THC and Endocannabinoid-Boosting Drugs Reduced Brain Reward Signaling in Mice | Research

The takeaway

THC and drugs that boost the endocannabinoid 2-AG reduced self-stimulation of the brain's reward system in mice, while boosting anandamide alone had little effect.

Readers interested in how cannabinoids affect the brain's reward system and what that means for addiction potential.

THC reduced brain reward self-stimulation rather than enhancing it

What the researchers found

Researchers tested how THC and drugs that increase natural brain cannabinoids affected the brain's reward system in mice using intracranial self-stimulation (ICSS), where animals press a lever to electrically stimulate the medial forebrain bundle.

THC and JZL184 (a MAGL inhibitor that boosts 2-AG) both reduced operant responding for brain stimulation, food, and spontaneous movement. The FAAH inhibitor PF-3845 (which boosts anandamide) had little effect.

The dual FAAH-MAGL inhibitor SA-57, which boosts both anandamide and 2-AG, produced ICSS depression similar in magnitude to THC. All effects were blocked by the CB1 receptor antagonist rimonabant but not by a CB2 antagonist.

Why it matters

The finding that THC and 2-AG boosting reduce brain reward signaling, rather than enhance it, helps explain why THC's reinforcing effects have been difficult to detect in rodent models. It also clarifies that the two main endocannabinoids (anandamide and 2-AG) have different effects on reward circuits.

The numbers in context

THC and JZL184 attenuated ICSS, food responding, and locomotion. PF-3845 had minimal effects. SA-57 depression was similar in magnitude to THC. JZL184 elevated brain 2-AG. SA-57 elevated both anandamide and 2-AG. CB1 antagonist rimonabant blocked all effects.

How the study worked

Male mice underwent intracranial self-stimulation testing, operant responding for food, and locomotor activity measurements. THC, JZL184, PF-3845, and SA-57 were tested at multiple doses. Brain endocannabinoid levels were quantified. CB1 and CB2 antagonists were used to determine receptor involvement.

What this study cannot tell us

ICSS is one model of reward but does not capture all aspects of drug reinforcement. Mice were tested acutely, and chronic effects may differ. The doses used may not reflect typical human cannabis exposure patterns. Rodent reward neurobiology does not perfectly map to human experience.

How to read the evidence

This is an animal study using operant behavior paradigms in mice. It provides mechanistic insights about cannabinoid effects on reward circuits that require interpretation for human relevance.

When this study was published

Published in 2015. Understanding of endocannabinoid roles in reward and motivation has continued to develop.

The bigger picture

This research complicates the simple narrative that cannabinoids activate the reward system like other drugs of abuse. Instead, THC and endocannabinoid elevation appear to suppress reward-seeking behavior in this paradigm, which may help explain why cannabis has a lower addictive potential than some other substances.

Questions still open

Why does THC reduce brain reward stimulation rather than enhance it? Would chronic exposure to MAGL inhibitors change their effects on the reward system?

Common questions

If THC reduces reward signaling, why do people use cannabis recreationally?

The ICSS paradigm measures one specific type of reward response. Human cannabis use involves complex experiences including altered perception, relaxation, and social context that are not captured by lever-pressing for brain stimulation in mice.

What is the difference between anandamide and 2-AG?

Both are endocannabinoids, the brain's own cannabis-like molecules, but they are produced and broken down by different enzymes and appear to have different functional roles. This study found that boosting 2-AG mimicked THC's effects while boosting anandamide alone did not.

Read the original research

Δ9-tetrahydrocannabinol and endocannabinoid degradative enzyme inhibitors attenuate intracranial self-stimulation in mice.

The Journal of pharmacology and experimental therapeutics, 352(2), 195-207

View on PubMed ↗Publisher’s paper ↗

Citation

Wiebelhaus, Jason M; Grim, Travis W; Owens, Robert A; Lazenka, Matthew F; Sim-Selley, Laura J; Abdullah, Rehab A; Niphakis, Micah J; Vann, Robert E; Cravatt, Benjamin F; Wiley, Jenny L; Negus, S Stevens; Lichtman, Aron H. (2015). Δ9-tetrahydrocannabinol and endocannabinoid degradative enzyme inhibitors attenuate intracranial self-stimulation in mice.. The Journal of pharmacology and experimental therapeutics, 352(2), 195-207. https://doi.org/10.1124/jpet.114.218677