Aqueous Extract of Semen Ziziphi Spinosae Exerts Anxiolytic Effects during Nicotine Withdrawal via Improvement of Amygdaloid CRF/CRF1R Signaling

Abstract

Anxiety during nicotine withdrawal (NicW) is a key risk factor for smoking relapse. Semen Ziziphi Spinosae (SZS), which is a prototypical hypnotic-sedative herb in Oriental medicine, has been clinically used to treat insomnia and general anxiety disorders for thousands of years. Thus, the present study evaluated the effects of the aqueous extract of SZS (AESZS) on NicW-induced anxiety in male rats that received subcutaneous administrations of nicotine (Nic) (0.4 mg/kg, twice a day) for 7 d followed by 4 d of withdrawal. During NicW, the rats received four intragastric treatments of AESZS (60 mg/kg/d or 180 mg/kg/d). AESZS dose-dependently attenuated NicW-induced anxiety-like behaviors in the elevated plus maze (EPM) tests and 180 mg/kg/d AESZS inhibited NicW-induced increases in plasma corticosterone. Additionally, the protein and mRNA expressions of corticotropin-releasing factor (CRF) and CRF type 1 receptor (CRF1R) increased in the central nucleus of the amygdala (CeA) during NicW, but these changes were suppressed by 180 mg/kg/d AESZS. A post-AESZS infusion of CRF into the CeA abolished the attenuation of anxiety by AESZS and 180 mg/kg/d AESZS suppressed NicW-induced increases in norepinephrine and 3-methoxy-4-hydroxy-phenylglycol levels in the CeA. The present results suggest that AESZS ameliorated NicW-induced anxiety via improvements in CRF/CRF1R and noradrenergic signaling in the CeA.

Purification of spinosin from Ziziphi Spinosae Semen using macroporous resins followed by preparative high‐performance liquid chromatography

“…spinosa (Bunge) Hu ex H. F. Chou, is a well‐known traditional Chinese medicine that has been used to treat anxiety and insomnia for thousands of years in China . Modern pharmacological research shows that the extract of ZS possesses many kinds of biological activities including a sedative‐hypnotic effect , an antidepressant effect , an anxiolytic effect , and so on. These bioactivities are mainly attributed to the rich active components in ZS, especially flavonoids, saponins, and alkaloids .…”

“…sedative-hypnotic effect [3], an antidepressant effect [4], an anxiolytic effect [5], and so on. These bioactivities are mainly attributed to the rich active components in ZS, especially flavonoids, saponins, and alkaloids [6].…”

Isoliquiritigenin Attenuates Anxiety‐Like Behavior and Locomotor Sensitization in Rats after Repeated Exposure to Nicotine

“…Withdrawal from repeated use of NIC in rodents produces substantial anxiety-like behaviors in various instrumental tests, including the EPM test; these tests have been validated in previous studies in our laboratory and by other groups [12,29]. As expected, in the present study, the ethological phenotype of anxiety was observed in the EPM test in that the NIC withdrawal rats exhibited decreased numbers of entries into open arms and spent less time in the open arms of the EPM compared to saline-treated controls.…”

“…At 30 min after the final dose of ISL, the rats were checked in the EPM to assess anxiety-like behaviors, as described previously [12]. Briefly, the EPM was comprised of two open arms (50 cm long × 10 cm wide) and two closed arms (enclosed by dark acrylic walls 40 cm high), which were elevated above the floor to a height of 50 cm, and monitored with a video-tracking system (Shanghai Xinruan Technology Co., Shanghai, China).…”

“…Repeated NIC exposure causes adaptive alterations in the reward circuits to change the patterns of physiological responses to internal and external stimuli, such as augmented response to a challenge dose of drugs of abuse, decreased reward neurotransmission [10], and elevated activities of the stress systems, which underlie both the sensitized behavioral response and withdrawal syndrome [3,11]. ese allostatic changes involve diverse brain reward circuits, fundamentally taking place at the level of neurotransmitters, which ultimately become the targets for pharmacotherapies [3,12]. Elevated glutamatergic transmission in the NaccSh during NIC withdrawal contributes to both positive [13] and negative reinforcement [9,14,15].…”