Blocking the Enzyme That Breaks Down Anandamide Had Opposite Effects on Nicotine Reward in Mice Versus Rats | Research

The takeaway

FAAH inhibition (which raises anandamide levels) enhanced nicotine reward in mice but blocked it in rats, with the species difference possibly explained by non-cannabinoid substrates like OEA and PEA acting on TRPV1 and PPAR-alpha receptors.

Read this if you are interested in how the endocannabinoid system interacts with nicotine addiction.

Opposite species effects: FAAH inhibition enhanced nicotine reward in mice, blocked it in rats

What the researchers found

The review described a puzzling finding: when FAAH, the enzyme that degrades anandamide, is inhibited or genetically deleted, the effects on nicotine dependence differ dramatically between species. In mice, FAAH disruption enhanced nicotine reward (conditioned place preference) and worsened withdrawal. In rats, FAAH inhibition blocked nicotine reward and had no effect on withdrawal.

The review proposed that this species difference may be due to FAAH's non-cannabinoid substrates. FAAH also degrades OEA and PEA, which act on TRPV1 and PPAR-alpha receptors rather than cannabinoid receptors. The balance between cannabinoid and non-cannabinoid effects of FAAH inhibition may differ between species.

Why it matters

Species differences in drug responses are a critical challenge for translating animal research to humans. If FAAH inhibition has opposite effects in mice and rats, knowing which species better predicts human responses is essential before developing FAAH inhibitors as smoking cessation aids.

The numbers in context

FAAH substrates: anandamide (CB1/CB2), OEA (PPAR-alpha), PEA (PPAR-alpha, TRPV1). In mice: FAAH inhibition/knockout enhanced nicotine CPP and withdrawal. In rats: FAAH inhibition blocked nicotine CPP, no withdrawal effect.

How the study worked

Mini-review covering pharmacological and genetic studies of FAAH inhibition in nicotine conditioned place preference and withdrawal models in both mice and rats. Discussed cannabinoid and non-cannabinoid receptor systems involved.

What this study cannot tell us

Review of a limited number of studies. The species difference mechanism was proposed but not proven. It remains unknown whether human responses to FAAH inhibition more closely resemble mice or rats. Different FAAH inhibitors and experimental protocols across studies complicate comparison.

How to read the evidence

Mini-review of conflicting animal findings; preliminary evidence with unresolved species differences.

When this study was published

Published in 2013. FAAH inhibitor development has continued, with some compounds entering human clinical trials.

The bigger picture

This review highlights that the endocannabinoid system is more complex than just CB1 and CB2 receptors. FAAH inhibition affects multiple signaling systems simultaneously, and the therapeutic implications depend on which effects predominate in humans.

Questions still open

Which species better predicts human responses to FAAH inhibition for nicotine dependence? Could selective targeting of specific FAAH substrates achieve the desired effect? Would FAAH inhibitors work as smoking cessation aids in humans?

Common questions

Could manipulating the endocannabinoid system help with nicotine addiction?

The concept is promising but the details are complicated. Blocking the enzyme FAAH (which raises anandamide and other signaling molecules) reduced nicotine reward in rats, suggesting a potential treatment pathway. However, the same manipulation enhanced nicotine reward in mice. Until this species difference is resolved, it remains uncertain whether this approach would help or hinder smoking cessation in humans.

Why do mice and rats respond differently?

FAAH breaks down not just the endocannabinoid anandamide but also other molecules like OEA and PEA that act on completely different receptors (TRPV1, PPAR-alpha). The balance of these effects may differ between species. In rats, the non-cannabinoid effects may dominate, reducing nicotine reward. In mice, the cannabinoid effects may dominate, enhancing it.

Read the original research

The role of fatty acid amide hydrolase inhibition in nicotine reward and dependence.

Life sciences, 92(8-9), 458-62

View on PubMed ↗Publisher’s paper ↗

Citation

Muldoon, Pretal P; Lichtman, Aron H; Parsons, Loren H; Damaj, M Imad. (2013). The role of fatty acid amide hydrolase inhibition in nicotine reward and dependence.. Life sciences, 92(8-9), 458-62. https://doi.org/10.1016/j.lfs.2012.05.015