Abstract
BackgroundEthanol withdrawal (EtOHW) anxiety is a crucial risk factor for alcoholic relapse. The neuropeptide nociceptin/orphanin FQ (N/OFQ) acts upon its receptor (NOP) to antagonize corticotropin-releasing factor (CRF) and elicit anxiolytic actions. Semen Ziziphi Spinosae (SZS), a prototypical hypnotic-sedative herb in Oriental medicine, exhibits anxiolytic effects during nicotine withdrawal by improving amygdaloid CRF/CRF1 receptor (CRFR1) signaling. Therefore, we evaluated the effects of SZS on EtOHW anxiety and the involvement of amygdaloid CRF/CRFR1 and N/OFQ/NOP pathways.MethodsMale Sprague Dawley rats received intraperitoneal injections of 2 g/kg EtOH (20% v/v) once daily for 28 d followed by a 3-d withdrawal. During EtOHW, the rats were given once-daily intragastric treatments of a methanol extract of SZS (MESZS, 60 or 180 mg/kg/d). Anxiety-like behaviors were measured with the open field (OF) and elevated plus maze (EPM) tests, and plasma corticosterone (CORT) levels were examined by an enzyme-linked immunosorbent assay. mRNA and protein expression levels of the neuropeptides and their receptors were determined by quantitative polymerase chain reaction and Western blot assays.ResultsMESZS increased the distance traveled in the center zone of the OF and dose-dependently elongated the duration of staying in the center zone in EtOHW rats. MESZS increased both the number of entries into and the time spent in the open arms of the EPM by EtOHW rats. And, MESZS inhibited the over secretion of plasma CORT during EtOHW. EtOHW enhanced CRF and CRFR1 gene and protein expression in the central nucleus of the amygdala (CeA), which were inhibited by 180 mg/kg/d MESZS. EtOHW increased amygdaloid NOP mRNA and protein expression but spared N/OFQ mRNA expression, and 180 mg/kg/d MESZS further promoted these increases. Additionally, a post-MESZS intra-CeA infusion of either CRF or the selective NOP antagonist UFP-101 abolished the expected anxiolytic effect of 180 mg/kg/d MESZS.ConclusionsThese results suggest that MESZS ameliorates EtOHW anxiety by improving both CRF/CRFR1 and N/OFQ/NOP transmissions in the CeA.
Highlights
Ethanol withdrawal (EtOHW) anxiety is a crucial risk factor for alcoholic relapse
Prepro-N/ Nociceptin/orphanin FQ (OFQ) and N/ OFQ peptide receptor (NOP) mRNA levels are altered in the central nucleus of the amygdala (CeA) during EtOHW, and nociceptin/orphanin FQ (N/OFQ) inhibits the CRFinduced increase in gamma aminobutyric acid (GABA) release when iontophoretically added to ex vivo CeA slice preparations [19]
3 d after terminating EtOH, the EtOHW rats exhibited significant decreases in the distance traveled in the center zone and the time remaining in the center zone compared with saline-treated control rats [distance traveled in the center zone: F(3, 28) = 10.21, p < 0.001; saline-treated control group (68.88 ± 6.47, n = 8) vs. EtOH-treated control group (29.75 ± 3.27, n = 8), p < 0.001; time staying in the center zone: F(3, 28) = 10.61, p < 0.001; saline-treated control group (14.38 ± 1.59, n = 8) vs. EtOH-treated control group (6.13 ± 0.55, n = 8), p < 0.001]
Summary
The neuropeptide nociceptin/orphanin FQ (N/OFQ) acts upon its receptor (NOP) to antagonize corticotropin-releasing factor (CRF) and elicit anxiolytic actions. We evaluated the effects of SZS on EtOHW anxiety and the involvement of amygdaloid CRF/ CRFR1 and N/OFQ/NOP pathways. Corticotropinreleasing factor (CRF) is the prototypical pro-stress neuropeptide, and chronic EtOH treatment abnormally elevates CRF/CRF receptor 1 (CRFR1) signaling in the CeA, which is associated with EtOHW anxiety and excessive drinking in rodents. Increased expression of both CRF and CRFR1 transcripts in the CeA of EtOHW mice [10] and intraCeA administration of the CRF antagonist alpha-helical CRF attenuates EtOHW-induced anxiety-like behavior in rats [11]. The CRF and N/OFQ neuropeptidergic systems in the CeA constitute a promising target for treating EtOHW anxiety
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