Oral buspirone causes a shift in the dose-response curve between
the elevated-plus maze and Vogel conflict tests in long-Evans rats:
Relation of brain levels of buspirone and 1-PP to anxiolytic action

Kim

Biological & Pharmaceutical Bulletin

et al. 2013

The aim of this study was to identify the effects of 85% methanolic extract of Morus alba leaves (EMA), which is a traditional herb, in mice. The effects of EMA on the anxiolytic-like behaviour were studied using the elevated plus maze (EPM) and hole-board test. To elucidate the mode of action of the anxiolytic-like effects of EMA, the mice were subjected to the co-administration of EMA (200 mg/kg, per os (p.o.)) and either antagonist. EMA (at 200 or 400 mg/kg) significantly increased the percentages of time-spent in the open arms and entries into the open arms of the EPM versus vehicle-treated control group (p<0.05). Moreover, in the hole-board test, EMA (200 and 400 mg/kg) significantly increased the number of head-dips versus vehicle-treated control group (p<0.05). However, there were no changes in the locomotor activity and myorelaxant effects in any group compared with the vehicle-treated control group. In addition, the anxiolytic-like effects of EMA were abolished by thioperamide (10 mg/kg, intraperitoneally (i.p.)), which is a histamine H 3 receptor antagonist. Moreover, results from reverse transcription polymerase chain reaction (RT-PCR) also revealed that the amygdalal histidine decarboxylase mRNA expression levels in EMA (200 mg/kg)-treated group were significantly higher than those in the vehicle-treated controls (p<0.05). These results suggest that EMA might prove to be an effective anxiolytic agent and that EMA acts via the histaminergic system in central nerve system. Key words anxiety; Morus alba; elevated plus-maze; histamine; thioperamide Mulberry tree (Morus alba L., Moraceae) is cultivated in China, Japan and Korea and is an important herbal material in traditional Chinese medicine. For example, the root bark of mulberry trees has long been used for anti-inflammatory, diuretic, antitussive, and antipyretic purposes in Oriental medicine.1) Moreover, fruit extract of M. alba was reported to modulate the monoamine oxidase activity during exercise and to promote the capability of physical activities.2) In addition to those herbal materials from M. alba, the leaves of this plant are one of the well-known traditional Chinese medicinal herbs and have been traditionally used to cure or prevent diabetic hyperglycemia.3,4) Based on those traditional usages, researchers reported that nitric oxide synthase positive neurons were decreased by the treatment with M. alba extracts in the various hypothalamic areas in the streptozotocin-induced diabetic rat brain. 4) Interestingly, those hypothalamic areas, including the paraventricular nucleus and ventromedial hypothalamic nucleus are rich in histaminergic neurons originating from the tuberomammillary body.5) These findings suggest a possibility that the leaves of M. alba may affect the activity of the histaminergic nervous system. Moreover, several clinically useful anxiolytics have been found to affect the turnover rate of brain histamine in the rat brain. For example, diazepam inhibits histamine turnover by acting on γ-aminobutyric acid (GABA) A receptors ...

Section: Discussionsupporting

confidence: 74%

Involvement of Histaminergic System in the Anxiolytic-Like Activities of <i>Morus alba</i> Leaves in Mice

Kim

Biological & Pharmaceutical Bulletin

et al. 2013

“…Second, unlike the majority of previous animal studies of nicotine’s putative anxiolytic effects (i.e., those employing the social interaction test or elevated plus maze) the current runway conflict test uses a methodology that is much more akin to the prototypical behavioral screens for anxiolytic agents, such as the Vogel Test or the Geller–Seifter Test. In such tests the animals’ responding for a positive stimulus (e.g., food) is altered by contingent presentation of a negative stimulus (shock) the effects of which can be reversed by pretreatment with anxiolytic agents (Houser 1978; McCloskey 1987; Vaidya et al 2005). To our knowledge, the current results are the first to demonstrate an anxiolytic effect of i.v.…”

Section: Discussionmentioning

confidence: 99%

“…mild shock) paired with reinforcer delivery. Drugs that effectively reduce this behavioral suppression are presumed to have anti-anxiety properties and in fact have proven to be effective anxiolytics in the human clinical population (e.g., Houser 1978; McCloskey 1987; Vaidya et al 2005). It was therefore of interest to assess the anxiolytic properties of nicotine in two procedurally different test paradigms: i.e., an operant runway model of approach-avoidance conflict, and an open field test that assesses the animal’s unconditioned fear of open spaces.…”

Section: Introductionmentioning

confidence: 99%

Anxiolytic effects of nicotine in a rodent test of approach–avoidance conflict

et al. 2009

Rationale Nicotine has been reported to produce both anxiolytic and/or anxiogenic effects in humans and animals. Objectives This study examined whether pretreatment with nicotine would alter anxiety in a unique runway model of approach-avoidance conflict. Materials and methods Food-restricted rats were trained to run a straight alley once a day to obtain food upon goal-box entry. Beginning on trial 11, food reward was followed by a series of five foot shocks (0.3-0.4 mA, 0.5 s) in the goal box. Non-shocked control rats continued to run for food only. The resulting association of the goal box with both a positive (food) and negative (foot shock) stimulus produced an approach-avoidance conflict (subjects exhibited "retreat behaviors" in which they would approach the goal box, stop, and then retreat back towards the start box). Once retreats were established, their sensitivity to nicotine pretreatment (0.0, 0.03, 0.045, 0.06, or 0.075 mg/kg, i.v.) was compared to saline. In subsequent tests, the effects of nicotine (0.06 or 0.03 mg/kg) were examined on spontaneous activity (locomotion) and center-square entries in an open field (anxiety). Results Doses of 0.06 and 0.075 mg/kg, but not lower doses of nicotine, reduced the number of runway retreats, and 0.06 mg/kg nicotine increased the number of open-field center entries relative to saline. No effects on locomotion were observed. Conclusions Nicotine reduced approach-avoidance conflict and increased the rats' willingness to enter the center of an open field, suggesting that the drug can produce anxiolytic properties and that such effects may serve as an important factor in the persistence of smoking behavior.

“…As mentioned, PmP is a presynaptic alpha 2 -adrenoceptor antagonist with less activity than buspirone on 5HT1A receptors [28,[33][34]. It has lower or greater anxiolytic effects than buspirone depending on the animal model considered [33][34][35][36] but, unlike gepirone, has no antidepressant-like effects in animals [37][38]. However, only human studies can definitely clarify the role that it may have in the anxiolytic/antidepressant effects of its different parent drugs.…”

Section: Cyp-mediated N-dealkylation Of Arylpipera-zine Derivativesmentioning

confidence: 99%

N-Dealkylation of Arylpiperazine Derivatives: Disposition and Metabolism of the 1-Aryl-Piperazines Formed

Caccia

2007

CDM

In recent years several arylpiperazine derivatives have reached the stage of clinical application, mainly for the treatment of depression, psychosis or anxiety. Examples are the pyrimidinylpiperazine buspirone, the chlorophenylpiperazine derivatives nefazodone and trazodone, the dichlorophenylpiperazine aripiprazole and the benzisothiazolyl derivatives perospirone and ziprasidone. Most of them undergo extensive pre-systemic and systemic metabolism including CYP3A4-dependent N-dealkylation to 1-aryl-piperazines. These metabolites are best known for the variety of serotonin receptor-related effects they cause in man and animals, although some have affinity for other neurotransmitter receptors; others, however, are still largely unexplored despite uncontrolled use as amphetamine-like designer drugs. Once formed they distribute extensively in tissues, including brain which is the target site of most arylpiperazine derivatives, and are then primarily biotransformed by CYP2D6-dependent oxidation to hydroxylates which are excreted as conjugates; only 1-(2-benzisothiazolyl)-piperazine is more susceptible to sulfur oxidation than to aromatic hydroxylation. In studies analysing animal brain and human blood, 1-aryl-piperazine concentrations were either higher or lower than the parent compound(s), although information is available only for some derivatives. At steady state, the metabolite-to-parent drug ratios varied widely among individuals taking the same dosage of the same arylpiperazine derivative. This is consistent with the known individual variability in the expression and activity of CYP3A4 and CYP2D6. This review also surveys current published information on physiological and pathological factors affecting the 1-aryl-piperazine-to-parent drug ratios and examines the potential role of 1-aryl-piperazine formation in the pharmacological actions of the arylpiperazine derivatives that are already or will shortly be available in major markets.