Identification of Potential Human Ryanodine Receptor 1 Agonists and Molecular Mechanisms of Natural Small-Molecule Phenols as Anxiolytics.

Natural small-molecule phenols (NSMPs) possess certain ubiquitous bioactivities including the anxiolytic effect. Ryanodine receptor 1 (RyR1) may be one of the potentially critical pharmacological targets for studying the anxiolytic activity of NSMPs. However, detailed molecular mechanisms of NSMPs have not been fully clarified.

Melatonin pretreatment attenuates acute methamphetamine-induced aggression in male ICR mice.

Aggression is one of the symptoms of methamphetamine (MA) use and withdrawal, which can exacerbate MA addiction and relapse. Many studies have demonstrated that poor sleep is significantly associated with aggression. Melatonin has been indicated to be effective in treating sleep disorders induced by MA, and it can also protect neuronal cells against MA-induced neurotoxicity.

Anxiolytic effect of a novel 9,10-dihydrophenanthrene, juncuenin H, is associated with metabolic changes in cortical serotonin/dopamine levels in mice.

Two novel phenanthrenoids, juncuenin H (1) and dijuncuenin B (2), together with eight known phenanthrenoids, effusol (3), dehydroeffusol (4), juncusol (5), dehydrojuncusol (6), juncuenin B (7), dehydrojuncuenin B (8), juncuenin A (9), and dehydrojuncuenin A (10), were isolated from the underground parts of Juncus setchuenensis. The structures of the compounds were determined by 1D and 2D NMR and mass spectroscopy. The anxiolytic activities of compounds 1, 6, 9, and 10 were evaluated.

Exposure to female estrous is beneficial for male mice against transient ischemic stroke.

Objective: Exposure to female estrous, a natural rewarding experience, alleviates anxiety and depression, and the contribution of this behavior to stroke outcome is unknown. The aim of this study was to evaluate whether exposure to female estrous is beneficial to recovery following transient ischemic stroke in male mice.

Methods: Cerebral ischemia was induced in male ICR mice with thread occlusion of the middle cerebral artery (MCAO) for 30 min followed by reperfusion.

Support for Natural Small-Molecule Phenols as Anxiolytics.

Natural small-molecule phenols (NSMPs) share some bioactivities. The anxiolytic activity of NSMPs is attracting attention in the scientific community. This paper provides data supporting the hypothesis that NSMPs are generally anxiolytic.

[Review on anxiolytic effect of natural small-molecule phenols].

Phenolic compounds have multiple bioactivities, such as anti-oxidant, anti-tumor, anti-bacterial, and anti-inflammatory activities. Recent literatures have demonstrated that flavonoids have a significant anti-anxiety effect on the central nervous system. In addition, studies showed that flavonoids acted as pro-drugs, which were transformed into smaller phenols through intestinal microflora.

[Chinese herbal medicine enhances sexual function and c-Fos/nNOS expression in the nucleus accumbens of orchidectomized rats].

Results: There was a decrease in accessory genital organ weight, plasma testosterone, and sexual behavior, as well as a low number of c-Fos-positive cells and a large nNOS-positive cell area in orchidectomized rats. Administration of the herbal medicine increased accessory genital organ weight, testosterone level, mating behavior, and c-Fos-positive cell number, while it decreased the nNOS-positive cell area in orchidectomized rats.

Conclusion: An increase of plasma testosterone after administration of "kidney-nourishing" herbal medicine might contribute to the elevated sexual function and activity in orchidectomized rats.

A conjugate vaccine attenuates morphine- and heroin-induced behavior in rats.

Background: Currently approved medications for opioid addiction have shown clinical efficacy, but undesired side effects, dependence induced by the medications themselves, and low treatment compliance necessitate the need for novel therapies.

Methods: A novel morphine-keyhole limpet hemocyanin conjugate vaccine was synthesized with 6-glutarylmorphine as the hapten and a lengthened linker of 6 carbon atoms. The titer and specificity of the triggered antibody were assessed by enzyme-linked immunosorbent assay.

Anxiolytic effects of orcinol glucoside and orcinol monohydrate in mice.

Context: Anxiety is a common psychological disorder, often occurring in combination with depression, but therapeutic drugs with high efficacy and safety are lacking. Orcinol glucoside (OG) was recently found to have an antidepressive action.

Objective: To study the therapeutic potential of OG and orcinol monohydrate (OM) as anxiolytic agents.

Two new anxiolytic phenanthrenes found in the medullae of Juncus effusus.

Six phenanthrenes, 2-methoxy-7-hydroxy-1-methyl-5-vinyl phenanthrene (1), juncusin (2), dehydroeffusol (3), juncusol (4), effusol (5), and dehydroeffusal (6), were isolated from the medullae of Juncus effusus L. Compounds 1 and 2 were identified as being new structures, and both of them showed anxiolytic activity at dosages of 10 and 2.5 mg/kg, respectively.

Effects of dehydroeffusol on spasmogen-induced contractile responses of rat intestinal smooth muscles.

Dehydroeffusol is a naturally occurring phenanthrene isolated from Juncus effusus. In the context of screening new drugs against gastrointestinal spasms, we investigated its effects on isolated rat jejunum in vitro. Dehydroeffusol (30-90 µM) slightly and transiently enhanced contractions in a concentration-dependent manner but significantly inhibited the contractions induced by KCl (100 mM), (±)-Bay-K8644 (5 µM), pilocarpine (90 µM), and histamine (100 µM).

Insular muscarinic signaling regulates anxiety-like behaviors in rats on the elevated plus-maze.

Anxiety is one of the most prevalent neuropsychiatric disorders, and little is known about its pathogenesis. In order to investigate the neural mechanisms of this mental disorder, we used rat behavior in the elevated plus-maze as an animal model of anxiety and the insular cortex (insula) as a brain target. The microinjection of non-selective and selective M1 and M4 muscarinic acetylcholine receptor (mAChR) agonists or antagonists was used to explore whether the insular muscarinic receptor and its subtypes regulate levels of anxiety.

Involvement of the insular nitric oxide signaling pathway in the expression of morphine-induced conditioned place preference in rats.

Nitric oxide (NO) has been recently reported to play an important role in the rewarding effects of addictive drugs. The regional NO signaling in the brain, however, is not completely clear. Here, we studied the effects of insular NO signaling on the expression of morphine-induced conditioned place preference (CPP).

Effects of ginsenosides on opioid-induced hyperalgesia in mice.

Opioid-induced hyperalgesia (OIH) is characterized by nociceptive sensitization caused by the cessation of chronic opioid use. OIH can limit the clinical use of opioid analgesics and complicate withdrawal from opioid addiction. In this study, we investigated the effects of Re, Rg1, and Rb1 ginsenosides, the bioactive components of ginseng, on OIH.

Involvement of insular muscarinic cholinergic receptors in morphine-induced conditioned place preference in rats.

Rationale: Drug addiction represents a pathological usurpation of neural processes involved in learning and memory. Retrieval of drug-related memories can result in drug craving and relapse. Recently, the insula was identified as part of the neuronal circuit responsible for the processing of drug memory; however, its precise role remains unclear.

Phenanthrenes from Juncus effusus with anxiolytic and sedative activities.

Eight phenanthrenes, 7-carboxy-2-hydroxy-1-methyl-5-vinyl-phenanthrene (1); 2,7-dihydroxy-1-methyl-5-aldehyde-9,10-dihydrophenanthrene (2); dehydroeffusol (3); dehydrojuncusol (4); 7-carboxy-2-hydroxy-1-methyl-5-vinyl-9,10-dihydrophenanthrene (5); 8-carboxy-2-hydroxy-1-methyl-5-vinyl-9,10-dihydrophenanthrene (6); effusol (7) and juncusol (8), were isolated from the aerial part of Juncus effusus. Compounds 1 and 2 were identified as new constituents. Compounds 7 and 8 showed anxiolytic and sedative activities.

A morphine/heroin vaccine with new hapten design attenuates behavioral effects in rats.

Heroin use has seriously threatened public heath in many countries, but the existing therapies continue to have many limitations. Recently, immunotherapy has shown efficacy in some clinical studies, including vaccines against nicotine and cocaine, but no opioid vaccines have been introduced in clinical studies. The development of a novel opioid antigen designed specifically for the prevention of heroin addiction is necessary.

Glycogen synthase kinase 3β in the nucleus accumbens core is critical for methamphetamine-induced behavioral sensitization.

As a ubiquitous serine/threonine protein kinase, glycogen synthase kinase 3β (GSK-3β) has been considered to be important in the synaptic plasticity that underlies dopamine-related behaviors and diseases. We recently found that GSK-3β activity in the nucleus accumbens (NAc) core is critically involved in cocaine-induced behavioral sensitization. The present study further explored the association between the changes in GSK-3β activity in the NAc and the chronic administration of methamphetamine.

Anxiolytic and sedative effects of dehydroeffusol from Juncus effusus in mice.

Dehydroeffusol, a phenanthrene isolated from Juncus effusus L., possesses characteristic anxiolytic and sedative properties, as determined by an array of behavioral tests in mice. In the elevated plus-maze test, dehydroeffusol significantly increased the number of entries into the open arms and the time the mice spent in these arms in a dose-dependent manner, with a minimum effective dose of 2.

Effects of polyinosinic-polycytidylic acid (Poly I:C) on naloxone-precipitated withdrawal in morphine-dependent mice.

Viral infections are frequently found in opioid addicts, subjecting them to immune challenge. However, the effects of immune challenge on opioid withdrawal are not fully understood. In the present study, mice were intraperitoneally injected with 2mg/kg polyinosinic-polycytidylic acid (Poly I:C, a viral mimetic) for 3 days to induce an immune challenge, followed by subcutaneous injection of morphine 3 times per day for 3 days to induce morphine dependence.

Synthetic double-stranded RNA polyinosinic-polycytidylic acid augments morphine-induced conditioned place preference in rats.

Three experiments were performed to study the effects of immune challenge on the rewarding properties of opiates. Intraperitoneal injection of polyinosinic-polycytidylic acid (Poly I:C, 1 mg/kg) was used to trigger an immune challenge. Conditioned place preference (CPP) in rats trained with alternating subcutaneous injections of morphine (5 mg/kg) and saline was used to assess the rewarding effect of morphine.

Role of BDNF and GDNF in drug reward and relapse: a review.

Brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) are neurotrophic factors that are critical for the growth, survival, and differentiation of developing neurons. These neurotrophic factors also play important roles in the survival and function of adult neurons, learning and memory, and synaptic plasticity. Since the mid-1990s, investigators have studied the role of BDNF and GDNF in the behavioral effects of abused drugs and in the neuroadaptations induced by repeated exposure to drugs in the mesocorticolimbic dopamine system.

Interferon-alpha reinstates morphine-conditioned place preference through opioid receptors in rats.

Cytokine interferon-alpha (IFN-alpha) is an immunomodulator and neuromodulator, which modulates central nervous system function partially by activating opioid receptors. However, the role that IFN-alpha plays in relapse to drug abuse is still largely unknown. Thus, we studied whether human recombinant INF-alpha (rIFN-alpha) would reinstate morphine-conditioned place preference (CPP) in rats.

Russujaponols G-L, illudoid sesquiterpenes, and their neurite outgrowth promoting activity from the fruit body of Russula japonica.

Six new illudoid sesquiterpene, russujaponols G-L (1-6) were isolated from the fruit bodies of Russula japonica. Their structures were established primarily by 2D NMR experiments. Furthermore, russujaponols I-K showed neurite outgrowth promoting activity in the primary cultured rat cortical neurons.

Blockade of cue- and drug-induced reinstatement of morphine-induced conditioned place preference with intermittent sucrose intake.

Sucrose intake has been suggested to alter the expression of morphine-induced conditioned place preference (CPP). To date, the potential effects of sucrose intake on the extinction and drug-induced reinstatement of CPP have not been determined. In the present study, sucrose solution (15%) was given prior to, during, and following the acquisition of morphine-induced CPP.