Adolescent THC Treatment Does Not Potentiate the Behavioral Effects in Adulthood of Maternal Immune Activation.

Both in utero exposure to maternal immune activation and cannabis use during adolescence have been associated with increased risk for the development of schizophrenia; however, whether these exposures exert synergistic effects on brain function is not known. In the present study, mild maternal immune activation (MIA) was elicited in mice with prenatal exposure to polyinosinic-polycytidylic acid (poly(I:C)), and ∆9-tetrahydrocannabinol (THC) was provided throughout adolescence in cereal (3 mg/kg/day for 5 days). Neither THC nor MIA pretreatments altered activity in assays used to characterize hyperdopaminergic states in adulthood: amphetamine hyperlocomotion and prepulse inhibition of the acoustic startle reflex. Adolescent THC treatment elicited deficits in spatial memory and enhanced spatial reversal learning in adult female mice in the Morris water maze, while exposure to MIA elicited female-specific deficits in fear extinction learning in adulthood. There were no effects in these assays in adult males, nor were there interactions between THC and MIA in adult females. While doses of poly(I:C) and THC were sufficient to elicit behavioral effects, particularly relating to cognitive performance in females, there was no evidence that adolescent THC exposure synergized with the risk imposed by MIA to worsen behavioral outcomes in adult mice of either sex.

Efficacy of Souroubea-Platanus Dietary Supplement Containing Triterpenes in Beagle Dogs Using a Thunderstorm Noise-Induced Model of Fear and Anxiety.

A novel botanical dietary supplement, formulated as a chewable tablet containing a defined mixture of Souroubea spp. vine and Platanus spp. Bark, was tested as a canine anxiolytic for thunderstorm noise-induced stress (noise aversion). The tablet contained five highly stable triterpenes and delivered 10 mg of the active ingredient betulinic acid (BA) for an intended 1 mg/kg dose in a 10 kg dog. BA in tablets was stable for 30 months in storage at 23 °C. Efficacy of the tablets in reducing anxiety in dogs was assessed in a blinded, placebo-controlled study by recording changes in blood cortisol levels and measures of behavioral activity in response to recorded intermittent thunder. Sixty beagles were assigned into groups receiving: placebo, 0.5×, 1×, 2×, and 4× dose, or the positive control (diazepam), for five days. Reduction in anxiety measures was partially dose-dependent and the 1× dose was effective in reducing inactivity time (p = 0.0111) or increased activity time (p = 0.0299) compared with placebo, indicating a decrease in anxiety response. Cortisol measures also showed a dose-dependent reduction in cortisol in dogs treated with the test tablet.

Impact of Acute and Persistent Excitation of Prelimbic Pyramidal Neurons on Motor Activity and Trace Fear Learning.

Drug-induced neuroadaptations in the mPFC have been implicated in addictive behaviors. Repeated cocaine exposure has been shown to increase pyramidal neuron excitability in the prelimbic (PL) region of the mouse mPFC, an adaptation attributable to a suppression of G protein-gated inwardly rectifying K+ (GIRK) channel activity. After establishing that this neuroadaptation is not seen in adjacent GABA neurons, we used viral GIRK channel ablation and complementary chemogenetic approaches to selectively enhance PL pyramidal neuron excitability in adult mice, to evaluate the impact of this form of plasticity on PL-dependent behaviors. GIRK channel ablation decreased somatodendritic GABAB receptor-dependent signaling and rheobase in PL pyramidal neurons. This manipulation also enhanced the motor-stimulatory effect of cocaine but did not impact baseline activity or trace fear learning. In contrast, selective chemogenetic excitation of PL pyramidal neurons, or chemogenetic inhibition of PL GABA neurons, increased baseline and cocaine-induced activity and disrupted trace fear learning. These effects were mirrored in male mice by selective excitation of PL pyramidal neurons projecting to the VTA, but not NAc or BLA. Collectively, these data show that manipulations enhancing the excitability of PL pyramidal neurons, and specifically those projecting to the VTA, recapitulate behavioral hallmarks of repeated cocaine exposure in mice.SIGNIFICANCE STATEMENT Prolonged exposure to drugs of abuse triggers neuroadaptations that promote core features of addiction. Understanding these neuroadaptations and their implications may suggest interventions capable of preventing or treating addiction. While previous work showed that repeated cocaine exposure increased the excitability of pyramidal neurons in the prelimbic cortex (PL), the behavioral implications of this neuroadaptation remained unclear. Here, we used neuron-specific manipulations to evaluate the impact of increased PL pyramidal neuron excitability on PL-dependent behaviors. Acute or persistent excitation of PL pyramidal neurons potentiated cocaine-induced motor activity and disrupted trace fear conditioning, effects replicated by selective excitation of the PL projection to the VTA. Our work suggests that hyperexcitability of this projection drives key behavioral hallmarks of addiction.

Genistein attenuates cognitive deficits and neuroapoptosis in hippocampus induced by ketamine exposure in neonatal rats.

Ketamine is a frequently used anesthetic in pediatric patients that can cause cognitive impairment. Genistein, a bioactive component of soy products, has been shown to suppress neuronal death through regulating the expression of apoptosis related genes. In this study, we hypothesized that genistein could alleviate ketamine-induced cognitive impairment by ameliorating hippocampal neuronal loss and tested this hypothesis in rats. Neonatal rats were treated with ketamine and genistein. Hippocampal tissue was harvested for histological and biochemical analysis to determine neuronal apoptosis and proteins involved in the apoptotic pathways. Behavioral assays including contextual fear conditioning test and Morris water maze test were performed to assess cognitive functions, including learning and memory. We found that in fear conditioning test, genistein restored freezing time in ketamine treated rats in a dose dependent manner. Similarly, genistein attenuated impaired learning and memory in Morris water maze test in rats treated with ketamine. Additionally, ketamine-induced neuronal apoptosis in rat hippocampus was attenuated by genistein treatment. Finally, we found that genistein partially restored proteins associated with apoptosis, including Bax, Bcl-2, cleaved caspase 3, and phosphorylated GSK-3ß and Akt. Genistein suppresses hippocampal neuronal loss and cognitive disruption induced by ketamine in rats.

Vertical exposition to Luffa operculata extract deregulates behavior and hypothalamus neurotransmitters in juvenile rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Luffa operculata (L.) Cogn (Cucurbitaceae) is a traditional plant popularly used in the abortion induction, against sinusitis and is toxic. AIM OF THE STUDY: To verify the influence of the aqueous extract obtained from the dry fruit of L. operculata (BNE) on the male rats vertically exposed to a subabortive dose of BNE, by evaluating alterations in behavior and neurochemical features in hypothalamus, striatum and frontal cortex, at a juvenile age, after receiving a stress challenge given by the use of the "New York subway stress" technique (NYS). MATERIALS AND METHODS: Pregnant female rats (F0 generation) received 1.0 mg/kg BNE, or distilled water (100 mL/kg), by gavage, between gestation days GD17 and GD21. The pups were weaned at PND21 and were kept up to PND60 (juvenile age) in controlled environmental conditions. Four groups were obtained: control (CG), experimental (EG), stress control (SCG) and stress experimental (SEG) After being stressed, the animals were behavioral screened for in the open field (OF) and in light-dark box (LDB) apparatuses. They were euthanized, and the liver, kidneys and brain were removed for both macroscopic and microscopic analyses, and for quantification of vanillylmandelic acid (VMA), norepinephrine (NE), dopamine (DA) and its metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC) and the serotonin (5-HT) and its metabolite 5-hydroxyindolylacetic acid (5-HIAA) were accessed in the hypothalamus, frontal cortex and striatum. RESULTS AND DISCUSSION: although most of the behavior changes were due to the stress challenge, the rats spent more time in the dark side of the LDB and were less likely to explore the light side, indicating that the treatment with BNE induced to fear. Interferences of BNE over behavior were due to impairment of VMA, NE, 5-HT and DA and increasing of DOPAC in the hypothalamus, and an increase of 5-HIAA in the frontal cortex, indicating alterations in the hypothalamic-hypophysis-adrenal axis (HHAA). No macroscopic or histopathological changes were observed in the liver, kidneys, or brain, although GFAP was diminished in the SCG, as expected for stressed rats. CONCLUSION: the vertical exposition of juvenile rats to BNE led to the manifestation of fear and to a down regulation of the hypothalamic-hypophysis-adrenal axis.

Dysregulation of behavioral and autonomic responses to emotional and social stimuli following bidirectional pharmacological manipulation of the basolateral amygdala in macaques.

The amygdala is a key component of the neural circuits mediating the processing and response to emotionally salient stimuli. Amygdala lesions dysregulate social interactions, responses to fearful stimuli, and autonomic functions. In rodents, the basolateral and central nuclei of the amygdala have divergent roles in behavioral control. However, few studies have selectively examined these nuclei in the primate brain. Moreover, the majority of non-human primate studies have employed lesions, which only allow for unidirectional manipulation of amygdala activity. Thus, the effects of amygdala disinhibition on behavior in the primate are unknown. To address this gap, we pharmacologically inhibited by muscimol or disinhibited by bicuculline methiodide the basolateral complex of the amygdala (BLA; lateral, basal, and accessory basal) in nine awake, behaving male rhesus macaques (Macaca mulatta). We examined the effects of amygdala manipulation on: (1) behavioral responses to taxidermy snakes and social stimuli, (2) food competition and social interaction in dyads, (3) autonomic arousal as measured by cardiovascular response, and (4) prepulse inhibition of the acoustic startle (PPI) response. All modalities were impacted by pharmacological inhibition and/or disinhibition. Amygdala inhibition decreased fear responses to snake stimuli, increased examination of social stimuli, reduced competitive reward-seeking in dominant animals, decreased heart rate, and increased PPI response. Amygdala disinhibition restored fearful response after habituation to snakes, reduced competitive reward-seeking behavior in dominant animals, and lowered heart rate. Thus, both hypoactivity and hyperactivity of the basolateral amygdala can lead to dysregulated behavior, suggesting that a narrow range of activity is necessary for normal functions.

Inhaled Lavandula angustifolia essential oil enhances extinction learning and inhibits memory updating in mice submitted to the contextual fear conditioning.

ETHNOPHARMACOLOGICAL RELEVANCE: Lavender (Lavandula angustifolia) essential oil (EO) has a long history of use in emotional illness, including anxiety disorders. Cognitive mechanisms of learning and memory play a pivotal role in the etiology and maintenance of anxiety since exposure to cues related to aversive situations induces high arousal and anticipatory anxiety. Memory become labile after its reactivation and can be modulated by reconsolidation or extinction. Inhibition of memory reconsolidation or facilitation of memory extinction may be effective in preventing or minimizing the effect of contextual cues on anticipatory anxiety. AIM OF THE STUDY: We investigated the effect of Lavandula angustifolia EO in the memory updating of conditioned contextual fear. MATERIALS AND METHODS: Adult male C57Bl6 mice were submitted to fear conditioning. Two days after conditioning the mice underwent a reactivation session in a hybrid context and were then immediately exposed to vaporized water or essential oil at concentrations of 1%, 2.5% or 5% for 3 h. Two days later, the mice were tested in the original or an altered context and their freezing behavior was measured. In addition, mice were subjected to a fear memory recovery protocol followed by a reinstatement session. RESULTS: In the contextual fear test, 1% essential oil, but not 2.5% or 5%, reduced the freezing behavior response, whereas after a reinstatement session, exposure to 1% essential oil increased the freezing behavior response. CONCLUSIONS: These results suggest that Lavandula angustifolia essential oil enhances memory extinction and, consequently, inhibits memory updating.

Discovery of a NAPE-PLD inhibitor that modulates emotional behavior in mice.

N-acylethanolamines (NAEs), which include the endocannabinoid anandamide, represent an important family of signaling lipids in the brain. The lack of chemical probes that modulate NAE biosynthesis in living systems hamper the understanding of the biological role of these lipids. Using a high-throughput screen, chemical proteomics and targeted lipidomics, we report here the discovery and characterization of LEI-401 as a CNS-active N-acylphosphatidylethanolamine phospholipase D (NAPE-PLD) inhibitor. LEI-401 reduced NAE levels in neuroblastoma cells and in the brain of freely moving mice, but not in NAPE-PLD KO cells and mice, respectively. LEI-401 activated the hypothalamus-pituitary-adrenal axis and impaired fear extinction, thereby emulating the effect of a cannabinoid CB1 receptor antagonist, which could be reversed by a fatty acid amide hydrolase inhibitor. Our findings highlight the distinctive role of NAPE-PLD in NAE biosynthesis in the brain and suggest the presence of an endogenous NAE tone controlling emotional behavior.

Hypobaric hypoxia induced fear and extinction memory impairment and effect of Ginkgo biloba in its amelioration: Behavioral, neurochemical and molecular correlates.

Regulated fear and extinction memory is essential for balanced behavioral response. Limbic brain regions are susceptible to hypobaric hypoxia (HH) and are putative target for fear extinction deficit and dysregulation. The present study aimed to examine the effect of HH and Ginkgo biloba extract (GBE) on fear and extinction memory with the underlying mechanism. Adult male Sprague-Dawley rats were evaluated for fear extinction and anxious behavior following GBE administration during HH exposure. Blood and tissue (PFC, hippocampus and amygdala) samples were collected for biochemical, morphological and molecular studies. Results revealed deficit in contextual and cued fear extinction following 3 days of HH exposure. Increased corticosterone, glutamate with decreased GABA level was found with marked pyknosis, decrease in apical dendritic length and number of functional spines. Decline in mRNA expression level of synaptic plasticity genes and immunoreactivity of BDNF, synaptophysin, PSD95, spinophilin was observed following HH exposure. GBE administration during HH exposure improved fear and extinction memory along with decline in anxious behavior. It restored corticosterone, glutamate and GABA levels with an increase in apical dendritic length and number of functional spines with a reduction in pyknosis. It also improved mRNA expression level and immunoreactivity of neurotrophic and synaptic proteins. The present study is the first which demonstrates fear extinction deficit and anxious behavior following HH exposure. GBE administration ameliorated fear and extinction memory dysregulation by restoration of neurotransmitter levels, neuronal pyknosis and synaptic connections along with improved neurotrophic and synaptic protein expressions.

Coriandrum sativum Extract Prevents Alarm Substance-Induced Fear- and Anxiety-Like Responses in Adult Zebrafish.

Anxiety disorders appear to involve distinct neurobiological mechanisms and several medications are available against this mental health problem. However, pharmacological therapeutic approaches display undesirable side effects for patients, particularly when long-term therapy is required. Some evidences have suggested that Coriandrum sativum extract (CSE) provide sedative and anxiolytic effects. We investigate if CSE could attenuate anxiety-like behaviors induced by novelty and alarm substance exposures in zebrafish. Adult zebrafish were injected with vehicle, clonazepam, or CSE (25, 50 or 100 mg/kg) and submitted to novel tank test. At the end, saline or alarm substance was added and anxiety-like responses were recorded. Twenty-four hours after, fish were submitted to the light/dark test. Novelty associated with alarm substance exposure decreased distance traveled and total time mobile in novel tank, and CSE (at 50 and 100 mg/kg) prevented these alterations similarly to clonazepam. Alarm substance reduced the time spent in white compartment (p = 0.0193 as compared with vehicle group). Clonazepam and CSE prevented this anxiogenic effect of alarm substance. CSE presents anxiolytic effects against alarm substance-induced locomotor and anxiogenic responses similarly to clonazepam. These data corroborate with the use of this plant in traditional medicine and provides a putative new pharmacological intervention for anxiety disorders.

Sodium Butyrate Reduces Brain Amyloid-ß Levels and Improves Cognitive Memory Performance in an Alzheimer's Disease Transgenic Mouse Model at an Early Disease Stage.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline and neuropathological features, including abnormal deposition of amyloid-ß (Aß) peptides, intracellular neurofibrillary tangles, and neuronal death. Identifying therapeutics which can reduce memory deficits at an early stage of the disease has the advantage of slowing or even reversing disease progression before irreversible brain damage has occurred. Consequently, in this study, we investigated the ability of the histone deacetylase inhibitor sodium butyrate (NaB) to attenuate memory deficits in the 5xFAD mouse model of AD following a 12-week feeding regimen. 5xFAD mice demonstrate a unique time course of Aß pathology, developing Aß plaques as early as 2 months. Male mice were assigned to either a control diet or a NaB-supplemented diet which was administered at either 5 mg/kg/day, or 15 mg/kg/day for 12 weeks (each group, N = 15). Supplementation commenced at an early disease stage (8-10 weeks of age). Behavioral testing (contextual and cued fear conditioning) was undertaken, and brain Aß levels measured, at the end of the 12-week intervention. NaB had profound effects on Aß levels and on associative learning and cognitive functioning. A 40% reduction in brain Aß levels and a 25% increase in fear response in both the cued and contextual testing was observed in the NaB-treated animals compared to the control group. These findings suggest that NaB warrants further investigation as a potential therapeutic agent in the treatment of cognitive deficits associated with early stages of AD.

Cannabinoids and the endocannabinoid system in anxiety, depression, and dysregulation of emotion in humans.

PURPOSE OF REVIEW: This review is to summarize most recent evidence published in the last 18 months on medical and recreational use of cannabis and cannabinoids in relation to anxiety, depression (unipolar and bipolar), and dysregulation of emotions as part of posttraumatic stress disorders (PTSD) and emotionally instable personality disorders. It also covers the investigation of endocannabinoids as potential biomarkers in these conditions. This is important with increasing medicinal use of cannabinoids and growing social tolerance towards recreational cannabis use. RECENT FINDINGS: There is some recent evidence suggesting cannabinoids, cannabidiol or cannabidiol-enriched cannabis preparations have anxiolytic properties. In addition, depression may be worsened by cannabis use, however, randomized controlled trials (RCT) are lacking. New evidence also suggests that cannabidiol or cannabidiol-enriched cannabis use for PTSD and emotion regulation can induce hyporesponse to fear and stress. Further, several lines of evidence point to the endocannabinoid system as a key player in some of the reviewed disorders, in particular anxiety and PTSD. SUMMARY: The most recent evidence for a therapeutic use of cannabinoids in the reviewed conditions is weak and lacking well designed RCTs. However, there is some indication of the role of the endocannabinoid system in these conditions that warrant further studies.

Alpha2-adrenergic dysregulation in congenic DxH recombinant inbred mice selectively bred for a high fear-sensitized (H-FSS) startle response.

Patients with anxiety disorders and posttraumatic stress disorder (PTSD) exhibit exaggerated fear responses and noradrenergic dysregulation. Fear-related responses to α2-adrenergic challenge were therefore studied in DxH C3H/HeJ-like recombinant inbred (C3HLRI) mice, which are a DBA/2J-congenic strain selectively bred for a high fear-sensitized startle (H-FSS). C3HLRI mice showed an enhanced acoustic startle response and immobility in the forced swim test compared to DBA/2J controls. The α2-adrenoceptor antagonist yohimbine (Yoh; 5.0 mg/kg) induced an anxiogenic and the α2-adrenoceptor agonist clonidine (Clon; 0.1 mg/kg) an anxiolytic effect in the open field (OF) in C3HLRI but not DBA/2J mice. In auditory fear-conditioning, Yoh (5.0 mg/kg)-treated C3HLRI mice showed higher freezing during fear recall and extinction learning than DBA/2J mice, and a higher ceiling for the Yoh-induced deficit in fear extinction. No strain differences were observed in exploration-related anxiety/spatial learning or the Clon-induced (0.1 mg/kg) corticosterone surge. A global analysis of the behavioral profile of the two mouse strains based on observed and expected numbers of significant behavioral outcomes indicated that C3HLRI mice showed significantly more often fear- and stress-related PTSD-like behaviors than DBA/2J controls. The analysis of the robustness of significant outcomes based on false discovery rate (FDR) thresholds confirmed significant differences for the strain-Yoh-interactions in the OF center and periphery, the Yoh-induced general extinction deficit, strain differences in conditioned fear levels, and at the dose of 5.0 mg/kg for the Yoh-induced ceiling in freezing levels among others. The current findings are consistent with previous observations showing alterations in the central noradrenergic system of C3HLRI mice (Browne et al., 2014, Stress 17:471-83). Based on their behavioral profile and response to α2-adrenergic stimulation, C3HLRI mice are a valuable genetic model for studying adrenergic mechanisms of anxiety disorders and potentially also of PTSD.

Mapping the estrous cycle to context-specific extinction memory.

In Pavlovian renewal paradigms, intact female rats have previously failed to exhibit renewal of appetitive behavior after extinction. However, when treated with exogenous estradiol, female rats exhibit robust renewal behavior. The current study aims to investigate whether the estrous cycle can influence renewal of appetitive behaviors and activity in brain areas known to support the renewal effect. We further aimed to examine whether the estrous cycle would similarly affect renewal of two different types of appetitive behaviors. We first establish that rats in the proestrous stage of the estrous cycle during extinction exhibit elevated renewal behavior compared with rats in either metestrous/diestrous stages, and only rats in proestrus during extinction training (but not during the renewal test) exhibit elevated renewal behavior. Furthermore, we show that this estrous cycle dependent effect on renewal only applies to the conditioned approach behavior toward the food delivery site but not the conditioned approach behavior toward the light cue associated with food delivery. Finally, we examined FOS activity within the prelimbic and infralimbic areas of the medial prefrontal cortex, the dorsal and ventral hippocampal formation, the paraventricular nucleus of the thalamus, the nucleus accumbens, and areas of the amygdala. Particularly in the hippocampus and amygdala, FOS expression which corresponded to the behavioral differences between groups was observed. Results from this study suggest that context information processing may vary as a function of endogenous female hormones across the gonadal hormone cycle and that encoding and retrieval of this information is accomplished in a state-specific manner. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Vitamin A deficiency impairs contextual fear memory in rats: Abnormalities in the glucocorticoid pathway.

Vitamin A and its active metabolite, retinoic acid (RA), play a key role in the maintenance of cognitive functions in the adult brain. Depletion of RA using the vitamin A deficiency (VAD) model in Wistar rats leads to spatial memory deficits in relation to elevated intrahippocampal basal corticosterone (CORT) levels and increased hippocampal 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) activity. All of these effects are normalised by vitamin A supplementation. However, it is unknown whether vitamin A status also modulates contextual fear conditioning (CFC) in a glucocorticoid-associated fear memory task dependent on the functional integrity of the hippocampus. In the present study, we investigated the impact of VAD and vitamin A supplementation in adult male rats on fear memory processing, plasma CORT levels, hippocampal retinoid receptors and 11ß-HSD1 expression following a novelty-induced stress. We also examined whether vitamin A supplementation or a single injection of UE2316, a selective 11ß-HSD1 inhibitor, known to modulate local glucocorticoid levels, had any beneficial effects on contextual fear memory and biochemical parameters in VAD rats. We provide evidence that VAD rats exhibit a decreased fear conditioning response during training with a poor contextual fear memory 24 hours later. These VAD-induced cognitive impairments are associated with elevated plasma CORT levels under basal conditions, as well as following a stressful event, with saturated CORT release, altered hippocampal retinoid receptors and 11ß-HSD1 expression. Vitamin A supplementation normalises VAD-induced fear conditioning training deficits and all biochemical effects, although it cannot prevent fear memory deficits. Moreover, a single injection of UE2316 not only impairs contextual fear memory, but also reduces plasma CORT levels, regardless of the vitamin A status and decreases slightly hippocampal 11ß-HSD1 activity in VAD rats following stress. The present study highlights the importance of vitamin A status with respect to modulating fear memory conditioning in relation to plasma CORT levels and hippocampal 11ß-HSD1.

[Effects of Dacryodes edulis fruit oil on anxiety symptoms and cognitive performance in mice, after prolonged administration]. / Effets de l'huile des fruits de Dacryodes edulis sur les symptômes de l'anxiété et les performances cognitives chez la souris, après administration prolongée.

OBJECTIVE: To study the effects of prolonged administration of Dacryodes edulis (G. Don) H.J. Lam (HDE) fruit oil on the symptoms of anxiety and cognitive performance in mice. METHODS: Anxiolytic activity and effects of HDE (5 and 10 ml/kg) on cognitive performance were evaluated in male mice after oral administration for 45 days. Anxiolytic effects were investigated in open field test, elevated plus Maze and hole board test. The Morris Water Maze test was used to evaluate cognitive performance in mice. Efficacy of HDE (5 and 10 ml/kg) was compared with that of fluoxetine (2 mg/kg p.o). RESULTS: HDE decreases the total distance traveled, significantly increases the number of adjustments and the number of entries in the central area of open field. In the elevated cross labyrinth test, HDE increases the number of entries and the time spent in the open arms. HDE significantly increases the number of head insertion into the holes. In the Morris Water Maze test, HDE reduces latency before finding the platform and increases the time spent in the target quadrant. CONCLUSION: The results confirm anxiolytic effects and improved cognitive performance after prolonged oral administration of HDE in rodents.

Cannabidiol (CBD) reduces anxiety-related behavior in mice via an FMRP-independent mechanism.

Fragile X Syndrome is a neurodevelopmental disorder which affects intellectual, social and physical development due to mutation of the Fragile X mental retardation 1 (FMR1) gene. The resultant loss of Fragile X mental retardation protein can be modelled by Fmr1 gene knockout (KO) in mice. The current study investigated the behavioural effects of cannabidiol (CBD; a non-psychoactive phytocannabinoid) in male Fmr1 KO mice as a preclinical model for therapeutic discovery. Vehicle or CBD (5 or 20 mg/kg body weight) was administered to adult Fmr1 KO and wild type-like (WT) mice before they were tested in behavioural tasks including: open field (OF), elevated plus maze (EPM), spontaneous alternation, social preference, and passive avoidance tasks. Fmr1 KO mice were hyperlocomotive and hyperexplorative and habituated more slowly to a novel environment compared to control animals. Furthermore, Fmr1 KO mice showed fewer anxiety-related behaviours across tests. Effects of CBD were subtle and limited to the EPM, where CBD decreased the anxiety response of all mice tested. Acute CBD had no impact on locomotion or anxiety-related parameters in the OF. Cognitive performance of Fmr1 KO mice was equivalent to controls and not affected by CBD treatment. Brain concentrations of CBD were equivalent between genotypes, but in animals sacrificed 90 min post-administration, decreased plasma CBD in Fmr1 KO mice compared to WT suggested more rapid clearance of CBD by transgenic animals. Overall, acute CBD at the doses chosen did not selectively normalize behavioural abnormalities in Fmr1 KO mice, but reduced anxiety-like behaviour in both Fmr1 KO and WT mice.

Saikosaponin­D improves fear memory deficits in ovariectomized rats via the action of estrogen receptor­α in the hippocampus.

Saikosaponin­D (SSD), which is the main bioactive component in the traditional Chinese medicine Chai Hu (Bupleurum falcatum L), possesses estrogen­like properties and is widely used in treating estrogen­related neurological disorders. The current study aimed to investigate the protective effects of SSD on the fear memory deficit in ovariectomized (OVX) rats and the potential underlying mechanism. SSD treatment significantly prolonged freezing time in OVX rats in a manner similar to that of estradiol (E2), whereas this effect was markedly suppressed by co­administration of ICI182780, a non­selective estrogen receptor (ER) inhibitor. The expression of ERα in the hippocampus of OVX rats was significantly elevated by SSD; however, Erß expression and E2 synthesis were not markedly affected by SSD treatment. Collectively, this study demonstrated that SSD­mediated fear memory improvement in OVX rats may be attributed not to E2 levels or ERß activity, but to ERα activation in the hippocampus.

Conditioned stimulus presentations alter anxiety level in fear-conditioned mice.

It is generally believed that fear is rapidly triggered by a distinct cue while anxiety onset is less precise and not associated with a distinct cue. Although it has been claimed that both processes can be measured with certain independence of each other, it is unclear how exactly they differ. In this study, we measured anxiety in mice that received discriminative fear conditioning using behavioral, heart rate and calcium (Ca2+) responses in the ventral hippocampal CA1 (vCA1) neurons. We found that the occurrence of fear significantly interfered with anxiety measurements under various conditions. Diazepam reduced basal anxiety level but had no effect during the presentation of conditioned stimulus (CS). Injection of an inhibitory peptide of PKMzeta (ZIP) into the basolateral amygdala almost entirely abolished CS-triggered fear expression and reduced anxiety to basal level. Heart rate measures suggested a small reduction in anxiety during CS-. Calcium responses in the lateral hypothalamus-projecting vCA1 neurons showed a steady decay during CS suggesting a reduced anxiety. Thus, under our experimental conditions, CS presentations likely reduce anxiety level in the fear-conditioned mice.

MLC901 during sleep deprivation rescues fear memory disruption in rats.

Several lines of evidence suggest that sleep deprivation disrupts cognitive and emotional abilities and changes the expression of distinctive categories of genes in the brain. In the present study, saline- or MLC901 (a traditional Chinese medicine)-treated male Wistar rats were first submitted to a modified water box (for 24-h sleep deprivation) and then trained in contextual and tone fear conditioning tasks with the purpose to evaluate the effect of MLC901 during sleep deprivation on fear memory retention. Hippocampal mRNA measurement was performed by reverse transcription-polymerase chain reaction (RT-PCR). We found that the exposure of rats to 24 h of sleep deprivation impaired contextual and tone fear memory retention, while administration of MLC901 (0.2, 0.4, and 0.8 mg/kg, once/12 h; i.p.) during sleep deprivation abolished memory deficits. Meanwhile, different doses of MLC901 alone had no effect on performance in both tasks. We observed that MLC901 increased the expression levels of pro-apoptotic BAD, anti-apoptotic Bcl-xL, and Tfam as an index of mitochondrial biogenesis compared to sleep-deprived rats, while MLC901 during sleep deprivation increased BAX, BAD, and Bcl-xL compared to the control group. Sleep deprivation decreased BAX and Tfam, by itself. MLC901 only decreased BAX and Tfam and increased BAD level compared to the non-sleep-deprived control group. It is suggested that MLC901 might be a therapeutic option for memory impairment during sleep deprivation.