Cannabinoid Receptor-Expressing Neurons in the Brain's Reward Center Are Fast-Spiking Cells That Control Output | Research

The takeaway

Researchers discovered that CB1-expressing neurons in the nucleus accumbens are exclusively fast-spiking interneurons that become hyperexcitable during cocaine withdrawal, potentially suppressing the reward center's output.

Read this if you are interested in the neuroscience of how cannabinoid receptors work in the brain's reward system.

CB1-expressing NAc neurons were exclusively fast-spiking interneurons

What the researchers found

Using genetically modified mice with fluorescent tagging of CB1-expressing neurons, researchers made several discoveries about these cells in the nucleus accumbens (NAc). All CB1-expressing neurons were fast-spiking interneurons (FSIs), a specific type of inhibitory neuron. These FSIs were electrically coupled to each other, forming a network that could synchronize neural activity.

Critically, after cocaine withdrawal, these CB1-expressing FSIs became hyperexcitable, meaning they fired more readily. Since FSIs inhibit the main output neurons (medium spiny neurons) of the NAc, increased FSI activity would reduce NAc output, potentially contributing to the low motivation and anhedonia characteristic of drug withdrawal.

Why it matters

The nucleus accumbens is the brain's key reward center. Understanding that cannabinoid-receptor neurons in this area are specifically fast-spiking interneurons that can shut down reward circuit output provides a new understanding of how the endocannabinoid system regulates motivation, reward, and the withdrawal state.

The numbers in context

CB1-expressing NAc neurons were exclusively FSIs. FSIs were electrically coupled to each other. FSIs provided feed-forward inhibition of MSNs. FSI excitability increased after cocaine withdrawal.

How the study worked

Generated a knock-in mouse line expressing td-Tomato fluorescent protein in CB1-positive neurons. Used electrophysiology to characterize cell types, electrical coupling, and synaptic connections. Measured changes in membrane excitability following cocaine exposure and withdrawal.

What this study cannot tell us

The study was conducted in mice using cocaine, not cannabis, as the drug of abuse. Results from genetically modified mouse lines may not perfectly reflect natural neuron function. The in vitro electrophysiology may not fully capture in vivo dynamics. The specific relevance to cannabis use was not directly tested.

How to read the evidence

Sophisticated genetic and electrophysiological study in mice; preliminary but mechanistically rigorous.

When this study was published

Published in 2012. Research on cannabinoid receptor-expressing interneurons in addiction circuits has continued.

The bigger picture

This study reveals a new mechanism by which drugs of abuse might produce withdrawal symptoms. If cocaine withdrawal increases the excitability of inhibitory neurons that suppress reward circuit output, this could explain the anhedonia, low motivation, and depression-like symptoms that drive relapse.

Questions still open

Does cannabis withdrawal produce similar changes in FSI excitability? Could modulating FSI activity during drug withdrawal reduce anhedonia and prevent relapse? Do these findings explain why cannabis affects motivation in chronic users?

Common questions

What are fast-spiking interneurons?

Fast-spiking interneurons are a type of brain cell that fires very rapidly and inhibits (quiets) nearby neurons. In the nucleus accumbens, they act as a brake on the main output neurons. When these inhibitory cells become more active, they reduce the reward center's overall output, which could affect motivation and pleasure.

What does this have to do with cannabis?

The CB1 cannabinoid receptor is the main target of THC. This study found that neurons expressing CB1 in the reward center are specifically fast-spiking interneurons. This means that when cannabis activates CB1 receptors in this area, it is specifically affecting the inhibitory brake cells, not the main output neurons. This could explain some of cannabis's effects on motivation and reward.

Read the original research

Cannabinoid receptor 1-expressing neurons in the nucleus accumbens.

Proceedings of the National Academy of Sciences of the United States of America, 109(40), E2717-25

View on PubMed ↗Publisher’s paper ↗

Citation

Winters, Bradley D; Krüger, Juliane M; Huang, Xiaojie; Gallaher, Zachary R; Ishikawa, Masago; Czaja, Krzysztof; Krueger, James M; Huang, Yanhua H; Schlüter, Oliver M; Dong, Yan. (2012). Cannabinoid receptor 1-expressing neurons in the nucleus accumbens.. Proceedings of the National Academy of Sciences of the United States of America, 109(40), E2717-25. https://doi.org/10.1073/pnas.1206303109