Huang-Lian-Jie-Du decoction alleviates depressive-like behaviors in dextran sulfate sodium-induced colitis mice via Trem2/Dap12 pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Huang-Lian-Jie-Du decoction (HLJD), a traditional Chinese medicine prescription, has been implicated as effective in treating colitis, depression and inflammation-related diseases. Whether HLJD decoction could ameliorate colitis-induced depression was still unknown and the underlying mechanism was needed to be clarified. AIM OF THE STUDY: Our study aimed to explore the effect and the underlying mechanism of HLJD treatment on colitis-induced depression and the involvement of the inflammatory factors and microglial-activated related genes. MATERIALS AND METHODS: The chronic colitis model was established by treating male mice with 1% dextran sulfate sodium (DSS) for 8 weeks. One week after DSS-treated, HLJD decoction was administered orally with 2 and 4 g/kg daily for 7 weeks. Behavior tests (Open field/Elevated plus maze/Novel object recognition) and TUNEL staining were then assessed. The expression of inflammatory-related genes and microglial dysregulation were measured by RT-PCR and the expression of Trem2, Danp12 and Iba1 were assessed by immunofluorescence methods. RESULTS: Depressive-like behaviors were observed in mice treated with DSS, which suffered colitis. Compared to normal control (NC-V) mice, the density of TUNEL + cells in the habenula (Hb), hippocampus (HIP), and cortex were significantly higher in colitis (DSS-V) mice, especially in Hb. Compared to NC-V and several brain regions, the expression levels of the Il-1ß, Il-10 and Dap12 mRNA were significantly increased in the lateral habenula (LHb) of colitis mice. Moreover, the expression of Trem2, Dap12 and Iba1 were increased in LHb of DSS-V mice. HLJD treatment could alleviate depressive-like behaviors, reduce the density of TUNEL + cells in Hb and the expression of Il-6, Il-10 and Dap12 mRNA in LHb of DSS-V mice. The overexpression of Trem2, Dap12 and Iba1 in LHb of DSS-V mice were reversed after HLJD treatment. CONCLUSION: These results reveal LHb is an important brain region during the process of colitis-induced depression. HLJD treatment could alleviates depressive-like behaviors in colitis mice via inhibiting the Trem2/Dap12 pathway in microglia of LHb, which would contribute to the precise treatment. It provides a potential mechanistic explanation for the effectiveness of HLJD treatment in colitis patients with depression.

Gabra6100Q allele Sprague-Dawley rats have a higher sensitivity to hypnosis induced by isoflurane and ethanol than the wild type rats.

BACKGROUND: The neurobiological mechanisms underlying how general anesthetics render a patient's unconsciousness (hypnosis) remains elusive. The role of the cerebellum in hypnosis induced by general anesthetics is unknown. Gabra6100Q allele Sprague-Dawley (SD) rats have a naturally occurring single nucleotide polymorphism in the GABAA receptor α6 subunit gene that is expressed exclusively in cerebellum granule cells. METHODS: We examined the loss of righting reflex (LORR) induced by isoflurane, and ethanol in Gabra6100Q rats compared with those in wild type (WT) SD rats. We also examined the change of c-Fos expression induced by isoflurane exposure in cerebellum granule cells of both mutant and WT rats. RESULTS: Gabra6100Q rats are more sensitive than WT rats to the LORR induced by isoflurane and ethanol. Moreover, isoflurane exposure induced a greater reduction in c-Fos expression in cerebellum granule cells of Gabra6100Q rats than WT rats. CONCLUSIONS: Based on these data, we speculate that cerebellum may be involved in the hypnosis induced by some general anesthetics and thus may represent a novel target of general anesthetics.

Electroacupuncture Relieves Pain During Alcohol Withdrawal.

Background: Alcohol use disorder (AUD) is one of the most prevalent chronic relapsing substance use disorders. The negative emotional state, including pain hypersensitivity that often occurs during abstinence, is believed to be a significant driving force for intensive seeking and relapse drinking. Studies have revealed that this may involve the inhibition of midbrain dopamine transmission and activation of the "antireward" system in the lateral habenula (LHb). Acupuncture has been proven effective in reducing pain and certain syndromes associated with AUD. There have been extensive studies conducted on acupuncture. However, the neuroanatomical basis behind acupuncture practice is still unclear. Objective: To briefly describe recent research about acupuncture on pain, particularly those related to AUD. Results: Preclinical studies found that electrostimulation of acupoints (electroacupuncture [EA]) effectively relieves hyperalgesia during withdrawal from chronic alcohol administration. This effect is mediated by the µ-opioid receptors in the LHb. Other studies revealed that the analgesic effect of EA could be mediated by mechanisms independent of the opioid system. Other evidence shows that acupuncture's strong anti-inflammatory effect also contributes to its analgesic effect. Conclusion: Acupuncture could alleviate pain, including the pain in alcoholics, through mechanisms either dependent or independent of the opioid system. Since alcohol abuse causes inflammation, which is also a significant cause of pain, the strong anti-inflammatory effect of acupuncture may also contribute to its analgesic effect. Thus, acupuncture is a nonaddictive therapeutic choice for pain related to substance use disorders, including alcohol.

Acupuncture for alcohol use disorder.

Alcohol use disorder (AUD) is a common medical and social problem, affecting about 240 million people in the world. To address this major health concern, the currently available treatments for AUD need to be improved. Acupuncture, a popular form of complementary and alternative therapy, is emerging as an effective treatment for AUD. This review summarizes how preclinical and clinical studies are related to the application of acupuncture for AUD. These studies suggest that if used correctly, acupuncture may effectively reduce alcohol intake, attenuate alcohol withdrawal syndrome, and rebalance AUD-induced maladaptation in neurotransmitters and hormones in related brain areas. The progress of research in this field is at an early stage. Future investigations with rigorous design and carefully constructed protocols are still needed.

Electroacupuncture Attenuates Hyperalgesia in Rats Withdrawn from Chronic Alcohol Drinking via Habenular Mu Opioid Receptors.

BACKGROUND: Hyperalgesia or increased sensitivity to pain is often found in alcoholics during alcohol withdrawal and may contribute to relapse drinking. Alternative therapies such as acupuncture and electroacupuncture (EA), through mechanisms involving opioid receptors, may reduce pain and substance dependence and withdrawal syndromes. The lateral habenula (LHb), an epithalamic structure rich in mu opioid receptors (MORs), is a critical target for both drugs of abuse and pain. We previously observed hyperalgesia in rats withdrawn from chronic ethanol (EtOH) drinking and found that EA at the acupoint Zusanli (ST36) reduced EtOH intake. This raised question of whether EA can alleviate hyperalgesia during alcohol withdrawal and, if so, whether the mechanism involves MORs in the LHb. METHODS: We trained male rats to drink EtOH using the intermittent access 20% EtOH 2-bottle free-choice drinking paradigm for 8 weeks, after which the alcohol supply was discontinued. We measured pain sensitivity using radiant heat (a light beam directed at the hind paw of rats) and compared the paw withdrawal latencies (PWLs) with and without EA at ST36. RESULTS: The PWLs were significantly shorter in rats at 24, 48, and 72 hours and 7 days after the discontinuation of EtOH when compared to EtOH-naïve rats. After a single administration of 2-Hz EA for 20 minutes at ST36, the PWLs at 24 hours after the withdrawal of EtOH were significantly greater than those of the sham group (2-Hz EA at the tail). Furthermore, the effect of EA on PWLs was significantly attenuated by bilateral intrahabenula infusion of the MOR antagonist naltrexone. CONCLUSIONS: These results suggest that EA can alleviate hyperalgesia during EtOH withdrawal through a mechanism involving MORs in the habenula. Based on this, EA could be of potential value as a therapy for hyperalgesia in alcohol dependence.

Electroacupuncture decreases excessive alcohol consumption involving reduction of FosB/ΔFosB levels in reward-related brain regions.

New therapies are needed for alcohol abuse, a major public health problem in the U.S. and worldwide. There are only three FDA-approved drugs for treatment of alcohol abuse (naltrexone, acamprosate and disulfuram). On average these drugs yield only moderate success in reducing long-term alcohol consumption. Electroacupuncture has been shown to alleviate various drugs of abuse, including alcohol. Although previous studies have shown that electroacupuncture reduced alcohol consumption, the underlying mechanisms have not been fully elucidated. ΔFosB and FosB are members of the Fos family of transcription factors implicated in neural plasticity in drug addiction; a connection between electroacupuncture's treatment of alcohol abuse and the Fos family has not been established. In this study, we trained rats to drink large quantities of ethanol in a modified intermittent access two-bottle choice drinking procedure. When rats achieved a stable baseline of ethanol consumption, electroacupuncture (100 Hz or 2 Hz, 30 min each day) was administered at Zusanli (ST36) for 6 consecutive days. The level of FosB/ΔFosB in reward-related brain regions was assessed by immunohistochemistry. We found that the intake of and preference for ethanol in rats under 100 Hz, but not 2 Hz electroacupuncture regiment were sharply reduced. The reduction was maintained for at least 72 hours after the termination of electroacupuncture treatment. Conversely, 100 Hz electroacupuncture did not alter the intake of and preference for the natural rewarding agent sucrose. Additionally, FosB/ΔFosB levels in the prefrontal cortex, striatal region and the posterior region of ventral tegmental area were increased following excessive ethanol consumption, but were reduced after six-day 100 Hz electroacupuncture. Thus, this study demonstrates that six-day 100 Hz electroacupuncture treatment effectively reduces ethanol consumption and preference in rats that chronically drink excessive amount of ethanol. This effect of electroacupuncture may be mediated by down-regulation of FosB/ΔFosB in reward-related brain regions.

Low frequency electroacupuncture selectively decreases voluntarily ethanol intake in rats.

Although there is increasing clinical acceptance of acupuncture and electroacupuncture (EA) as a treatment of substance abuse-related disorders, our understanding of this treatment remains incomplete. Previous clinical and pre-clinical studies have shown that acupuncture and EA are effective in reducing ethanol consumption. Recent studies have shown that Sprague-Dawley (SD) rats under an intermittent-access two-bottle choice drinking procedure (IE procedure) voluntarily drank high amounts of ethanol. However, an effect of EA on ethanol consumption of the SD rats under this drinking procedure has not been demonstrated. In the present study, we demonstrated that SD rats escalated their ethanol intake and subsequently developed ethanol dependence under the IE procedure. A single low (2 Hz), but not high frequency (100 Hz) EA treatment applied at the bilateral acupoint Zusanli (ST36), but not at the tail reduced voluntary intake of, and preference for ethanol, but not sucrose. Furthermore, repeated EA treatments decreased the intake of and preference for ethanol, without resulting in a rebound increase in ethanol intake when the EA treatments were terminated. These observations indicate that EA may be a useful treatment for alcohol abuse.

A method to generate human mesenchymal stem cell-derived neurons which express and are excited by multiple neurotransmitters.

The present study describes a protocol to generate heterogenous populations of neurotransmitter-producing neurons from human mesenchymal stem cells (MSCs). MSCs are bone marrow (BM)-derived cells which undergo lineage- specific differentiation to generate bone, fat, cartilage and muscle, but are also capable of transdifferentiating into defined ectodermal and endodermal tissues. The purpose of this study is to evaluate the potential of MSCs as an alternative source of customized neurons for experimental neurobiology or other regenerative approaches. Our neuronal protocol utilizes freshly harvested human MSCs cultured on specific surfaces and exposed to an induction cocktail consisting of low serum concentration, retinoic acid (RA), growth factors and supplements. Here we report on the types of neurotransmitters produced by the neurons, and demonstrate that the cells are electrically responsive to exogenous neurotransmitter administration.