A novel NMDA receptor-based intervention to suppress compulsion-like alcohol drinking

Compulsive drives for alcohol, where intake persists despite adverse consequences, are substantial obstacles to treating Alcohol Use Disorder (AUD). However, there are limited treatment options and thus considerable interest in identifying new, potent and safe pharmacotherapies. We found that non-canonical N-methyl-d-aspartate receptors (NMDARs), active at hyperpolarized potentials, drive compulsion-like alcohol drinking in rats without affecting regular, alcohol-only intake. Congruent human studies suggest that NMDAR inhibition reduces alcohol drinking in treatment-seekers but not non-treatment-seekers and suppresses craving. These cross-species studies of consumption under conflict indicate that inhibiting non-canonical NMDARs could be of clinical value for AUD. d-serine activates NMDARs overall, but actually inhibits non-canonical NMDARs. Also, d-serine has been widely tested in humans as a moderate NMDAR modulator, but some nephrotoxicity concerns remain, and thus any strategy that reduces d-serine exposure could be of broad utility. Here, co-administration of sodium benzoate (NaBenz), which reduces d-serine breakdown, allowed subthreshold d-serine levels to suppress compulsion-like alcohol drinking without altering normal alcohol-only consumption, providing a novel intervention for AUD and underscoring the importance of non-canonical NMDARs for compulsion-like intake. Low NaBenz doses alone had no average effect on intake. NaBenz/d-serine reduced compulsion-like intake in nearly all animals, while higher d-serine alone decreased compulsion-like intake with less of an effect in lower-drinking subjects. Thus, combining subthreshold NaBenz and d-serine suppressed compulsion-like intake, helping both to alleviate some d-serine concerns, and, importantly, to reduce consequence-resistant consumption across nearly all individuals. Therefore, NaBenz/d-serine likely represents an FDA-approved and immediately-accessible pharmacotherapy to help counteract compulsion-like drives and treat AUD.