How Does Ketamine Affect Brain Circuits Involved in Compulsive Behaviors?

What you need to know

• Ketamine rapidly reduced compulsive grooming behavior in mice with a genetic mutation linked to OCD
• The effects lasted up to 7 days, similar to ketamine’s effects in human OCD patients
• Ketamine increased activity in a brain circuit connecting the prefrontal cortex to the striatum
• Directly activating this circuit reduced compulsive grooming, while inhibiting it increased grooming
• The findings provide new insights into how ketamine may work as a fast-acting OCD treatment

Background on OCD and Current Treatments

Obsessive-compulsive disorder (OCD) is a mental health condition characterized by unwanted, intrusive thoughts (obsessions) and repetitive behaviors or mental acts (compulsions). It affects about 2-3% of people worldwide and can severely impact quality of life.

Current medications for OCD, like selective serotonin reuptake inhibitors (SSRIs), often take 2-3 months to start working and don’t help everyone. About 30-40% of people with OCD don’t respond adequately to available treatments. There’s a clear need for faster-acting and more effective options.

Recent small clinical trials have shown that ketamine, a drug that acts on glutamate signaling in the brain, can rapidly reduce OCD symptoms within hours. The effects can last up to a week after a single dose. However, the exact brain mechanisms underlying ketamine’s effects in OCD are not well understood.

New Insights from Mouse Studies

To investigate how ketamine impacts brain circuits involved in compulsive behaviors, researchers used a type of genetically engineered mouse that exhibits excessive grooming behavior similar to human OCD. These mice have a mutation in a gene called SAPAP3, which has been linked to OCD and related disorders in humans.

The study found that a single dose of ketamine rapidly reduced compulsive grooming in the OCD-like mice for up to 3 days. This timeline closely matches ketamine’s effects seen in human OCD patients.

To understand the brain circuits involved, the researchers used advanced neuroscience techniques to measure and manipulate the activity of specific groups of neurons. They focused on a circuit connecting two key brain regions implicated in OCD:

1. The dorsomedial prefrontal cortex (dmPFC) - involved in decision-making and behavioral flexibility
2. The dorsomedial striatum (DMS) - important for selecting and initiating actions

How Ketamine Affects Brain Circuit Activity

In normal mice, activity in the dmPFC-DMS circuit decreased when the mice started grooming. However, in the OCD-like mice, this normal drop in activity was absent.

Interestingly, ketamine increased activity in this circuit specifically in the OCD-like mice during grooming, but not in normal mice. This suggests ketamine may help “normalize” the abnormal circuit activity associated with compulsive behaviors.

To test if this increase in circuit activity was directly responsible for reducing compulsive grooming, the researchers used optogenetics - a technique that allows precise control of neuron activity using light. They found:

• Activating the dmPFC-DMS circuit reduced compulsive grooming in OCD-like mice
• Inhibiting the circuit increased grooming behavior in normal mice

These results show that the activity of this specific brain circuit can bidirectionally control compulsive grooming behavior. The fact that ketamine increases activity in this circuit provides strong evidence that this may be a key mechanism for its rapid anti-OCD effects.

Conclusions

• Ketamine rapidly reduces compulsive behaviors in an OCD-like mouse model, with similar timing to its effects in human patients
• It does this by increasing activity in a brain circuit connecting the prefrontal cortex and striatum
• Directly activating this circuit is sufficient to reduce compulsive behaviors
• The findings provide new insights into the brain mechanisms of OCD and ketamine’s therapeutic effects
• This work may help guide the development of new rapid-acting treatments for OCD that target similar brain circuits

While more research is needed to fully translate these findings to humans, this study significantly advances our understanding of the brain circuits involved in OCD and how ketamine may exert its fast-acting effects. It provides a strong foundation for further studies aimed at developing better treatments for this challenging disorder.