Effects of a Peripherally Restricted Hybrid Inhibitor of CB1 Receptors and iNOS on Alcohol Drinking Behavior and Alcohol-Induced Endotoxemia.

Luis Santos-Molina,Yuhong Lin,Malliga R Iyer,George Kunos,Ozge Gunduz-Cinar,Casey M Wood,Alexa Herrerias,Charles N Zawatsky,Bin Gao,Resat Cinar,Grzegorz Godlewski

doi:10.3390/molecules26165089

Abstract

Alcohol consumption is associated with gut dysbiosis, increased intestinal permeability, endotoxemia, and a cascade that leads to persistent systemic inflammation, alcoholic liver disease, and other ailments. Craving for alcohol and its consequences depends, among other things, on the endocannabinoid system. We have analyzed the relative role of central vs. peripheral cannabinoid CB1 receptors (CB1R) using a “two-bottle” as well as a “drinking in the dark” paradigm in mice. The globally acting CB1R antagonist rimonabant and the non-brain penetrant CB1R antagonist JD5037 inhibited voluntary alcohol intake upon systemic but not upon intracerebroventricular administration in doses that elicited anxiogenic-like behavior and blocked CB1R-induced hypothermia and catalepsy. The peripherally restricted hybrid CB1R antagonist/iNOS inhibitor S-MRI-1867 was also effective in reducing alcohol consumption after oral gavage, while its R enantiomer (CB1R inactive/iNOS inhibitor) was not. The two MRI-1867 enantiomers were equally effective in inhibiting an alcohol-induced increase in portal blood endotoxin concentration that was caused by increased gut permeability. We conclude that (i) activation of peripheral CB1R plays a dominant role in promoting alcohol intake and (ii) the iNOS inhibitory function of MRI-1867 helps in mitigating the alcohol-induced increase in endotoxemia.

Highlights

We have recently reported that the brain non-penetrant CB1 receptors (CB1R) antagonist, JD5037, representing the second generation of CB1R antagonists, significantly suppresses alcohol preference and proposed that endocannabinoids engage CB1R in ghrelin-producing cells of the stomach to promote alcohol drinking in a manner sensitive to blockade by JD5037 [33]
To further document the role of central CB1R in these effects, we tested the ability of i.c.v.-administered rimonabant in antagonizing CP55,940-induced catalepsy and hypothermia
Genetic deletion or pharmacologic inhibition of enzymes involved in endocannabinoid genetic deletion or pharmacologic inhibition of enzymes involved in endocannabinoid degradation was reported to increase alcohol intake and preference in rodent drinking paradigms [38]