threat responses. Unlike the amygdala (which handles immediate fear), the BNST processes more prolonged, uncertain threats that produce anxiety-like states.

Read the original research

CB1 and CB2 receptors in the bed nucleus of the stria terminalis differently modulate anxiety-like behaviors in rats.

Progress in neuro-psychopharmacology & biological psychiatry, 110, 110284

View on PubMed ↗Publisher’s paper ↗

Citation

Gomes-de-Souza, Lucas; Bianchi, Paula C; Costa-Ferreira, Willian; Tomeo, Rodrigo A; Cruz, Fábio C; Crestani, Carlos C. (2021). CB1 and CB2 receptors in the bed nucleus of the stria terminalis differently modulate anxiety-like behaviors in rats.. Progress in neuro-psychopharmacology & biological psychiatry, 110, 110284. https://doi.org/10.1016/j.pnpbp.2021.110284