Sauchinone Blocks Ethanol Withdrawal-Induced Anxiety but Spares Locomotor Sensitization: Involvement of Nitric Oxide in the Bed Nucleus of the Stria Terminalis

Abstract

Both the positive (manifested by locomotor sensitization) and negative (withdrawal symptoms) reinforcing effects of ethanol (EtOH) involve central nitric oxide (NO) signaling. Sauchinone (a bioactive lignan in Saururus chinensis) has been shown to improve methamphetamine-induced behavioral and neurochemical changes via the NO signaling pathway. Thus, this study evaluated the effects of sauchinone on locomotor sensitization and anxiety during EtOH withdrawal (EtOHW). Male adult Sprague-Dawley rats were treated with 1.5 g/kg/day of EtOH (20%, vol/vol) via intraperitoneal injection for 28 days, followed by a 3-day withdrawal. During withdrawal, the rats were given intragastric sauchinone (2.5, 7.5, or 25 mg/kg/day) once a day. EtOH locomotor sensitization was determined by challenging EtOHW rats with 0.75 g/kg EtOH, while EtOHW-induced anxiety was assessed using the elevated plus maze (EPM). None of the three doses of sauchinone affected EtOH locomotor sensitization. However, in the EPM, treatment of EtOHW rats with sauchinone at 7.5 or 25 mg/kg/day increased both the number of entries into and the time spent in the open arms. Moreover, the two doses of sauchinone inhibited the oversecretion of plasma corticosterone during EtOHW. In the bed nucleus of the stria terminalis (BNST), EtOHW increased NO production, enhanced gene and protein expression of both inducible nitric oxide synthase (iNOS) and neuronal NOS (nNOS), and also elevated protein levels of corticotropin-releasing factor, which were all inhibited by 25 mg/kg/day sauchinone. In an in vitro experiment, sauchinone (3, 10, and 30 μM) inhibited H2O2-stimulated nNOS protein expression in neuronal PC12 cells. Finally, intra-BNST infusion of sodium nitroprusside, a NO donor, after sauchinone (25 mg/kg/day) administration, abolished its expected anxiolytic effect. Taken together, these results indicate that sauchinone attenuates anxiety-like behavior in rats during EtOHW but spares EtOH locomotor sensitization, and the anxiolytic effect is mediated via the NO signaling pathway in the BNST.

Alterations and correlations of gut microbiota, fecal, and serum metabolome characteristics in a rat model of alcohol use disorder

“…The EPM was 80 cm elevated from the floor. The methods according the references of Jiao ( Jiao et al, 2021 ) with some modifications. Rats were placed on the central platform facing an open arm individually, and the activity of the rat in the maze for 5 min was recorded by an automated video tracking system.…”

Solitary Nitric Oxide Signaling Mediates Mild Stress-Induced Anxiety and Norepinephrine Release in the Bed Nucleus of the Stria Terminalis during Protracted Ethanol Withdrawal

“…A wide range of neurotransmitters and neuropeptides, including glutamate, gamma-aminobutyric acid (GABA), nitric oxide (NO), galanin, and neuropeptide Y, are present in the NTS-A2 and regulate NE neuronal activities [ 17 ]. It is well documented that NO synthase (NOS) inhibiters have anxiolytic effects [ 18 – 20 ]; moreover, the NO system plays an important role in EtOHW anxiety and NE release induced by drug abuse. Bonassoli et al [ 21 ] reported that EtOHW activated NO-producing neurons in the brainstem, while local infusion of NOS inhibitors into the brainstem regions such as the periaqueductal gray matter area and the dorsal raphe nucleus mitigates EtOHW anxiety [ 22 , 23 ].…”