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.
Highlights
Alcoholism imposes a tremendous burden on human health and society, and effective treatments are lacking [1]
Primary antibodies against inducible NO synthase (NOS), neuronal NOS (nNOS), corticotropin-releasing factor (CRF), and β-actin were supplied by Abcam, and horseradish peroxidaseconjugated secondary antibody was provided by Cell Signaling Technology (Beverly, MA, USA)
When rats were treated with Sau (2.5, 7.5, and 25 mg/kg/ day), daily during a 3-day EtOH withdrawal (EtOHW) period, Sau at all three doses had no effect on EtOH locomotor sensitization
Summary
Alcoholism imposes a tremendous burden on human health and society, and effective treatments are lacking [1]. Similar to other drugs of abuse, ethanol (EtOH) dependence is elicited and maintained by positive (rewarding effects) and negative (affective withdrawal symptoms) reinforcement mechanisms, which are targeted by pharmacological treatments of alcoholism [2]. Some rewarding effects of EtOH such as euphoria and gratification in human beings are difficult to be established in animal models, some animal models have been used to measure EtOH reward, including rodent models of behavioral and neurochemical sensitization [3, 4]. Locomotor sensitization is closely associated with challenge-induced sensitization of dopamine release in the nucleus accumbens during EtOHW [4, 7], a form of neurochemical sensitization characterizing the rewarding effect [8]. Us, rodent locomotor sensitization provides a behavioral and neurochemical readout of the positive reinforcement induced by EtOH and is useful in screening potential pharmacological agents for treating EtOH dependence Locomotor sensitization is closely associated with challenge-induced sensitization of dopamine release in the nucleus accumbens during EtOHW [4, 7], a form of neurochemical sensitization characterizing the rewarding effect [8]. us, rodent locomotor sensitization provides a behavioral and neurochemical readout of the positive reinforcement induced by EtOH and is useful in screening potential pharmacological agents for treating EtOH dependence
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