Withdrawal Anxiety Research Articles

Anxiolytic effects of Dichrocephala integrifolia leaf aqueous extract on alcohol withdrawal-induced anxiety in mice: Involvement of the GABAergic pathway

Ethanol withdrawal syndrome is a life-threatening state that results from a sudden termination of chronic alcohol intake. One of the manifestations of ethanol withdrawal syndrome is anxiety. Dichrocephala integrifolia is a plant used in Africa in the treatment of alcohol use disorders. This study aimed to evaluate the effects of Dichrocephala integrifolia on ethanol withdrawal anxiety in mice. Young adult Swiss mice were arranged into seven groups of six mice each. Groups II to VII received ethanol in increasing concentration for 20 days. Following ethanol withdrawal, mice were administered distilled water (Group II), Dichrocephala integrifolia (25,50,100 and 200 mg/kg) (Groups III-VI) or diazepam (Group VII). Behavioural assessments were performed using the elevated plus maze, the open field and the hole board tests. Gamma-aminobutyric acid (GABA) concentration, GABA-Transaminase and glutamic acid decarboxylase activities were assessed in the brain. In the elevated plus maze, Dichrocephala integrifolia (100 mg/kg) significantly (p < 0.01) increased the percentage of open arms entries from 20.5 ± 1.56% in the negative control, to 65.3 ± 2.46%. In the hole board, the number of head dipping raised from 27.17 ± 0.60 in the negative control to 61.33 ± 2.82 (p < 0 0.01) at the dose 200 mg/kg of Dichrocephala integrifolia. Likewise, diazepam, Dichrocephala integrifolia (200 mg/kg) significantly (p < 0.01) raised GABA concentration from 267.70 ± 5.18 µg/g of tissue in the negative control to 395 ± 5.55 µg/g of tissue. The plant extract (200 mg/kg) reduced the activity of GABA-Transaminase from 101 ± 2.60 pg/min/mg of tissue in the negative control to 42.5 ± 2.35 pg/min/mg of tissue. From these results, we can conclude that, by enhancing the GABAergic neurotransmission, Dichrocephala integrifolia has anxiolytic activities against ethanol withdrawal anxiety and can therefore be a good drug candidate for the treatment of alcohol addiction.

Distinct eLPBChAT projections for methamphetamine withdrawal anxiety and primed reinstatement of conditioned place preference.

Methamphetamine (METH) withdrawal anxiety symptom and relapse have been significant challenges for clinical practice, however, the underlying neuronal basis remains unclear. Our recent research has identified a specific subpopulation of choline acetyltransferase (ChAT+) neurons localized in the external lateral portion of parabrachial nucleus (eLPBChAT), which modulates METH primed-reinstatement of conditioned place preference (CPP). Here, the anatomical structures and functional roles of eLPBChAT projections in METH withdrawal anxiety and primed reinstatement were further explored. Methods: In the present study, a multifaceted approach was employed to dissect the LPBChAT+ projections in male mice, including anterograde and retrograde tracing, acetylcholine (Ach) indicator combined with fiber photometry recording, photogenetic and chemogenetic regulation, as well as electrophysiological recording. METH withdrawal anxiety-like behaviors and METH-primed reinstatement of conditioned place preference (CPP) were assessed in male mice. Results: We identified that eLPBChAT send projections to PKCδ-positive (PKCδ+) neurons in lateral portion of central nucleus of amygdala (lCeAPKCδ) and oval portion of bed nucleus of the stria terminalis (ovBNSTPKCδ), forming eLPBChAT-lCeAPKCδ and eLPBChAT-ovBNSTPKCδ pathways. At least in part, the eLPBChAT neurons positively innervate lCeAPKCδ neurons and ovBNSTPKCδ neurons through regulating synaptic elements of presynaptic Ach release and postsynaptic nicotinic acetylcholine receptors (nAChRs). METH withdrawal anxiety and METH-primed reinstatement of CPP respectively recruit eLPBChAT-lCeAPKCδ pathway and eLPBChAT-ovBNSTPKCδ pathway in male mice. Conclusion: Our findings put new insights into the complex neural networks, especially focusing on the eLPBChAT projections. The eLPBChAT is a critical node in the neural networks governing METH withdrawal anxiety and primed-reinstatement of CPP through its projections to the lCeAPKCδ and ovBNSTPKCδ, respectively.

PHARMACOGNOSTICAL AND PHARMACOLOGICAL EVALUATION OF OXALIS CARNICULATA LINN. FOR ANTI-DIPSOTROPIC AND ANTI-PYRETIC ACTIVITY

Ayurveda is an ancient system of health care that is native to the Indian subcontinent. The present study was based on the pharmacognostic and pharmacological evaluation of Oxalis carniculata linn. for anti-dipsotropic and anti-pyretic activity. Oxalis corniculata Linn. (Family: Oxalidaceae) is a well-known plant in India and is one of the most versatile medicinal plants having a wide spectrum of biological activity. All the chemicals with specifications were issued from the departmental store. The whole plant of Oxalis carniculata was collected from Moradabad area in the month of June &amp; July. The whole plant was collected and washed with water. The whole plant was dried under the shade. The dried material was stored in air tight container. The whole plant was authenticated by Dr. G.P. Sinha Scientist-E &amp; Head Botanical Survey of India Central Regional Centre 10, Chatham Line, Allahabad-211002, UP, India. Macroscopy, microscopy and physicochemical evaluation of Oxalis carniculata. The extraction was performed using Soxhlet apparatus then pharmacognostic and analytical evaluation of the herb were done. The extract was also used for acute toxicity to determine the dose. The anti-dipsotropic potential was evaluated through withdrawal anxiety and alcohol consumption model, however antipyretic activity was evaluated through brewer’s yeast inducted pyrexia model. In aqueous extract treated animals, the rectal temperature was estimated as 38.63±0.14#ºC and 38.18±0.13#ºC at the dose of 200mg/kg and 400mg/kg, respectively that showed for its anti-pyretic action. In our study on day 11, the ethanol-treated animals spent significantly more time in the ethanol-paired chamber as compared to the saline-paired chamber (P&lt;0.001). EE (200 and 400 mg/kg) administration led to a dose-dependent reversal of withdrawal anxiety as evidenced by significant increase in time spent in the open arm (P &lt; 0.01). In concluded that in anti-dipsotropic activity, EE200 and EE400 showed significant increase in the time spent in open arm of plus maze indicating the reduction in anxiety after alcohol withdrawal and reduction in the total ethanol consumption. This indicates that Oxalis corniculata Linn. have significant anti-dipsotropic and anti-pyretic activity.

Gegen-Qinlian decoction-A traditional Chinese medicine formula-Alleviates methamphetamine withdrawal induced anxiety by targeting GABAergic interneuron-pyramidal neuron pathway in mPFC.

Methamphetamine (Meth) withdrawal elicits anxiety, which is a public health concern with limited therapeutic options. Previous studies implied a strong correlation between mPFC and Meth withdrawal. Here, we examined the role of Gegen-Qinlian decoction (GQD) in Meth withdrawal anxiety and explored potential therapeutic targets in mPFC. We found that intra-gastric administration of GQD during the withdrawal period efficiently alleviated anxiety-like behaviours in Meth-withdrawn mice. Further, GQD could restore Meth withdrawal-triggered pathway of GABAergic interneurons (GABA IN)-pyramidal neurons (PN) in the mPFC of Meth-withdrawn mice, especially the prelimbic cortex (PrL) sub-region and PV-positive GABA IN. While, GQD had no obvious effects on the glial cells in the mPFC of Meth-withdrawn mice. By transcriptomic analysis and validation of several gene candidates, we found that genes in the MAPK signalling pathway, especially those related to heat shock proteins, including Hspa1a, Hspa1b and Hspb1, might be GQD-targeting genes in mPFC to treat Meth withdrawal anxiety, as indicated that these genes were up-regulated by Meth withdrawal but rescued by GQD in mPFC. Collectively, our findings identified for the first time that GQD could efficiently alleviate Meth withdrawal anxiety, partially through regulating the local GABA IN-PN pathway and transcriptomic profile of mPFC. The present study confirms that TCM, such as GQD, will be a desirable therapeutic approach in the treatment of drug addiction and related emotional deficits.

Gegen-Qinlian decoction alleviates anxiety-like behaviors in methamphetamine-withdrawn mice by regulating Akkermansia and metabolism in the colon

BackgroundAnxiety is a prominent withdrawal symptom of methamphetamine (Meth) addiction. Recently, the gut microbiota has been regarded as a promising target for modulating anxiety. Gegen-Qinlian decoction (GQD) is a classical Traditional Chinese Medicine applied in interventions of various gut disorders by balancing the gut microbiome. We aim to investigate whether GQD could alleviate Meth withdrawal anxiety through balancing gut microbiota and gut microenvironment.MethodsMeth withdrawal anxiety models were established in mice. GQD were intragastric administrated into Meth-withdrawn mice and controls. Gut permeability and inflammatory status were examined in mice. Germ-free (GF) and antibiotics-treated (Abx) mice were used to evaluate the role of gut bacteria in withdrawal anxiety. Gut microbiota was profiled with 16s rRNA sequencing in feces. Metabolomics in colon tissue and in Akkermansia culture medium were performed.ResultsMeth withdrawal enhanced anxiety-like behaviors in wild-type mice, and altered gut permeability, and inflammatory status, while GQD treatment during the withdrawal period efficiently alleviated anxiety-like behaviors and improved gut microenvironment. Next, we found Germ-free (GF) and antibiotics-treated (Abx) mice did not develop anxiety-like behaviors by Meth withdrawal, indicating the essential role of gut bacteria in Meth withdrawal induced anxiety. Then, it was observed that gut microbiota was greatly affected in Meth-withdrawn mice, especially the reduction in Akkermansia. GQD can rescue the gut microbiota and reverse Akkermansia abundance in Meth-withdrawn mice. Meanwhile, GQD can also restore the Meth-impaired Akkermansia growth in vitro. Further, GQD restored several common metabolite levels both in colon in vivo and in Akkermansia in vitro.ConclusionsWe revealed a novel effect of GQD on Meth withdrawal anxiety and identified its pharmacological target axis as “Akkermansia-Akkermansia metabolites-gut metabolites-gut microenvironment”. Our findings indicated that targeting gut bacteria with TCM, such as GQD, might be a promising therapeutic strategy for addiction and related withdrawal symptoms.

The effectiveness of child-centered play therapy on behavior problems of children

This study aims to examine Child-Centered Play Therapy's effect on reducing behavioral problems in five- and six-year-old children living in Istanbul. The study was conducted with 20 children from socio-economically disadvantaged families. Families applied for support to a play therapy room established in a primary school. A pre-test and post-test control group design is used. Child-Centered Play Therapy sessions were implemented in the experimental group for eight weeks as individual sessions. Data due to the children's behavior problems were collected from parents via the “Social Competence and Behavior Evaluation-30 Scale” and the family pre-interview form. Mann Whitney-U Test and Wilcoxon Test analyzed data. Results of the experimental group (ingroup analyses) show a significant difference between pre-test and post-test scores of social competence, anger aggression, and anxiety withdrawal subscales, as hypothesized. However, analyses of between groups’ post-test comparisons show significant differences only in the social competence subscale. Between groups, post-test scores, comparisons of anger-aggression, and anxiety withdrawal subscales showed no significant differences. The results are discussed; additionally, observations of the researcher as a play therapist are presented.

Two Models of the Development of Social Withdrawal and Social Anxiety in Childhood and Adolescence: Progress and Blind Spots.

This commentary features a review of two recently reformulated models of the development of child and adolescent: (1) social withdrawal by Rubin and Chronis-Tuscano 2021, and (2) social anxiety by Spence and Rapee 2016. The articles that present these reformulated models now cover advances made during the prior 12 to 18 years of research, including increased knowledge of genetic vulnerability to anxiety and longitudinal patterns of development, and acknowledgement of multiple pathways towards and away from the development of social withdrawal or social anxiety (i.e., equifinality, multifinality). However, these reformulated models also contain several blind spots. The model of social withdrawal development would be improved by explicitly referring to peer treatment (not only attitudinal peer rejection), especially peer exclusion; and incorporating the potential development of clinically significant anxiety in childhood (not only adolescence) and delays in developmental milestones in adulthood. The model of social anxiety development would be improved by featuring social withdrawal as a proximal affective-behavioral profile (rather than a temperament) and drawing upon the literature on social withdrawal and its links to peer relations. Overall, there is a continuing lack of integration between developmental and clinical research and models of the development of social withdrawal and social anxiety.

An extended amygdala-midbrain circuit controlling cocaine withdrawal-induced anxiety and reinstatement.

SUMMARYAlthough midbrain dopamine (DA) circuits are central to motivated behaviors, our knowledge of how experience modifies these circuits to facilitate subsequent behavioral adaptations is limited. Here we demonstrate the selective role of a ventral tegmental area DA projection to the amygdala (VTADA→amygdala) for cocaine-induced anxiety but not cocaine reward or sensitization. Our rabies virus-mediated circuit mapping approach reveals a persistent elevation in spontaneous and task-related activity of inhibitory GABAergic cells from the bed nucleus of the stria terminalis (BNST) and downstream VTADA→amygdala cells that can be detected even after a single cocaine exposure. Activity in BNSTGABA→midbrain cells is related to cocaine-induced anxiety but not reward or sensitization, and silencing this projection prevents development of anxiety during protracted withdrawal after cocaine administration. Finally, we observe that VTADA→amygdala cells are strongly activated after a challenge exposure to cocaine and that activity in these cells is necessary and sufficient for reinstatement of cocaine place preference.

The Effect of Krocina™ on Decreasing Substance User Withdrawal Syndrome, Craving, Depression and Stress: A Double-Blind Randomized Parallel Clinical Trial

Introduction Due to the association between substance use abstinence with some psychological syndromes, the use of herbal medicines such as Crocus sativus L. have been considered as a proper approach to controlling withdrawal syndrome. The present study aimed to identify the effect of Krocina™ in reducing withdrawal symptoms, craving, depression, stress, anxiety and durability of treatment in the detoxification period and abstinence phase. Methods In a double-blind randomized parallel clinical trial, 72 opioid users passing the detoxification period who were referred to the Soroush Center during 2020, randomly categorized into the two groups. Motivational interviewing sessions and 15 mg of Krocina™ twice a day were provided for six weeks for the cases. The placebo group received pills with the same coating and motivational interviewing. Withdrawal symptoms, craving, depression, stress and anxiety were assessed at the start of the study and then weekly using the Clinical Opiate Withdrawal Scale, Obsessive-Compulsive Drug Use Scale, and the Depression Anxiety Stress Scales-21, respectively. SPSS-v16 was used for statistical analyses. Results Drug withdrawal symptoms and craving did not indicate a significant difference by Krocina™ intervention during the time (p > 0.05). Furthermore, depression, stress and anxiety were statistically similar between Krocina™ and placebo groups (p > 0.05). Moreover, we found similar findings between the two groups when analyzing only patients with negative urinary test (F = 0.03;p = 0.86). Conclusion Our finding rejected the effectiveness of 30 mg/day of Krocina™ for six weeks as an effective substance for decreasing withdrawal symptoms, craving, depression, anxiety and stress at the detoxification period and abstinence phase.

Possible influence of neurosteroids in the anxiolytic effects of alpha-casozepine

Alpha-casozepine (α CZP), a tryptic hydrolysate of milk casein is a decapeptide shown to promote sleep and produce anxiolytic or anticonvulsant activity. Intriguingly, studies indicate structural similarities to benzodiazepine (BZD)-like molecules (e.g., diazepam), resulting in positive modulation of γ-aminobutyric acid A type (GABAA) receptors. However, some unexplained anomalous behaviour of α-CZP includes 1) 1000 times less affinity for BZD site on GABAA receptor in vitro conditions, whereas in vivo it showed 10-fold increased affinity when compared to diazepam; 2) anxiolytic effects were observed only in stressed conditions and 3) unlike diazepam, it failed to exhibit dependence or habituation. Interestingly, neurosteroids like allopregnanolone or its analogues that are synthesized de novo have both genomic and non-genomic actions. The rapid nongenomic neuronal inhibition of these compounds is mediated by GABAA receptors through autocrine and paracrine actions. Studies have shown that changes in the levels of neurosteroids during acute (rise) and chronic stress (decreased), consequently, altering the senetivity of GABAA receptor subunits. Neurosteroids even at low concentration (nanomolar range) potentiate the response of GABA indirectly, while at higher concentrations they directly activate the receptor-channel complex. Interestingly, coadministration of neurosteroids and BZPs has shown not only to prevent the development of tolerance of BZP and augmented recovery from BZP withdrawal anxiety and hyperactivity in mice. The combination also produced synergetic anxiolytic effects. Taken together, the evidence suggests possible implications of neurosteroids in the actions of CZP via BZD receptors. The present hypothesis brings out the possible role of neurosteroids and the various factors that might participate in CZP-induce anxiolytic effects.

A standardized polyherbal preparation POL-6 diminishes alcohol withdrawal anxiety by regulating Gabra1, Gabra2, Gabra3, Gabra4, Gabra5 gene expression of GABAA receptor signaling pathway in rats

BackgroundAlcohol abuse is a major problem worldwide and it affects people’s health and economy. There is a relapse in alcohol intake due to alcohol withdrawal. Alcohol withdrawal anxiety-like behavior is a symptom that appears 6–24 h after the last alcohol ingestion.MethodsThe present study was designed to explore the protective effect of a standardized polyherbal preparation POL-6 in ethanol withdrawal anxiety in Wistar rats. POL-6 was prepared by mixing the dried extracts of six plants Bacopa monnieri, Hypericum perforatum, Centella asiatica, Withania somnifera, Camellia sinesis, and Ocimum sanctum in the proportion 2:1:2:2:1:2 respectively. POL-6 was subjected to phytochemical profiling through LC-MS, HPLC, and HPTLC. The effect of POL-6 on alcohol withdrawal anxiety was tested using a two-bottle choice drinking paradigm model giving animals’ free choice between alcohol and water for 15 days. Alcohol was withdrawn on the 16th day and POL-6 (20, 50, and 100 mg/kg, oral), diazepam (2 mg/kg) treatment was given on the withdrawal days. Behavioral parameters were tested using EPM and LDT. On the 18th day blood was collected from the retro-orbital sinus of the rats and alcohol markers ALT, AST, ALP, and GGT were studied. At end of the study, animals were sacrificed and the brain was isolated for exploring the influences of POL-6 on the mRNA expression of GABAA receptor subunits in the amygdala and hippocampus.ResultsPhytochemical profiling showed that POL-6 contains major phytoconstituents like withaferin A, quercetin, catechin, rutin, caeffic acid, and β-sitosterol. In-vivo studies showed that POL-6 possesses an antianxiety effect in alcohol withdrawal. Gene expression studies on the isolated brain tissues showed that POL-6 normalizes the GABAergic transmission in the amygdala and hippocampus of the rats.ConclusionThe study concludes that POL-6 may have therapeutic potential for treating ethanol-type dependence.

The Chinese version of obsessive compulsive drug use scale: validation in outpatient methadone maintenance treatment program

BackgroundThe Obsessive Compulsive Drug Use Scale (OCDUS) measures the overall craving level within a period from a multidimensional perspective. However, no studies have addressed the validity of the new OCDUS factor structure, presented in 2016, in China. Additionally, there is lack of evidence on the interaction among risk factors for relapse. We aimed to assess the psychometric properties of the scores of the Chinese version of the OCDUS in patients with heroin dependence receiving methadone maintenance treatment (MMT). Further, we aimed to assess the correlations of the OCDUS scores with withdrawal symptoms, depression, anxiety, and nicotine dependence.MethodsWe enrolled 113 adults (age 32–64 years) and administered them with the OCDUS, Subjective Opioid Withdrawal Scale (SOWS), Beck Depression Inventory-II (BDI-II), State-Trait Anxiety Inventory (STAI), and Fagerstrom Test for Nicotine Dependence (FTND).ResultsExploratory factor analysis identified a 3-dimensional component that included “Frequency of craving,” “Inference of heroin,” and “Control of heroin.” These factors showed acceptable internal consistency, adequate item-total correlations, and significant item-subscale correlations. There was no correlation between the OCUDS scores and age, education, duration of receiving MMT, and MMT dosages. However, there was a significant correlation between the OCDUS total scores and the SOWS, STAI, BDI-II, and FTND scores. The scores of all the subscales were associated with the SOWS scores; further, the scores of the first two subscales were associated with BDI-II scores while only the scores of the first subscale were associated with the FTND scores.ConclusionsOur findings support the reliability and structure validity of the OCDUS scores. Heroin craving, withdrawal symptoms, negative emotions, and nicotine dependence, which are considered as risk factors for heroin relapse, might interact with each other. There is a need for further studies on the underlying mechanism of these clinical phenomena.

Effect of Withania somnifera (L.) Dunal aqueous root extract on reinstatement using conditioned place preference and brain GABA and dopamine levels in alcohol dependent animals

Ethnopharmacological relevanceWithania somnifera (L.) Dunal (WS), a known‘Rasayana’ (rejuvenating agent) as per Ayurveda is prescribed to promote health, to increase longevity and to hasten recovery in disease convalescent stages. WS has demonstrated protective effect on alcohol dependence and withdrawal anxiety in previous experimental studies. Aim of the studyTo evaluate effect of WS on conditioned place behavioral paradigm (model of relapse) and on GABA and dopamine levels in critical brain areas in alcohol dependent animals. MethodologyFollowing Animal Ethics Committee permission, the mice (n = 24) were divided into the following study groups for experiment 1: 1 -distilled water (vehicle control), 2 -WS and 3 -Naltrexone. They were conditioned on conditioned place preference (CPP) using alcohol (2 gm/kg)/saline (1 ml) administered intraperitoneally for 8 days. WS and Naltrexone were administered during the period of extinction (6–8 days). Effect of WS (650 mg/kg) on reinstating behaviour of mice (time spent in alcohol paired compartment) primed with alcohol injection was noted. In experiment 2, effect of WS (450 mg/kg/) on GABA and dopamine levels in the midbrain, striatum and cortex (ng/gm) were measured in alcohol dependent rats (n = 24) following the first phase of standardisation assay (n = 36). The rats were made alcohol dependent for 15 days (intermittent access model) and WS was administered concurrently. GABA and dopamine levels were measured on Day 16. ResultsWS group showed decrease in time spent in alcohol paired compartment alike Naltrexone and it differed significantly compared to the distilled water control group (p < 0.05) Alcohol-dependent rats showed significant decrease in GABA and increase in dopamine levels vs distilled water in the midbrain, striatum and cortex. WS and Naltrexone administration showed rise in GABA and fall in dopamine in all the isolated brain parts in the respective groups (p < 0.05 vs alcohol treated group). ConclusionWithania somnifera protected animals from relapse and showed beneficial effects on the brain neurotransmitters involved in alcohol dependence. The study provides substantial evidence for its potential application in alcohol use disorder.

Isoliquiritigenin Attenuates Anxiety-Like Behavior and Locomotor Sensitization in Rats after Repeated Exposure to Nicotine.

As important components of positive and negative reinforcement, locomotor sensitization and withdrawal anxiety following repeated exposure to nicotine (NIC) constitute crucial risk factors for relapse to NIC use after abstinence. Glycyrrhiza radix (G. radix), an important tonic used in traditional Oriental medicine, has not only anxiolytic effects but also reduces NIC-induced locomotor sensitization. Isoliquiritigenin (ISL), a bioactive ingredient of G. radix, also exhibits neuropharmacological effects, including anxiolytic action. Previously, we reported that ISL suppressed cocaine-induced extracellular dopamine release in the nucleus accumbens shell (NaccSh) and attenuated methamphetamine-induced neurotoxicity. The present study was performed to evaluate the effects of ISL on both NIC withdrawal anxiety and locomotor sensitization. Adult male rats received subcutaneous administration of NIC hydrogen tartrate (0.4 mg/kg, twice a day) for 7 days followed by 4 days of withdrawal. During the period of NIC withdrawal, the rats received four intragastric treatments with ISL (3, 10, or 30 mg/kg/day). All three doses of ISL significantly inhibited NIC withdrawal-induced anxiety-like behaviors in the elevated plus maze (EPM) test, but only the 10 mg/kg/day and 30 mg/kg/day ISL doses attenuated locomotor sensitization induced by a challenge dose of NIC. Intracerebroventricular ISL also inhibited both NIC-induced withdrawal anxiety and locomotor sensitization, but intra-NaccSh injection of ISL blocked only NIC locomotor sensitization, which was abolished by post-ISL infusion of tert-butyl hydroperoxide (an oxidant) or N-methyl-d-aspartate (NMDA) into the NaccSh. Moreover, there was increased protein expression of phosphorylated Erk1/2 in the NIC-sensitized NaccSh, which was suppressed by ISL. Taken together, these results suggest that ISL can inhibit repeated NIC-induced withdrawal anxiety and locomotor sensitization, and the latter is mediated by antagonizing accumbal reactive oxygen species and NMDA receptor signaling.

Methanol extract of semen Ziziphi Spinosae attenuates ethanol withdrawal anxiety by improving neuropeptide signaling in the central amygdala

BackgroundEthanol withdrawal (EtOHW) anxiety is a crucial risk factor for alcoholic relapse. The neuropeptide nociceptin/orphanin FQ (N/OFQ) acts upon its receptor (NOP) to antagonize corticotropin-releasing factor (CRF) and elicit anxiolytic actions. Semen Ziziphi Spinosae (SZS), a prototypical hypnotic-sedative herb in Oriental medicine, exhibits anxiolytic effects during nicotine withdrawal by improving amygdaloid CRF/CRF1 receptor (CRFR1) signaling. Therefore, we evaluated the effects of SZS on EtOHW anxiety and the involvement of amygdaloid CRF/CRFR1 and N/OFQ/NOP pathways.MethodsMale Sprague Dawley rats received intraperitoneal injections of 2 g/kg EtOH (20% v/v) once daily for 28 d followed by a 3-d withdrawal. During EtOHW, the rats were given once-daily intragastric treatments of a methanol extract of SZS (MESZS, 60 or 180 mg/kg/d). Anxiety-like behaviors were measured with the open field (OF) and elevated plus maze (EPM) tests, and plasma corticosterone (CORT) levels were examined by an enzyme-linked immunosorbent assay. mRNA and protein expression levels of the neuropeptides and their receptors were determined by quantitative polymerase chain reaction and Western blot assays.ResultsMESZS increased the distance traveled in the center zone of the OF and dose-dependently elongated the duration of staying in the center zone in EtOHW rats. MESZS increased both the number of entries into and the time spent in the open arms of the EPM by EtOHW rats. And, MESZS inhibited the over secretion of plasma CORT during EtOHW. EtOHW enhanced CRF and CRFR1 gene and protein expression in the central nucleus of the amygdala (CeA), which were inhibited by 180 mg/kg/d MESZS. EtOHW increased amygdaloid NOP mRNA and protein expression but spared N/OFQ mRNA expression, and 180 mg/kg/d MESZS further promoted these increases. Additionally, a post-MESZS intra-CeA infusion of either CRF or the selective NOP antagonist UFP-101 abolished the expected anxiolytic effect of 180 mg/kg/d MESZS.ConclusionsThese results suggest that MESZS ameliorates EtOHW anxiety by improving both CRF/CRFR1 and N/OFQ/NOP transmissions in the CeA.

Centella asiatica extract normalizes GABAergic transmission in the rats amygdala and attenuates ethanol withdrawal anxiety like behavior associated with ethanol abstinence

Centella asiatica extract normalizes GABAergic transmission in the rats amygdala and attenuates ethanol withdrawal anxiety like behavior associated with ethanol abstinence

Effect of Valeriana wallichii on alcohol addiction in mice

Background: Alcoholism is the most common form of addiction and a worldwide problem. Alcohol addiction primarily leads to alcohol dependence and on abstinence leads to withdrawal effects. Common pharmacological properties of compounds used against alcohol addiction include anti-anxiety, anticonvulsant, antidepressant, and nootropic actions. valeriana wallichii known ethnopharmacologically for its sleep-inducing effects have all the above-pharmacological properties. Aim: Here, we screen valeriana for possible anti-addictive potential. Materials and Methods: Effect of valeriana was measured on ethanol withdrawal anxiety using elevated plus maze. The role of valeriana on chronic ethanol consumption (21 days) was measured using two bottle choice method of voluntary drinking. We also measured the effect of the above herb on cortico-hippocampal gamma-aminobutyric acid (GABA) levels. Results: Valeriana was found to reduce ethanol withdrawal anxiety in a dose-dependent manner. The herb also decreased ethanol intake and increased water intake significantly (P Abbreviations Used: GABA: Gamma-aminobutyric acid; CNS: Central nervous system; CPP: Conditioned place preference; EPM: Elevated plus maze; NMDA: N-Methyl D-aspartic acid; HIV: Human Immunodeficiency virus.

Protective effect of Ocimum sanctum Linn. leaf extract on ethanol withdrawal syndrome in Wistar rats

Objective: To evaluate the effects of Oscimum sanctum L (O. sanctum), an important medicinal herb, on alcohol withdrawal syndrome in Wistar rats. Methods: Liquid diet with 7.2%, v/v ethanol was administered to the rats for 21 d. Control group animals received sucrose as an isocaloric liquid diet. After alcohol withdrawal, rats were examined at 6th and 24th hour for major withdrawal signs that included anxiety and hyper locomotor activity. Ethanol withdrawal anxiety was tested using elevated plus maze, light and dark model; the hyper locomotor activity using actophotometer. O. sanctum leaf extract (100, 200 and 300 mg/kg, oral) and diazepam (2 mg/kg, i.p) were administered to the treatment group animals 30 min before alcohol withdrawal estimation. Drug treatment was also given 30 min before the second observation at 24th hour. On the last day of the protocol, rats were sacrificed by cervical dislocation liver, kidney and brain were isolated and preserved in formalin for further histopathological examination. Results: Findings from the present study revealed that O. Sanctum leaf extract treatment at doses 100, 200 and 300 mg/kg, oral had a significant protective effect on signs and symptoms of ethanol withdrawal in alcohol-dependent rats. However, no remarkable pathological and microscopic alterations were observed in histopathological examination. Conclusions:O. sanctum seems to be an active drug for the treatment of alcohol abstinence syndrome.

Protective Effects of Ferulic Acid in Alcohol Withdrawal Induced Anxiety and Depression in Mice

Background: Anxiety and depression are the most important troubling symptoms of continuous alcoholism. Objective: The present study was designed to examine the protective effects of ferulic acid in alcohol withdrawal-induced anxiety and depression in experimental mice.&#x0D; Methods: Male albino mice were divided into different groups. They were received 10% ethanol (2 g/kg; p.o.) twice on the first day and once on successive days for total six days, after 24 hrs. Withdrawal symptoms were observed using the different model for anxiety and depression such as elevated plus maze, open field test, hole board test, marble burying test and tail suspension test. Ferulic acid was tested as 10 and 20 mg/ kg, orally.&#x0D; Results: Treatment with ferulic acid (10 and 20 mg/kg, p.o) showed significant reduction of alcohol withdrawal syndromes in different models. Taken together our result showed a protective effect in alcohol withdrawal anxiety and depression as tested in well-established animal models.&#x0D; Conclusion: The present study showed that ferulic acid dose-dependently prevents alcohol withdrawal-induced anxiety and depression in mice.

α2 Subunit-Containing GABAA Receptor Subtypes Are Upregulated and Contribute to Alcohol-Induced Functional Plasticity in the Rat Hippocampus.

Alcohol (EtOH) intoxication causes changes in the rodent brain γ-aminobutyric acid receptor (GABAAR) subunit composition and function, playing a crucial role in EtOH withdrawal symptoms and dependence. Building evidence indicates that withdrawal from acute EtOH and chronic intermittent EtOH (CIE) results in decreased EtOH-enhanced GABAAR δ subunit-containing extrasynaptic and EtOH-insensitive α1βγ2 subtype synaptic GABAARs but increased synaptic α4βγ2 subtype, and increased EtOH sensitivity of GABAAR miniature postsynaptic currents (mIPSCs) correlated with EtOH dependence. Here we demonstrate that after acute EtOH intoxication and CIE, upregulation of hippocampal α4βγ2 subtypes, as well as increased cell-surface levels of GABAAR α2 and γ1 subunits, along with increased α2β1γ1 GABAAR pentamers in hippocampal slices using cell-surface cross-linking, followed by Western blot and coimmunoprecipitation. One-dose and two-dose acute EtOH treatments produced temporal plastic changes in EtOH-induced anxiolysis or withdrawal anxiety, and the presence or absence of EtOH-sensitive synaptic currents correlated with cell surface peptide levels of both α4 and γ1(new α2) subunits. CIE increased the abundance of novel mIPSC patterns differing in activation/deactivation kinetics, charge transfer, and sensitivity to EtOH. The different mIPSC patterns in CIE could be correlated with upregulated highly EtOH-sensitive α2βγ subtypes and EtOH-sensitive α4βγ2 subtypes. Naïve α4 subunit knockout mice express EtOH-sensitive mIPSCs in hippocampal slices, correlating with upregulated GABAAR α2 (and not α4) subunits. Consistent with α2, β1, and γ1 subunits genetically linked to alcoholism in humans, our findings indicate that these new α2-containing synaptic GABAARs could mediate the maintained anxiolytic response to EtOH in dependent individuals, rat or human, contributing to elevated EtOH consumption.