Anxiogenic Action Research Articles

Intraperitoneal administration of α-melanocyte stimulating hormone (α-MSH) suppresses food intake and induces anxiety-like behavior via the brain MC4 receptor-signaling pathway in goldfish.

α-Melanocyte stimulating hormone (α-MSH) is a peptide hormone released from the intermediate lobe of the pituitary which regulates body pigmentation. In addition to the pituitary, α-MSH is also produced in the midbrain, and exerts both anorexigenic and an anxiogenic actions. Acyl ghrelin and cholecystokinin are peripheral hormones derived from the digestive tract which affect the brain to control food intake and feeding behavior in vertebrates. In the present study, hypothesizing that plasma α-MSH may also stimulate the brain and exert central effects, we examined whether peripherally administered α-MSH affects food intake and psychomotor activity using a goldfish model. Intraperitoneal (IP) administration of α-MSH at 100 pmol g-1 body weight (BW) reduced food consumption and enhanced thigmotaxis. These α-MSH-induced actions were blocked by intracerebroventricular administration of HS024, an antagonist of the melanocortin 4 receptor (MC4R), at 50 pmol g-1 BW, whereas these actions were not attenuated by pretreatment with an IP-injected excess amount of capsaicin, a neurotoxin that destroys primary sensory (vagal and splanchnic) afferents, at 160 nmol g-1 BW. Transcripts for the MC4R showed higher expression in the diencephalon in other regions of the brain. These results suggest that, in goldfish, IP administered α-MSH is taken up by the brain, and also acts as anorexigenic and anxiogenic factor via the MC4R signaling pathway.

Intraperitoneal administration of arginine vasotocin (AVT) induces anorexigenic and anxiogenic actions via the brain V1a receptor-signaling pathway in the tiger puffer, Takifugu rubripes

Arginine vasotocin (AVT) is produced mainly in the hypothalamus and as a neurohypophyseal hormone peripherally regulates water-mineral balance in sub-mammals. In addition, AVT-containing neurons innervate several areas of the brain, and AVT also acts centrally as both an anorexigenic and anxiogenic factor in goldfish. However, it is unclear whether these central effects operate in fish in general. In the present study, therefore, we investigated AVT-like immunoreactivity in the brain of the tiger puffer, a cultured fish with a high market value in Japan and also a representative marine teleost species, focusing particularly on whether AVT affects food intake and psychomotor activity. AVT-like immunoreactivity was distributed higher in the ventral region of the telencephalon, the hypothalamus and midbrain. Intraperitoneal (IP) administration of AVT at 100 pmol g−1 body weight (BW) increased the immunoreactivity of phosphorylated ribosomal proteinS6 (RPS6), a neuronal activation marker, in the telencephalon and diencephalon, decreased food consumption and enhanced thigmotaxis. AVT-induced anorexigenic and anxiogenic actions were blocked by IP co-injection of a V1a receptor (V1aR) antagonist, Manning compound (MC) at 300 pmol g−1 BW. These results suggest that AVT acts as an anorexigenic and anxiogenic factor via the V1aR-signaling pathway in the tiger puffer brain.

Amelioration by Withania somnifera of neurobehavioural and immunological markers in time dependent sensitization induced post traumatic stress disorder in rats.

Posttraumatic stress disorder (PTSD) is a complex neuropsychiatric pathophysiology with an unmet need for safe, effective, and sustainable therapeutic modalities. Thus, the present study evaluated the effects of Withaniasomnifera (WS, Ashwagandha) on an experimental model of PTSD in rats. Wistar rats (200-250 g) were used and time-dependent sensitization (TDS) was used as the experimental model of PTSD. Standardized WS root extract (100 and 300 mg/kg, p.o. for 15 days) was administered with TDS and their effects were observed on neurobehavioral (anxiety) and brain cytokines, corticosterone, and oxidative stress markers. Exposure to TDS resulted in anxiogenic behavior in the elevated plus maze (EPM) test, i.e., reductions in open arm entries and open arm time, as compared to the control group. Pretreatment with WS extract (100 and 300 mg/kg × 14 days) attenuated the TDS-induced anxiogenic activity in a dose-related manner, and these WS effects were comparable to those seen after the comparator drug fluoxetine (10 mg/kg). Assay of brain homogenates showed that TDS also resulted in elevations in brain interleukin-6 and reduction in corticosterone levels in both the hippocampus and prefrontal cortex (PFC), which were reversed after WS pretreatments. Further, WS pretreatment also reversed the TDS-induced changes in brain oxidative stress markers, namely elevated malondialdehyde and reduced glutathione levels in both the hippocampus and PFC. These results suggest that WS could have potential as a therapeutic agent for treating PTSD by attenuating anxiogenesis, neuroimmune axis activation, and oxidative stress.

Targeting mediodorsal thalamic CB1 receptors to inhibit dextromethorphan-induced anxiety/exploratory-related behaviors in rats: The post-weaning effect of exercise and enriched environment on adulthood anxiety

Dextromethorphan (DXM) is an effective over-the-counter antitussive with an alarming increase as an abused drug for recreational purposes. Although reports of the association between DXM administration and anxiety, there are few investigations into the underlying DMX mechanisms of anxiogenic action. Thus, the present study aimed to investigate the role of the mediodorsal thalamus (MD) cannabinoid CB1 receptors (CB1Rs) in DXM-induced anxiety/exploratory-related behaviors in adult male Wistar rats. Animals were bilaterally cannulated in the MD regions. After one week, anxiety and exploratory behaviors were measured using an elevated plus-maze task (EPM) and a hole-board apparatus. Results showed that DXM (3–7 mg/kg, i. p.) dose-dependently increased anxiety-like behaviors. Intra-MD administration of ACPA (2.5–10 ng/rat), a selective CB1 receptor agonist, decreased anxiety-like effects of DXM. The blockade of MD CB1 receptors by AM-251 (40–120 ng/rat) did not affect the EPM task. However, it potentiated the anxiogenic response of an ineffective dose of DXM (3 mg/kg) in the animals. Moreover, the effect of post-weaning treadmill exercise (TEX) and enriched environment (EE) were examined in adulthood anxiety under the drug treatments. Juvenile rats were divided into TEX/EE and control groups. The TEX/EE-juvenile rats were placed on a treadmill and then exposed to EE for five weeks. Interestingly, compared to untreated animals, post-weaning TEX/EE inhibited the anxiety induced by DXM or AM-251/DXM. It can be concluded that the MD endocannabinoid system plays an essential role in the anxiogenic effect of dextromethorphan. Moreover, post-weaning exercise alongside an enriched environment may have an inhibitory effect on adulthood anxiety-like behaviors.

Neuronal nitric oxide synthase inhibition accelerated the removal of fluoxetine’s anxiogenic activity in an animal model of PTSD

While SSRIs are the current first-line pharmacotherapies against post-traumatic stress disorder (PTSD), they suffer from delayed onset of efficacy and low remission rates. One solution is to combine SSRIs with other treatments. Neuronal nitric oxide synthase (nNOS) has been shown to play a role in serotonergic signaling, and there is evidence of synergism between nNOS modulation and SSRIs in models of other psychiatric conditions. Therefore, in this study, we combined subchronic fluoxetine (Flx) with 7-nitroindazole (NI), a selective nNOS inhibitor, and evaluated their efficacy against anxiety-related behavior in an animal model of PTSD.We used the underwater trauma model to induce PTSD in rats. Animals underwent the open field (OFT) and elevated plus maze tests on days 14 (baseline) and 21 (post-treatment) after PTSD induction to assess anxiety-related behaviors. Between the two tests, the rats received daily intraperitoneal injections of 10 mg/kg Flx or saline, and were injected intraperitoneally before the second test with either 15 mg/kg NI or saline. The change in behaviors between the two tests was compared between treatment groups.Individual treatment with both Flx and NI had anxiogenic effects in the OFT. These effects were associated with modest increases in cFOS expression in the hippocampus. Combination therapy with Flx + NI did not show any anxiogenic effects, while causing even higher expression levels of cFOS.In conclusion, addition of NI treatment to subchronic Flx therapy accelerated the abrogation of Flx’s anxiogenic properties. Furthermore, hippocampal activity, as evidenced by cFOS expression, was biphasically related to anxiety-related behavior.

The 5-HT6R agonist E-6837 and the antagonist SB-271046 reverse the psychotic-like behaviors induced by ketamine.

Schizophrenia is a serious mental disorder that affects 1% of the world's population. Although various therapeutic tools have been developed since the appearance of the first generation of antipsychotics, the effect of these agents does not manage to attenuate a significant part of psychotic symptoms. Ketamine is an anesthetic agent able to produce psychotic-like symptoms through the antagonism of the glutamatergic N-methyl-d-aspartic acid (NMDA) receptors (NMDARs). This drug has been widely used to study new pharmacological tools with potential antipsychotic properties. On the contrary, it is known that the 5-HT6 receptor agonist and antagonist drugs induce procognitive, anxiolytic and antidepressant effects in different preclinical models. Therefore, the aim of this study was to evaluate the behavioral actions of the 5-HT6 receptors' agonist E-6837 and the antagonist SB-271046, in ICR-CD1 mice previously treated with a subchronic ketamine scheme (10 mg/kg i.p. daily for 5 days). Results showed that repeated administration of ketamine induced recognition memory deficit, anxiogenic effects, obsessive-compulsive behaviors and stereotyped movements. The acute administration of both 5-HT6 agents reversed the memory deficit and induced a decrease in anxiety, whereas SB-271046 administration produced a decrease in climbing behavior. The injection of either of these 5-HT6 drugs had no effect in the light-dark test. Surprisingly, when these drugs were injected together with ketamine, anxiogenic actions were produced. Current findings suggest that both agonist and antagonist 5-HT6 drugs play an important role in modulating psychotic-like symptoms induced by the subchronic blockade of NMDAR.

Calotropis gigantea- A Review

Calotropis gigantea plant has a family Asclepiadaceae commonly and sub family Apocynaceae known as Madar in Hindi. It is a perennial herb with a very long history of use in traditional medicines. Calotropis gigantea is a hoary, laticiferous shrub, which is also known as “the milkweed”. Calotropis is used as a traditional medicinal plant in whole world. Calotropis gigantea plant contain chemical constituents in which cardenolides, flavonoids, terpenes, pregnanes and nonprotein amino acid and more in various concentration. The root bark contains α-amyrin, β-amyrin, taraxasterol and its ψ-isomer taraxasteryl isovalerate, taraxasteryl acetate, gigantin, giganteol, isogiganteol, β-sitosterol and wax. The rootalso shows Nootropic activity in methanolic extract. The latex, leaves, flowers and bark are used as caustic, acrid, expectorant, to removes body hairs, anthelmintics and alsoused in leprosy, ulceration, cough, scabies ring worm of the scalp, piles, explosion on the body, asthma, enlargement of spleen or liver, edema and in painful joint swellings. Also, evaluate possible anxiogenic effect, sedative action and anxiolytic potential of crude ethanolic extract of Calotropis gigantealeaf. Methanolic extract of Calotropis gigantea root used as memory increasing activity. This review gives an idea about its pharmacological activity and phytochemistry.

Oxytocin-induced anxiogenic behavior in juvenile male rats

ABSTRACT Oxytocin (OT) is considered beneficial to mental health owing to its anxiolytic, prosocial, and anti-stress effects; however, the adverse effects of OT have been controversial, such as its potentially anxiogenic actions. Although OT influences drug abuse and reciprocally affects vulnerability to drug use, the relationship between OT’s anxiogenic working and nicotine preference intake has not been clearly defined. To clarify this issue, the effect of acute peripheral administration of OT on anxiety and nicotine preference was investigated in juvenile male rats. Anxiogenic behaviors were noticeably increased in OT-administrated rats, with an increase in serum corticosterone levels. Moreover, increased anxiety-like behaviors and corticosterone levels were observed in the OT analog carbetocin-injected rats. In the nicotine preference test, the rats’ aversive responses to initial nicotine choice and preference were not significantly different between saline-injected and OT-injected rats. However, when administered with OT, there was a significant negative correlation between anxiety-like behavior and low-dose nicotine consumption. Collectively, these results provide evidence that acute OT exposure could induce anxiogenic behavior with corticosterone augmentation, contributing to the attenuation of nicotine preference. This suggests that both aspects of OT, as well as their benefits and drawbacks, should be considered.

The Effects of Satureja hortensis L. Extract on Cisplatin-Induced Behavioral Alterations in the Tail Suspension Test

Abstract In order to evaluate the effects of Satureja hortensis L. extract on cisplatin-induced behavioral alterations in the tail suspension test (TST), we included 35 male Wistar albino rats in this study, divided into 7 equal groups. Cisplatin was administered (single dose of 7.5 mg/kg, i.p., on the fifth day) alone, and in groups with orally administered (for 10 days) Satureja hortensis L. extract (50, 100, and 200 mg/kg), and silymarin (100 mg/kg) in individual groups. The behavioral testing was performed in TST, and the following parameters were obtained: the latency to the first immobility, the number of immobility episodes, and the total duration of immobility. Cisplatin application increased the latency to the first immobility, but decreased the number of immobility episodes and the total duration of immobility. Oral administration of Satureja hortensis L. extract in a dose of 100 mg/kg attenuated cisplatin-induced alterations, and those effects were similar to silymarin group. The extract in a dose of 200 mg/kg diminished cisplatin-induced effect only for the total duration of immobility, while in a dose of 50 mg/kg, the extract had no impact on cisplatin effects. Although common use of this methodology would lead to a conclusion that cisplatin produced antidepressant effect, comparison with certain literature data allows the conclusion that this action of cisplatin may be attributed to its anxiogenic action that was attenuated by antioxidant supplementation (Satureja hortensis L.) in an adequate dose (100 mg/kg).

Maternal Geophagy of Calabash Chalk: Effects on Neurobehavior and Brain-Histomorphology of Mice

The aim of this study was to evaluate the behavior and the brain-histomorphology of mice due to the consumption of calabash chalk. Asian and African pregnant or breast-feeding women frequently consume calabash chalk/clay for morning sickness or as a nutritional supplement. However, scientists found high amounts of heavy metals, especially lead acetate in it. This study was conducted by twenty-four female Swiss-albino mice. They were divided into four groups: control group (gr 1:1ml distilled water) and three treated groups (gr 2, 3 & 4) with the doses of 200 mg/kg, 400 mg/kg and 600 mg/kg of calabash chalk suspension, respectively, by oral gavage. Four tests were performed to evaluate the behavioral changes along with measurement of body weight and histomorphology of cerebral cortex. The data were analyzed by SPSS-software. The study showed a significant decrease in body weight in all of the treated groups (p<0.01). Apart from the elevated plus maze test, decreased behavioral pattern was observed in a dose-dependent manner (in gr 3 & 4: p <0.001). The effect of calabash chalk on histomorphology of the cerebral cortex showed a higher cellular population, hypertrophy and vacuolations in the treated groups, in a dose-dependent manner. All the three neurobehavioral parameters showed anxiogenic effects of calabash chalk with the only exception of elevated plus maze test where it showed anxiolytic activity. Both anxiogenic and anxiolytic effects observed were highly suggestive of alteration in estrogenic activity. An elevated level of estrogen could be the key mediator of anxiolytic effects whereas anxiogenic activity might result from trace metals like arsenic and lead present in the calabash chalk.

N-(3-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}propyl)-1H-indazole-3-carboxamide (D2AAK3) as a potential antipsychotic: In vitro, in silico and in vivo evaluation of a multi-target ligand

Schizophrenia is a mental illness of not adequately understood causes that is not satisfactorily enough treated by current antipsychotics. In search for novel potential antipsychotics we performed structure-based virtual screening aimed to identify new dopamine D2 receptor antagonists. We found compound D2AAK3 with affinity to dopamine D2 receptor of 115 nM. D2AAK3 possesses additional nanomolar or low micromolar affinity to D1, D3, 5-HT1A, 5-HT2A and 5-HT7 receptors, which makes it a good hit for further development as a multifunctional ligand. The compound has also some affinity to M1 and H1 receptors. We used homology modeling, molecular docking and molecular dynamics to study interactions of D2AAK3 with its molecular targets at the molecular level. In behavioral studies D2AAK3 decreases amphetamine-induced hyperactivity (when compared to the amphetamine-treated group) measured as spontaneous locomotor activity in mice. In addition, passive avoidance test demonstrated that D2AAK3 improves memory consolidation after acute treatment in mice. Elevated plus maze tests indicated that D2AAK3 induces anxiogenic activity 30 min after acute treatment, whereas this effect has no longer been observed 60 min after administration of the studied compound in mice.

Can Plant Lectins be Alternatives to Treat Anxiety and Depressive Disorders?

Depression and anxiety disorder are the most common mental disorders worldwide and their treatments are combinations of pharmacological and psychotherapeutic approaches. Depression treatment depends largely on a pharmacotherapy that improves the transmission of monoamines in the brain. However, the drugs available have adverse reactions and do not contemplate positively all patients, which stimulates scientific research that seeks new molecules, including from natural sources. Lectins are proteins capable of binding reversibly and non-covalently to specific sugars. For example, it has been reported the antimicrobial, antitumor, antiparasitic, anti-inflammatory and antinociceptive activities of lectins. The ability of some lectins in modulating nociception and inflammation stimulated studies on the possible effects on processes that share some pathways and molecular agents, like depression and anxiety. Lectins isolated from plants showed antidepressant effects, which were demonstrated to be linked to activation of serotonergic, adrenergic, and dopaminergic systems as well as to inhibition of the glutamatergic system and L-arginine–NO–cGMP pathway. In view of their immunomodulatory properties, it is also suggested that lectins can ameliorate the inflammatory framework associated with depression. Anxiolytic effects were also reported and associated with modulation of GABAergic mechanisms, serotonergic system, and NO pathway. It should be taken in account that some lectins induced depressive-like behavior, associated with an neuroinflammatory action, as well anxiogenic action. Thus, it is important to use combinations of batteries for testing anxiety, depression, despair, and anhedonia behaviors in the studies with lectins. The mechanisms by which lectins exactly modulate depression or anxiety frameworks are still unclear but important windows had already been open by researchers and preclinical studies with lectins have indicated these proteins as candidates for alternative or complementary agents in therapies of depression and anxiety disorder.

Neurobehavioral responses in swiss albino mice induced by an aqueous leaf extract from a medicinal plant named Heliotropium incanum Ruiz & Pav.

It is of interest to examine the adverse neuro-behavioural responses on mice treated with the aqueous crude extract of Heliotropium incanum (AEHI), which were evaluated using various behavioral paradigms. On the basis of median lethal dose value, doses of AEHI were chosen to be 150mg/kg and 440mg/kg for further experiment. Four groups comprising of five mice each were divided for the 14 days experiment. Group I, the control group, received distilled water; Group II and III received AEHI (150 mg/kg body weight and 440 mg/kg body weight) respectively; Group IV received standard drugs, Diazepam/Fluoxetine, administered orally. On administration of AEHI, it was revealed that dose 440 mg/kg showed less exploration activity in the hole board test; decrease in the number of squares crossed in locomotory test, time period in the open arm in the plus maze test was significantly reduced and the immobility time was significantly extended in comparison to control and standard drugs. The microscopic study of brain revealed damaged hippocampus along with nerve cells degeneration. Consequently, the results concluded that the outcome of the AEHI produced evidences for the anxiogenic activity in mice.

Blood Oxidative Stress Modulates Alveolar Bone Loss in Chronically Stressed Rats

We aimed to investigate the effects of chronic stress (CS) on experimental periodontitis (EP) in rats. For this, 28 Wistar rats were divided into four groups: control, ligature-induced experimental periodontitis (EP), chronic stress (CS; by physical restraint model) and CS+EP (association of chronic stress and ligature-induced periodontitis). The experimental period lasted 30 days, including exposure to CS every day and ligature was performed on the 15th experimental day. After 30 days, the animals were submitted to the behavioral test of the elevated plus maze (EPM). Next, rats were euthanized for blood and mandible collection in order to evaluate the oxidative biochemistry (by nitric oxide (NO), reduced-glutathione activity (GSH), and thiobarbituric acid reactive substance levels (TBARS)) and alveolar bone characterization (by morphometric, micro-CT, and immunohistochemistry), respectively. The behavioral parameters evaluated in EPM indicated higher anxiogenic activity in the CS and CS+EP, groups, which is a behavioral reflex of CS. The results showed that CS was able to change the blood oxidative biochemistry in CS and CS+EP groups, decrease GSH activity in the blood, and increase the NO and TBARS concentrations. Thus, CS induces oxidative blood imbalance, which can potentialize or generate morphological, structural, and metabolic damages to the alveolar bone.

Флавоноид кверцетин уменьшает двигательную активность и повышает эмоциональную реактивность у крыс

This work is aimed at the investigation of the effects of polyphenolic flavonoid quercetin, possessing a wide range of pharmacological properties, on locomotor, emotional and anxiety-like behavior in rats under normal conditions. Intraperitoneal administration of quercetin at a dose of 5 mg/kg was found to induce several types of anxiety-like behavior in the open field (OF) test 2 hours after the injection. It was characterized by reduced time spent in the central zone of the arena, and increased — in the peripheral zone. Such effects were absent in the elevated plus maze (EPM) test. Additionally, quercetin induced an enhanced emotional reactivity in the OF test that manifested in a prolonged freezing duration and the increased number of fecal boli. A considerable decrease in the level of horizontal activity was detected in this test: the number of squares crossed in the peripheral and the central zones was decreased. Moreover, the number of supported rearings was decreased in both tests, which reflects an attenuation of the exploratory behavior. These findings indicate the anxiogenic action of quercetin. Elicited behavioral changes induced by quercetin were not linked to changes in the stress-induced protein Hsp70 content in the brain structures implicated in locomotion and emotion regulation. We propose that the decreased locomotor activity and increased emotional reactivity following quercetin administration in rats are associated with its modulatory effects on the intracellular kinase signaling pathways that play an important role in the neurobiological processes.

N-Acetylcysteine Protects against the Anxiogenic Response to Cisplatin in Rats.

Since cisplatin therapy is usually accompanied with numerous toxicities, including neurotoxicity, that involve tissue oxidative damage, the aim of this study was to evaluate the possible protective effect of N-acetylcysteine (NAC) on the anxiogenic response to cisplatin (CIS). Thirty-two male Wistar albino rats divided into four groups (control, cisplatin, NAC, and CIS + NAC). All treatments were delivered intraperitoneally. On day one, the control and cisplatin groups received saline while the NAC and CIS + NAC groups were administered with NAC (500 mg/kg). On the fifth day, the control group received saline while the CIS group was treated with cisplatin (7.5 mg/kg), the NAC group again received NAC (500 mg/kg), and the CIS + NAC group was simultaneously treated with cisplatin and NAC (7.5 and 500 mg/kg, respectively). Behavioral testing, performed on the tenth day in the open field (OF) and elevated plus maze (EPM) tests, revealed the anxiogenic effect of cisplatin that was significantly attenuated by NAC. The hippocampal sections evaluation showed increased oxidative stress (increased lipid peroxidation and decline in antioxidant enzymes activity) and proapoptotic action (predominantly by diminished antiapoptotic gene expression) following a single dose of cisplatin. NAC supplementation along with cisplatin administration reversed the prooxidative and proapoptotic effects of cisplatin. In conclusion, the results obtained in this study confirmed that antioxidant supplementation with NAC may attenuate the cisplatin-induced anxiety. The mechanism of anxiolytic effect achieved by NAC may include the decline in oxidative damage that down regulates increased apoptosis and reverses the anxiogenic action of cisplatin.

Phencynonate S-isomer as a eutomer is a novel central anticholinergic drug for anti-motion sickness

To compare and evaluate the differences of stereoselective activity, the binding affinity, metabolism, transport and molecular docking of phencynonate isomers to muscarinic acetylcholine receptor (mAChR) were investigated in this study. The rotation stimulation and locomotor experiments were used to evaluate anti-motion sickness effects. The competitive affinity with [3H]-QNB and molecular docking were used for studying the interactions between the two isomers and mAChR. The stereoselective mechanism of isomers was investigated by incubation with rat liver microsomes, a protein binding assay and membrane permeability assay across a Caco-2 cell monolayer using a chiral column HPLC method. The results indicated that S-isomer was more effective against motion sickness and had not anxiogenic action at therapeutic doses. S-isomer has the higher affinity and activity for mAChR in cerebral cortex and acted as a competitive mAChR antagonist. The stereoselective elimination of S-isomer was primarily affected by CYP1B1 and 17A1 enzymes, resulting in a higher metabolic stability and slower elimination. Phencynonate S isomer, as a eutomer and central anticholinergic chiral drug, is a novel anti-motion sickness drug with higher efficacy and lower central side effect. Our data assisted the development of a novel drug and eventual use of S-isomer in clinical practice.

The anxiolytic effects of Bai Le Mian capsule, a traditional Chinese hypnotic in mice

Bai Le Mian capsule (BLMC), which is composed of fifteen kinds of traditional Chinese Medicine, is a popular traditional Chinese medicine for the treatment of insomnia with anxiety. This study was to investigate the anxiolytic effect of BLMC in mice. BLMC (81, 162, and 325 mg/kg, i.g.) was given once or consecutively for 2 weeks, and anxiety behaviors were tested by the elevated plus maze, open field, and light/dark box, in normal mice and anxious model mice by meta-chlorophenyl-piperazine, a compound with known anxiogenic actions. In normal mice, single administration of BLMC at 325 mg/kg prolonged the time spent in central area by 2.1-fold in open-field test. Repeated administration once a day for 2 weeks, BLMC at 325 mg/kg increased the time spent in central area, open arms and light box by 2.8-, 2.0-, and 1.7-fold, respectively. Similarly, in anxious model mice, single treatment of BLMC at 325 mg/kg increased more time in the open arms by 2.1-fold. Consecutive administration for 2 weeks, BLMC at 325 mg/kg increased the time spent in open arms and light box by 2.3- and 2.1-fold. Immunohistochemical study showed that mCPP increased c-Fos expression in the central nucleus of the amygdala and bed nucleus of stria terminalis by 57% and 60%, and the mCPP-induced c-Fos expression could be reversed by single administration of BLMC. These results indicate that BLMC is an effective treatment for anxiety in mice.

Maternal stress and the MPOA: Activation of CRF receptor 1 impairs maternal behavior and triggers local oxytocin release in lactating rats

Maternal behavior and anxiety are potently modulated by the brain corticotropin-releasing factor (CRF) system postpartum. Downregulation of CRF in limbic brain regions is essential for appropriate maternal behavior and an adaptive anxiety response. Here, we focus our attention on arguably the most important brain region for maternal behavior, the hypothalamic medial preoptic area (MPOA).Within the MPOA, mRNA for CRF receptor subtype 1 (protein: CRFR1, gene: Crhr1) was more abundantly expressed than for subtype 2 (protein: CRFR2, gene: Crhr2), however expression of Crhr1, Crhr2 and CRF-binding protein (protein: CRFBP, gene: Crhbp) mRNA was similar between virgin and lactating rats. Subtype-specific activation of CRFR, predominantly CRFR1, in the MPOA decreased arched back nursing and total nursing under non-stress conditions. Following acute stressor exposure, only CRFR1 inhibition rescued the stress-induced reduction in arched back nursing while CRFR1 activation prolonged the decline in nursing. Furthermore, inhibition of CRFR1 strongly increased maternal aggression in the maternal defense test. CRFR1 activation had anxiogenic actions and reduced locomotion on the elevated plus-maze, however neither CRFR1 nor R2 manipulation affected maternal motivation. In addition, activation of CRFR1, either centrally or locally in the MPOA, increased local oxytocin release. Finally, inhibition of CRFBP (a potent regulator of CRFR activity) in the MPOA did not affect any of the maternal parameters investigated.In conclusion, activity of CRFR in the MPOA, particularly of subtype 1, needs to be dampened during lactation to ensure appropriate maternal behavior. Furthermore, oxytocin release in the MPOA may provide a regulatory mechanism to counteract the negative impact of CRFR activation on maternal behavior.

Acute and long-term effects of Δ9-tetrahydrocannabinol on object recognition and anxiety-like activity are age- and strain-dependent in mice

Use of exogenous cannabinoids disrupts the fine-tuned endocannabinoid receptor system, possibly leading to alterations in cognition, memory, and emotional processes that endure long after cannabinoid use has stopped. Long-term adolescent use may uniquely disrupt these behaviors when compared to adult use. The current study explored the acute and long-term behavioral effects of six 10mg/kg Δ9-tetrahydrocannabinol (THC) injections across the adolescent or early adult period in male inbred C57Bl/6J and DBA/2J mice. The acute and prolonged effects of THC on object memory using the novel object recognition task, unconditioned anxiety in the elevated plus maze and open field, and sedative effects in the open field were examined. Acute THC treatment resulted in anxiogenic activity in both strains, but only caused sedation in B6 mice. Repeated THC treatment resulted in a protracted effect on object recognition, but not unconditioned anxiety, assessed 4weeks later. In both strains, an adolescent history of THC treatment disrupted later object recognition. Interestingly, in B6 mice an adult history of THC exposure appeared to rescue a deficit in object recognition observed in vehicle-treated adults. Repeated THC administration also produced a protracted effected on CB1R protein expression. Animals treated with THC in adolescence maintained increased levels of CB1R protein expression compared to their adult THC-treated counterparts at five weeks following the last injection. These results indicate that THC use may have long-lasting effects with adolescence being a unique period of susceptibility.