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.
Highlights
Tobacco smoking is a leading preventable cause of disease and death worldwide [1]
It revealed that the 180 mg/kg/d dose, but not the 60 mg/kg/d dose, of aqueous extract of SZS (AESZS) administered for 4 d increased the time spent in the open arms of the elevated plus maze (EPM) in naive rats when tested 60 min after the fourth dose [percentage of entries into open arms: F(3, 20) = 1.51, p > 0.05, n = 6; percentage of time spent in open arms: F(3, 20) = 3.97, p < 0.05; naive group versus AESZS180 group, p < 0.05; distilled water (DW) group versus AESZS180 group, p < 0.05] (Figure 2), which was indicative of improvements in the innate anxiety in the rats
Similar to the abovementioned EPM findings, Nic-withdrawn rats exhibited anxiety-like behavior that was ameliorated by treatment with 180 mg/kg/d AESZS [percentage of entries into open arms: F(3, 20) = 7.96, p < 0.01; saline/DW/modified Ringer’s solution (MRS) group (33.25 ± 3.37 %, n = 6) versus Nic/DW/MRS group (16.83 ± 2.42%, n = 6), p < 0.01; Nic/DW/MRS group versus Nic/AESZS180/MRS group (28.58 ± 3.03%, n = 6), p < 0.05; percentage of time spent in open arms: F(3, 20) = 7.58, p < 0.01; saline/DW/MRS group (22.50 ± 3.09%, n = 6) versus Nic/DW/MRS group (8.89 ± 2.10%, n = 6), p < 0.01; Nic/DW/MRS group versus Nic/AESZS180/MRS group (23.69 ± 2.92%, n = 6), p < 0.01]
Summary
Tobacco smoking is a leading preventable cause of disease and death worldwide [1]. Nicotine (Nic) is the primary psychoactive and addictive component of tobacco and dependence on this drug is the main cause associated with continued smoking [2]. It has been estimated that most smokers attempt to quit using tobacco but few of them succeed due to the discomforts associated with Nic withdrawal (NicW) symptoms [3]. There is a growing interest in the development of novel and safe medications that can prevent or relieve the anxiety experienced during NicW so that smokers persist in the attempt to quit. Withdrawal-induced anxiety during the cessation of drugs of abuse, including Nic, is derived from dysregulation of brain stress systems which is characterized by escalated activities of corticotropin-releasing factor (CRF) and norepinephrine (NE) systems in brain regions involved in emotional processing [6, 7]
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