An important consideration is whether PPAR agonists decrease alcohol consumption via central or peripheral PPAR activation. The effective treatments increase Adh1 and decrease Aldh2 mRNA in the liver. This combination of changes (at the level of enzyme activity) leads to a build-up of acetaldehyde which is protective against developing alcohol dependence. Therefore it’s possible that the effects on the liver might contribute to the decreased alcohol consumption. However, Stopponi et al. (2011) found that a PPARγ agonist did not affect blood alcohol levels and blockade of central PPARs abrogated the anti-alcohol drinking effects, establishing the importance of central PPARs in this effect. The blood brain barrier penetrance of PPAR agonists is not well-studied, so the amount of drug reaching the brain is unknown. However, even if PPAR agonists do not have a direct effect in brain (because of lack of penetration), the fact that PPAR agonists change behavior suggests that there must be some change in brain signaling induced by PPAR agonists, whether it be direct or indirect. Thus, results from this study are still helpful in defining gene targets in brain to manipulate addiction-like behaviors.
