[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. The small phenolic metabolites were crucial for the anxiolytic effects of these flavonoids, indicating that natural small-molecule phenols(NSMP) generally have anxiolytic activities. In this paper, the supporting evidences (before June 2016) from SciFinder database have been summarized. Furthermore, NSMPs were classified according to chemical structures; their anxiolytic effects, mechanisms, and the structure-activity relationships were also discussed.

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. The effects of the vaccine on the morphine-induced elevation of dopamine levels in the nucleus accumbens were determined by high-performance liquid chromatography. The effects of the vaccine on morphine-induced locomotor sensitization and heroin-primed reinstatement of heroin self-administration were also assessed. RESULTS: After subcutaneous administration in rats, the vaccine triggered a high antibody titer, with comparable specificity for morphine, 6-acetylmorphine, and heroin, but no interaction with dissimilar therapeutic opioid compounds, including buprenorphine, naloxone, and nalorphine, was observed. The vaccine significantly prevented the elevation of dopamine levels in the nucleus accumbens induced by a single morphine challenge. Moreover, the vaccine prevented the expression of morphine-induced locomotor sensitization and heroin-primed reinstatement of heroin seeking, suggesting its potential for preventing relapse. CONCLUSION: These results demonstrate that active immunization with the present vaccine induces a robust morphine/heroin-specific antibody response in rats and attenuates the behavioral effects of morphine and heroin.

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.

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. A morphine-keyhole limpet hemocyanin conjugate was prepared and administered subcutaneously in rats. Antibody titers in plasma were measured using an enzyme-linked immunosorbent assay (ELISA). Competitive ELISA was used to assess the selectivity of the antibodies. Dopamine concentrations in the nucleus accumbens in rats after vaccine administration were determined by high-performance liquid chromatography with electrochemical detection. The effects of the vaccine on the heroin-primed restatement of self-administration and locomotor sensitization were evaluated. A novel hapten, 6-glutarylmorphine, was produced, and the vaccine generated a high antibody titer response. This vaccine displayed specificity for both morphine and heroin, but the anti-morphine antibodies could not recognize dissimilar therapeutic opioid compounds, such as buprenorphine, methadone, naloxone, naltrexone, codeine, and nalorphine. The morphine antibody significantly decreased morphine-induced locomotor activity in rats after immunization. Importantly, rats immunized with this vaccine did not exhibit heroin-primed reinstatement of heroin seeking when antibody levels were sufficiently high. The vaccine reduced dopamine levels in the nucleus accumbens after morphine administration, which is consistent with its behavioral effects. These results suggest that immunization with a novel vaccine is an effective means of inducing a morphine-specific antibody response that is able to attenuate the behavioral and psychoactive effects of heroin.

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

As a ubiquitous serine/threonine protein kinase, glycogen synthase kinase 3ß (GSK-3ß) has been considered to be important in the synaptic plasticity that underlies dopamine-related behaviors and diseases. We recently found that GSK-3ß 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-3ß activity in the NAc and the chronic administration of methamphetamine. We also examined whether blocking GSK-3ß activity in the NAc could alter the initiation and expression of methamphetamine (1 mg/kg, i.p.)-induced locomotor sensitization in rats using systemic administration of lithium chloride (LiCl, 100 mg/kg, i.p) and brain region-specific administration of the GSK-3ß inhibitor SB216763 (1 ng/side). We found that GSK-3ß activity increased in the NAc core, but not NAc shell, after chronic methamphetamine administration. The initiation and expression of methamphetamine-induced locomotor sensitization was attenuated by systemic administration of LiCl and direct infusion of SB216763 into the NAc core, but not NAc shell. These results indicate that GSK-3ß activity in the NAc core mediates the initiation and expression of methamphetamine-induced locomotor sensitization, suggesting that GSK-3ß may be a potential target for the treatment of psychostimulant addiction.

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 2.5 mg/kg. Dehydroeffusol also significantly increased the head-dips of mice in the hole-board test in a dose-dependent manner, with a minimum effective dose of 5 mg/kg. Dehydroeffusol reduced mouse locomotion in the open-field test with a minimum effective dose of 5 mg/kg. In the rota-rod test, 1-5 mg/kg dehydroeffusol did not decrease the fall-down time of mice. The above results confirm that dehydroeffusol possesses anxiolytic and sedative properties and does not affect the general movement coordination of mice. This suggests that dehydroeffusol is a novel anxiolytic chemical derived from herbal medicines.

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. In Experiment 1, rats were trained for morphine-CPP with 8-day alternate subcutaneous (s.c.) injections of morphine and saline, and the effect of human rIFN-alpha (20 000 IU/5 microl, intracerebroventricularly) on CPP reinstatement was examined after extinction. In Experiment 2, rats underwent morphine (5 mg/kg, s.c.) unconditioned training with 8 daily alternate injections of morphine (5 mg/kg, s.c.) and saline. Then, the effect of human rIFN-alpha (20 000 IU/5 microl, intracerebroventricularly) on reinstatement of CPP was examined after extinction. In Experiment 3, the effect of opioid receptor antagonist naloxone (1 mg/kg, intraperitoneally) on human rIFN-alpha-induced reinstatement of morphine-CPP was investigated. We found that human rIFN-alpha reinstated morphine-CPP in rats trained under morphine conditioning after extinction, but did not affect CPP in rats that underwent unconditioned training. Naloxone significantly inhibited human rIFN-alpha-induced reinstatement of morphine-CPP. These results indicate that IFN-alpha is a stimulus for reinstatement of morphine-CPP by activation of opioid receptors, which extends our understanding on the high comorbidity of heroin relapse and viral infection.

Effects of early postnatal sibling deprivation on anxiety and vulnerability to cocaine in offspring rats.

RATIONALE: Early-life experience has long-term consequences on affective behavior and drug abuse in adults. While many manipulations used to study these consequences alter mother-infant interactions, the effects of sibling interactions are less well characterized. OBJECTIVES: To examine the long-term effects of early postnatal sibling deprivation (EPSD) on anxiety-like behavior, sucrose preference and behavioral responses to cocaine in adult rats. MATERIALS AND METHODS: After EPSD manipulation, in which litters were culled to one pup on postnatal day 1 (PN1) or 7 (PN7), the dams' maternal behavior was observed. After the pups reached adulthood, we tested their behavioral responses in the elevated plus maze and sucrose consumption, and to cocaine conditioned place preference and cocaine sensitization. RESULTS: The pups with EPSD on PN1 received more maternal licking/grooming during the first postnatal week. EPSD on PN1 but not PN7 enhanced locomotor activity in the open field test and exploration of open arms in the elevated plus maze in both female and male offspring. While EPSD had no effect on sucrose intake in adult rats, it decreased vulnerability to cocaine sensitization and cocaine conditioned place preference in male but not female rats. CONCLUSION: Our findings that early postnatal sibling deprivation influences maternal licking/grooming behavior, as well as anxiety-like behavior and vulnerability to drugs in pups that have grown to adulthood, suggests that both sibling interaction and maternal behavior, play critical roles in individual development.

Sex- and age-dependent effects of early postnatal sibling deprivation on spatial learning and memory in adult rats.

In this study, we investigated the effects of early postnatal sibling deprivation (EPSD) on spatial learning and memory in adult rats. Litters were culled to one pup with its mother on postnatal day (PN) 1 or 7 and their spatial learning and memory ability were examined with Morris water maze in adult. EPSD on PN1 improved, but on PN7 impaired performance of the spatial learning task in adult female rats. However, EPSD did not have any effect on the spatial learning ability in adult male rats.

Role of stress in acquisition of alcohol-conditioned place preference in adolescent and adult mice.

BACKGROUND: Both clinical evidence and findings from animal models demonstrate that there are differences between adolescents and adults in alcohol dependence. As stress plays a critical role in processes of alcohol addiction, we tested whether stress is involved in alcohol vulnerability differently during adolescence and adulthood in mice. METHODS: To determine whether age differences exist in the acquisition of alcohol-conditioned place preference (CPP) in mice, adolescent and adult mice were trained for CPP with different doses of alcohol (0, 0.5, 1, and 2 g/kg, i.p.). To explore the effects of stress (footshock) on acquisition of alcohol CPP in mice of different ages, adolescent and adult mice underwent acute (1 day) or chronic (1 week) stress before CPP training. Acquisition of CPP was examined after the CPP training. RESULTS: Under nonstress conditions, adult mice acquired alcohol CPP when trained with 2 g/kg alcohol, while adolescent mice did not acquire alcohol CPP. After chronic but not acute stress exposure, adolescent mice acquired significant CPP trained with 2 g/kg alcohol that did not produce CPP under nonstress conditions. However, stress did not have significant effect on acquisition of CPP in adult mice trained CPP with 1 g/kg alcohol. CONCLUSIONS: These results indicate that there is an age difference in acquiring alcohol CPP and adolescent mice are more sensitive than adults to stress.

Conditioned drug reward enhances subsequent spatial learning and memory in rats.

RATIONALE: Chronic exposure to drugs of abuse alters neural processes that normally promote learning and memory. A context that is repeatedly paired with reinforcing drugs will acquire secondary reinforcing properties (conditioned reward). However, the effects of conditioned reward on spatial learning are unknown. OBJECTIVE: Using the conditioned place preference procedure and Morris water maze task, we examined the role of conditioned reward or aversion in spatial learning. MATERIALS AND METHODS: Groups of rats acquired morphine (10 mg/kg), cocaine (10 mg/kg), or oral sucrose (15%) conditioned place preference (CPP). Another group of morphine-dependent rats acquired conditioned place aversion (CPA) to a context paired with precipitated opiate withdrawal induced by naloxone injections (1 mg/kg). To examine the role of conditioned reward or aversion in spatial learning, rats were then exposed to the previously morphine-, cocaine-, sucrose- or naloxone-paired context for 10 min before training of spatial learning in the Morris water maze. RESULTS: Exposure to the morphine- or cocaine-paired but not the sucrose- or the naloxone-paired context decreased the latency to find the platform in the Morris water maze test. CONCLUSIONS: Our results provide the first evidence that conditioned drug reward promotes spatial learning. We speculate that this enhancement of spatial learning by the drug-paired context may promote contextual-cue-induced relapse to drug taking by facilitating exploratory drug-seeking behaviors.

Effects of stress during reactivation on rewarding memory.

When a stabilized memory is recalled or reactivated, it becomes labile and sensitive to disruptors such as protein-synthesis inhibitors. Previous evidence demonstrates that stress modulates different aspects of memory. The role of stress during reactivation on rewarding or aversive memory is not known, however. This study examines the effects of stress on rewarding or aversive memory using the conditioned place preference or conditioned place aversion paradigm. Rats were trained to acquire a sucrose and cocaine-conditioned place preference or naloxone-conditioned place aversion. Subsequently, rats were reexposed to the previous sucrose-paired, cocaine-paired and naloxone-paired chamber for 10 min before experiencing the stressful Morris water maze. All rats were tested for conditioned place preference or conditioned place aversion after the stressful water-maze task. After 5-day repeated exposure to the previously reward-paired chamber and experiencing stress, cocaine-conditioned place preference disappeared and sucrose-conditioned place preference was reversed; however, after 5-day repeated exposure to the previously naloxone-paired chamber and experiencing stress, naloxone-conditioned place aversion was not significantly changed. Our results provide the first evidence that the rewarding memory may have been reduced by exposing rats to stress during reexposure to the reward-paired context, which suggests that manipulations of drug memory during reactivation can provide a potential treatment for drug addiction.

Clonidine attenuates morphine withdrawal and subsequent drug sensitization in rhesus monkeys.

AIM: Clonidine is an alpha2 adrenoceptor agonist that is frequently used to reduce withdrawal symptoms during opioid detoxification in humans. The long-term effects of clonidine on withdrawal symptoms and its effects on subsequent drug exposure have not been thoroughly documented. The aim of the study was to determine if clonidine administered during morphine withdrawal in rhesus monkeys produces long-lasting effects on withdrawal symptoms and alters the effects of subsequently taken drugs of abuse. METHODS: Adult male rhesus monkeys were treated with increasing doses of morphine for 90 d to induce opiate (narcotic) dependence. The immediate and long-lasting effects of 1 week's administration of clonidine were measured via the recording of morphine withdrawal signs and the subsequent effects of challenge injections of morphine or cocaine. RESULTS: Monkeys chronically treated with morphine displayed withdrawal signs that lasted 2 weeks after cessation of morphine administration and displayed sensitized responses to subsequent morphine and cocaine injections. Clonidine significantly reduced certain morphine withdrawal signs and overall withdrawal score, but these effects did not persist upon cessation of clonidine treatment. Sensitization to the effects of morphine and cocaine were significantly reduced in monkeys previously treated with clonidine. CONCLUSION: Our results suggest that in addition to its short-term alleviating effect on morphine withdrawal signs, clonidine may reduce subsequent effects of drugs of abuse after prolonged abstinence.