Dihydromyricetin As a Novel Anti-Alcohol Intoxication Medication

Abstract

Alcohol use disorders (AUDs) constitute the most common form of substance abuse. The development of AUDs involves repeated alcohol use leading to tolerance, alcohol withdrawal syndrome, and physical and psychological dependence, with loss of ability to control excessive drinking. Currently there is no effective therapeutic agent for AUDs without major side effects. Dihydromyricetin (DHM; 1 mg/kg, i.p. injection), a flavonoid component of herbal medicines, counteracted acute alcohol (EtOH) intoxication, and also withdrawal signs in rats including tolerance, increased anxiety, and seizure susceptibility; DHM greatly reduced EtOH consumption in an intermittent voluntary EtOH intake paradigm in rats. GABA_A receptors (GABA_ARs) are major targets of acute and chronic EtOH actions on the brain. At the cellular levels, DHM (1 μm) antagonized both acute EtOH-induced potentiation of GABA_ARs and EtOH exposure/withdrawal-induced GABA_AR plasticity, including alterations in responsiveness of extrasynaptic and postsynaptic GABA_ARs to acute EtOH and, most importantly, increases in GABA_AR α4 subunit expression in hippocampus and cultured neurons. DHM anti-alcohol effects on both behavior and CNS neurons were antagonized by flumazenil (10 mg/kg in vivo; 10 μm in vitro), the benzodiazepine (BZ) antagonist. DHM competitively inhibited BZ-site [³H]flunitrazepam binding (IC₅₀, 4.36 μm), suggesting DHM interaction with EtOH involves the BZ sites on GABA_ARs. In summary, we determined DHM anti-alcoholic effects on animal models and determined a major molecular target and cellular mechanism of DHM for counteracting alcohol intoxication and dependence. We demonstrated pharmacological properties of DHM consistent with those expected to underlie successful medical treatment of AUDs; therefore DHM is a therapeutic candidate.