J. Microbiol. Biotechnol. (2011), 21(10), 1088–1096 doi: 10.4014/jmb.1106.06027 First published online 5 August 2011 Wild Ginseng Attenuates Anxiety- and Depression-Like Behaviors During Morphine Withdrawal Lee, Bombi 1 , Hyuk Kim 1 , Insop Shim 1,2 , Hyejung Lee 1,2 , and Dae-Hyun Hahm 1,2 * Acupuncture and Meridian Science Research Center, College of Oriental Medicine, Kyung Hee University, Seoul 130-701, Korea The Graduate School of Basic Science of Oriental Medicine, College of Oriental Medicine, Kyung Hee University, Seoul 130-701, Korea Received: June 13, 2011 / Revised: July 12, 2011 / Accepted: July 13, 2011 The purpose of this study was to evaluate whether wild ginseng (WG) administration could attenuate anxiety- and depression-like behaviors and expression of corticotrophin- releasing factor (CRF) and neuropeptide Y (NPY) following withdrawal from repeated morphine administration in rats. Male rats were administered daily doses of WG (50, 100, or 200 mg/kg, i.p.) for 5 days, 30 min before morphine injection (40 mg/kg, s.c). The anxiety- and depression-like behavioral responses were measured 72 h after the last morphine injection using an elevated plus maze (EPM) and forced swimming test (FST), respectively. Changes in hypothalamic CRF and NPY expressions were also examined by analyzing their immunoreactivities in the hypothalamus. Daily administration of WG significantly reduced anxiety- and depression-like behavior, and elicited the suppression of CRF expression and the stimulation of NPY expression in the hypothalamus. Our results demonstrated that WG extract might be effective at inhibiting the anxiety and depression responses due to morphine withdrawal by possibly modulating the hypothalamus CRF and NPY systems. Furthermore, these findings imply that WG extract can be used for developing new medication to cure or alleviate morphine withdrawal symptoms and to prevent relapses of morphine use. Keywords: Morphine, wild ginseng, anxiety, depression, neuropeptide Y, corticotrophin-releasing factor Morphine, a strong pain reliever, is widely used to treat moderate to severe pain and a number of other pathological indications. This said, the abuse of morphine and its subsequent withdrawal cause psychiatric side-effects, including anxiety and depression [20]. Many studies have demonstrated that morphine withdrawal causes anxiety- and depression-related disorders in humans and corresponding behavioral responses in animals [1, 21]. Anxiety and depression associated with morphine withdrawal can be alleviated by the administration of antidepressant or anxiolytic drugs, such as fluoxetine or agmatine [28]. However, some antidepressants exert undesirable side-effects, such as drowsiness, dryness of the mouth, headache, nausea, and sexual dysfunction [8]. Recent studies suggested that Panax ginseng (PG) was found to reduce depression symptoms and anxiety disorders in humans [2]. Some studies have reported that PG showed antidepressant-like activity in the forced swimming test (FST) and also reduced anxiety-like behavior in the elevated plus maze (EPM) test in an animal model [4, 27]. Wild ginseng (WG) is the ginseng (the root of Panax ginseng C.A. Mayer) that naturally grows in the mountains and is distinguished from field-cultivated ginseng. It is known to have more pharmacological efficacy and is thus more expensive than cultivated ginseng. In this study, WG indicates the ginseng that has grown undisturbed in the Korean forest for many years from the seeds initially scattered by humans [9]. In terms of seeding methods, it is also differentiated from truly wild ginseng of which the seeds have been distributed through natural vectors such as birds. Until now, there are still unresolved questions about the mechanisms underlying WG’s effect as a therapeutic intervention for treating psychiatric side-effects, including the withdrawal symptoms associated with morphine use. The effects of WG on morphine withdrawal-induced anxiety- and depression-like behavioral alterations have not been examined in animal models. In the present study, the pharmacological effects of WG extract on anxiety- and depression-related behaviors following repeated morphine administration and withdrawal were investigated. Morphine withdrawal-induced behaviors were examined using the EPM and the FST. We also tried to elucidate the underlying mechanism of the effect of WG administration on morphine *Corresponding author Phone: +82-2-961-0366; Fax: +82-2-963-2175; E-mail: dhhahm@khu.ac.kr, dhahm@paran.com