Natural brain peptides that act on cannabinoid receptors can both help and hurt memory in mice | Research

The takeaway

A peptide called hemopressin that blocks the CB1 receptor improved memory in healthy mice, while peptides that activate CB1 impaired it, but those same activating peptides reversed memory loss in an Alzheimer's model.

Read this if you're interested in how the brain's own cannabinoid system naturally regulates memory.

CB1-activating peptides reversed Alzheimer's-like memory loss in mice

What the researchers found

Hemopressin (Hp), a natural peptide that blocks the CB1 cannabinoid receptor, improved memory formation and extended how long mice retained memories in object recognition tasks. Two CB1-activating peptides, RVD and VD, had the opposite effect in healthy mice, impairing memory.

The picture reversed in mice modeling Alzheimer's disease. In mice pre-treated with amyloid-beta to induce memory impairment, the CB1-activating peptides RVD and VD actually restored memory function. Hemopressin alone had no effect in these impaired mice.

All effects were confirmed to work through CB1 receptors, as they could be blocked by the CB1 antagonist AM251.

Why it matters

This research reveals that the endocannabinoid system contains its own set of peptide regulators with opposing effects on memory. The finding that CB1 activation impairs memory in healthy brains but restores it in diseased brains highlights how context determines whether cannabinoid signaling helps or hurts cognition.

The numbers in context

Hemopressin improved both memory formation and retention in novel object recognition and object location recognition tasks. RVD and VD reversed memory impairment induced by amyloid-beta 1-42 injections given 14 days before testing. Effects were blocked by AM251 at 2 mg/kg.

How the study worked

Researchers administered peptides directly into the brains (intracerebroventricular infusion) of mice before testing them on novel object recognition and object location recognition tasks. They tested healthy young mice and mice that had received amyloid-beta injections 14 days earlier to model Alzheimer's-like memory impairment. Various antagonists were used to confirm the receptor mechanisms.

What this study cannot tell us

Peptides were delivered directly into the brain, a method not applicable to human treatment. The Alzheimer's model used (amyloid-beta injection) is simplified compared to actual disease progression. Mice were tested on relatively short timescales, leaving long-term effects unknown.

How to read the evidence

Animal study using direct brain injections in mice. Provides mechanistic insight but is far from human clinical application.

When this study was published

Published in 2016. Research on cannabinoid peptide ligands as potential memory therapeutics continues.

The bigger picture

The brain produces its own cannabinoid-targeting peptides that can modulate memory in both directions depending on the health state of the brain. This dual nature could explain some of the conflicting findings about cannabis and cognition and suggests that cannabinoid-based therapies might need to be tailored based on whether the brain is healthy or impaired.

Questions still open

Could these peptide ligands be developed into drugs deliverable through less invasive routes? Would the memory-restoring effects of CB1 activation hold up in more complex models of neurodegeneration? Do humans produce similar cannabinoid peptides with comparable memory effects?

Common questions

Does this mean cannabis could help with Alzheimer's?

The study found that specific cannabinoid-activating peptides restored memory in mice with Alzheimer's-like damage. However, these were purified peptides injected directly into the brain, which is very different from smoking or ingesting cannabis. The findings are promising for drug development but do not support cannabis as an Alzheimer's treatment.

Why did the same type of receptor activation have opposite effects?

In healthy brains, CB1 activation appeared to suppress normal memory processes. In damaged brains, the same activation may have compensated for disrupted signaling pathways. The brain's response to cannabinoid signals depends heavily on its current state.

Read the original research

Effects of the cannabinoid 1 receptor peptide ligands hemopressin, (m)RVD-hemopressin(α) and (m)VD-hemopressin(α) on memory in novel object and object location recognition tasks in normal young and Aβ1-42-treated mice.

Neurobiology of learning and memory, 134 Pt B, 264-74

View on PubMed ↗Publisher’s paper ↗

Citation

Zhang, Rui-San; He, Zhen; Jin, Wei-Dong; Wang, Rui. (2016). Effects of the cannabinoid 1 receptor peptide ligands hemopressin, (m)RVD-hemopressin(α) and (m)VD-hemopressin(α) on memory in novel object and object location recognition tasks in normal young and Aβ1-42-treated mice.. Neurobiology of learning and memory, 134 Pt B, 264-74. https://doi.org/10.1016/j.nlm.2016.07.030