Anxiogenic Effects Research Articles

6,5-Fused Ring, C2-Salvinorin Ester, Dual Kappa and Mu Opioid Receptor Agonists as Analgesics Devoid of Anxiogenic Effects.

Current common analgesics are mediated through the mu or kappa opioid receptor agonism. Unfortunately, selective mu or kappa receptor agonists often cause harmful side effects. However, ligands exhibiting dual agonism to the opioid receptors, such as to mu and kappa, or to mu and delta, have been suggested to temper undesirable adverse effects while retaining analgesic activity. Herein we report an introduction of various 6,5-fused rings to C2 of the salvinorin scaffold via an ester linker. In vitro studies showed that many of these compounds have dual agonism on kappa and mu opioid receptors. In vivo studies on the lead dual kappa and mu opioid receptor agonist demonstrated supraspinal thermal analgesic activity while avoiding anxiogenic effects in male mice, thus providing further strong evidence in support of the therapeutic advantages of dual opioid receptor agonists over selective opioid receptor agonists.

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.

Sex- and age- dependent effect of pre-gestational chronic stress and mirtazapine treatment on neurobehavioral development of Wistar rat offspring.

Hormonal fluctuations, such as the perinatal period, may increase susceptibility of women to depression, which in turn exert a negative impact on child’s neurodevelopment, becoming a risk factor in development of neuropsychiatric disorders. Moreover, the use of antidepressants during this critical period presents a serious health concern for both the mother and the child, due to the consequences of treatment in terms of the reliability and safety for the proper neurodevelopment of the organism being not well known. Atypical antidepressants, such as mirtazapine, that targets both serotonergic and noradrenergic systems in the central nervous system (CNS), represent a novel focus of research due to its unique pharmacological profile. The aim of this work was to study the effects of maternal depression and/or perinatal antidepressant mirtazapine treatment on the neurobehavioral development of the offspring. Pre-gestationally chronically stressed or non-stressed Wistar rat dams were treated with either mirtazapine (10 mg/kg/day) or vehicle during pregnancy and lactation followed by analysis of offspring’s behavior at juvenile and adolescent age. We found mirtazapine induced significant alterations of nursing behavior. In offspring, pregestational stress (PS) had an anxiogenic effect on adolescent males (p≤0.05) and increased their active behavior in forced swim test (p≤0.01). Interaction between pregestational stress and mirtazapine treatment variously induced anxiolytic changes of juvenile (p≤0.05) and adolescent (p≤0.05) females and impairment of spatial memory (p≤0.01) in adolescent females as well. Hippocampal density of synaptophysin, pre-synaptic protein marker, was decreased mainly by mirtazapine treatment. In conclusion, our results show mirtazapine induced significant alterations in maternal behavior and several sex- and age-dependent changes in neurobehavioral development of offspring caused by both prenatal mirtazapine treatment and/or chronic pregestational stress.

A Distinct Metabolically Defined Central Nucleus Circuit Bidirectionally Controls Anxiety-Related Behaviors.

Anxiety disorders are debilitating psychiatric diseases that affect ∼16% of the world's population. Although it has been proposed that the central nucleus of the amygdala (CeA) plays a role in anxiety, the molecular and circuit mechanisms through which CeA neurons modulate anxiety-related behaviors are largely uncharacterized. Soluble epoxide hydrolase (sEH) is a key enzyme in the metabolism of polyunsaturated fatty acids (PUFAs), and has been shown to play a role in psychiatric disorders. Here, we reported that sEH was enriched in neurons in the CeA and regulated anxiety-related behaviors in adult male mice. Deletion of sEH in CeA neurons but not astrocytes induced anxiety-like behaviors. Mechanistic studies indicated that sEH was required for maintaining the the excitability of sEH positive neurons (sEHCeA neurons) in the CeA. Using chemogenetic manipulations, we found that sEHCeA neurons bidirectionally regulated anxiety-related behaviors. Notably, we identified that sEHCeA neurons directly projected to the bed nucleus of the stria terminalis (BNST; sEHCeA-BNST). Optogenetic activation and inhibition of the sEHCeA-BNST pathway produced anxiolytic and anxiogenic effects, respectively. In summary, our studies reveal a set of molecular and circuit mechanisms of sEHCeA neurons underlying anxiety.SIGNIFICANCE STATEMENT Soluble epoxide hydrolase (sEH), a key enzyme that catalyzes the degradation of EETs, is shown to play a key role in mood disorders. It is well known that sEH is mostly localized in astrocytes in the prefrontal cortex and regulates depressive-like behaviors. Notably, sEH is also expressed in central nucleus of the amygdala (CeA) neurons. While the CeA has been studied for its role in the regulation of anxiety, the molecular and circuit mechanism is quite complex. In the present study, we explored a previously unknown cellular and circuitry mechanism that guides sEHCeA neurons response to anxiety. Our findings reveal a critical role of sEH in the CeA, sEHCeA neurons and CeA-bed nucleus of the stria terminalis (BNST) pathway in regulation of anxiety-related behaviors.

Diazepam binding inhibitor positively modulates α5β3 GABA-A receptors

Benzodiazepines (BZDs) exert their antiepileptic, anxiogenic, and somnogenic effects by binding to GABA-A receptors (GABARs). GABARs are inhibitory pentameric ligand-gated channels commonly formed by 2α, 2β and 1γ subunits, though some GABARs are formed by only α and β subunits. The high-affinity binding site for BZDs is located in the extracellular domain between the α and γ subunits and is absent in αβ receptors.

Flavonoid-Rich Fraction from Croton blanchetianus (Euphorbiaceae) Leaves Exerts Peripheral and Central Analgesic Effects by Acting via the Opioid and Cholinergic Systems.

The ethanolic extract from Croton blanchetianus leaves has been shown to have antinociceptive activity in mice. Here, we investigated the antinociceptive activity of an ethyl acetate fraction (EAF) from this extract in mice and the possible pathways involved in the analgesic effect. Adverse effects on behavior and motor coordination were also evaluated. The EAF was characterized by liquid chromatography coupled with mass spectrometry and evaluated (12.5, 25, and 50 mg/kg per os) in the acetic acid-induced abdominal writhing, formalin, hot plate, and tail immersion assays. Naloxone, atropine, glibenclamide, prazosin, or yohimbine was pre-administered to mice to investigate the involved pathways in the formalin test. The open-field, rotarod, and elevated plus-maze tests were used to assess behavior and locomotion. The main components of the EAF were quercetin-3-O-(2-rhamnosyl) rutinoside, hyperoside, quercetin rutinoside pentoside, and quercetin hexoside deoxyhexoside. EAF showed antinociceptive effects in all models and was effective against both neurogenic and inflammatory pain. The reversion of the effects in the formalin test by naloxone and atropine revealed that the EAF acted via the opioid and cholinergic systems. In the open-field test, the behavior of the animals treated with the EAF was like that of control, except at the highest dose, when hypnosis, eyelid ptosis, decreased walking, hygiene, and rearing behaviors were observed. No muscle relaxant effect was observed, but an anxiogenic effect was observed at all doses. This study provides new scientific evidence on the pharmacological properties of C. blanchetianus leaves and their potential for the development of phytomedicines with analgesic properties.

ANXIOGENIC EFFECT OF AN ATYPICAL ANTIPSYCHOTIC, OLANZAPINE IN PRE-CLINICAL MODELS

Introduction: Atypical antipsychotics, such as olanzapine, act on multiple neurotransmitter pathways and produce complex central nervous system effects. Pre-clinical and clinical studies conducted in the past, to study their effects on anxiety, have come up with confusing and contradictory observations. Some studies have even indicated anxiogenic effect of these novel drugs. These observations are significant, because anxiety symptoms are known to be present in about 65% of schizophrenia patients. Any possible anxiogenic effect by one of the extensively used antipsychotic can have adverse impact on these patients. Hence, this study was undertaken with the aim of evaluating olanzapine for its effects on anxiety, in preclinical models. Methods: Rats of either sex weighing between 150 and 300 g were placed into three groups of six each. For 10 days, oral doses of the test drug (olanzapine 2 mg/kg), the control drug (distilled water), and the standard drug (diazepam 1 mg/kg) were given. The animals were taken for the elevated plus maze (EPM) and light dark arena (LDA) screening tests on the 10th day, 1 h after the compounds were administered. Results: Olanzapine treatment significantly reduced the amount of time that animals spent in open arms (p<0.05) of the EPM, and highly lighted compartments (p<0.05) of LDA, as compared to animals receiving control treatment, showing a significant anxiogenic impact. Conclusions: Olanzapine has exhibited potential to produce anxiogenic effect in preclinical models. Hence, it is suggested to use olanzapine with caution in patients of schizophrenia with anxiety symptoms.

Lysergic Acid Diethylamide Produces Anxiogenic Effects in the Rat Light/Dark Test and Elevated Plus Maze

Recent clinical trials indicate favorable therapeutic outcomes of psychedelic-assisted psychotherapy for anxiety and treatment-resistant depression. Whereas the neurobiological systems underlying these effects are not well understood, animal behavioral models can serve to investigate these mechanisms. For the current study, we implemented 2 rodent models predictive of anxiolytic drug effects, a light/dark test and an elevated plus maze (EPM), to investigate the acute and subchronic effects of LSD, respectively. Forty-eight, adult male Sprague-Dawley rats were randomly assigned to receive LSD (0.00, 0.02, 0.04, 0.08 mg/kg) and assessed in the light/dark test 15 min after the first injection. Five additional injections were given, once every 48 hours, after which rats were assessed in the EPM either 48 (n = 24) or 72 hours (n = 24) after the last injection. A dose-dependent and statistically significant decrease was observed in number of entries into, F(3, 44) = 12.79, p < .001,η2 = .47, and time spent, F(3, 48) = 14.15, p < .001, ηp2 = .47, in the brightly lit compartment. In the EPM, closed arm entries, F(1, 17) = 28.85, p < .001, ηp2 =.36, and time spent in closed arms, F(1, 17) = 20.14, p < .001, ηp2=.99, were significantly higher compared to entries or time in open arms by rats assessed 48 hours after the last LSD injection, but not by rats tested 72 hours after the last injection. These findings indicate that acute and subchronic LSD treatment produce transient anxiogenic effects. In consideration of positive therapeutic outcomes of psychedelic-assisted psychotherapy, alternative preclinical models may be warranted to discern the mechanisms underlying the putative therapeutic effects of serotonergic hallucinogens.

Behavioral, neurochemical, and neuroimmune changes associated with social buffering and stress contagion

Social buffering can provide protective effects on stress responses and their subsequent negative health outcomes. Although social buffering is beneficial for the recipient, it can also have anxiogenic effects on the provider of the social buffering – a phenomena referred to as stress contagion. Social buffering and stress contagion usually occur together, but they have traditionally been studied independently, thus limiting our understanding of this dyadic social interaction. In the present study, we examined the effects of preventative social buffering and stress contagion in socially monogamous prairie voles (Microtus ochrogaster). We tested the hypothesis that this dynamic social interaction is associated with coordinated alterations in behaviors, neurochemical activation, and neuroimmune responses. To do so, adult male prairie voles were stressed via an acute immobilization restraint tube (IMO) either alone (Alone) or with their previously pair-bonded female partner (Partner) in the cage for 1 h. In contrast, females were placed in a cage containing either an empty IMO tube (Empty) or one that contained their pair-bonded male (Partner). Anxiety-like behavior was tested on the elevated plus maze (EPM) following the 60-mins test and brain sections were processed for neurochemical/neuroimmune marker labeling for all subjects. Our data indicate that females in the Partner group were in contact with and sniffed the IMO tube more, showed fewer anxiety-like behaviors, and had a higher level of oxytocin expression in the paraventricular nucleus of the hypothalamus (PVN) compared to the Empty group females. Males in the Partner group had lower levels of anxiety-like behavior during the EPM test, greater activation of corticotropin-releasing hormone expressing neurons in the PVN, lower activation of serotonin neurons in the dorsal raphe, and lower levels of microgliosis in the nucleus accumbens. Taken together, these data suggest brain region- and neurochemical-specific alterations as well as neuroinflammatory changes that may be involved in the regulation of social buffering and stress contagion behaviors.

Development of a mafedine lyophilizate for parenteral use

Introduction. Cerebrovascular disease (CVD) is the most important medical and social problem of modern neurology because they have the highest rates of morbidity, mortality and disablement in the population. The growing incidence of CVD as a result of an aging population worldwide requires the emergent development of therapeutics, diagnostic and preventive tools. However, the development of drugs for the treatment of brain diseases has limitations due to the presence of the blood-brain barrier, which protects the brain against most molecules from the bloodstream entering the central nervous system. At the St. Petersburg State Chemical Pharmaceutical University of the Ministry of Health of Russia the alpha-2 adrenergic agonist mafedine was synthesized, which has mild psychostimulant and anxiogenic effects and which may be used in the treatment of traumatic brain injury as a neuroprotective agent.Aim. The development of a dosage form of mafedine in order to improve its penetration into the central nervous system.Materials and methods. Mafedine (pharmaceutical substance) [6-oxo-1-phenyl-2-(phenylamino)-1,6-dihydropyrimidin-4-olate sodium] (St. Petersburg State Chemical-Pharmaceutical University of the Ministry of Health of Russia); lecithin, span-60, Tween-80, Poloxamer 188, mannitol, vitamin E, ascorbic acid, methylene chloride, dimethyl sulfoxide, acetonitrile, trifluoroacetic acid. The fine emulsion of mafedine was obtained by ultrasound. The dosage form of mafedine was obtained by freeze drying. Residual solvents were determined by gas chromatography. Quantitative analysis of mafedine was performed by high-performance liquid chromatography. Particle size and zeta potential of emulsion were determined on a Zetasizer Nano ZS.Results and discussion. Lyophilizate of mafedine was obtained and presenting as a light yellow porous, odorless tablet. The average mass of dry tablet was (0,17 ± 0,01) g with mafedine content is (26 ± 1) mg. The water content in the lyophilizate was 3,85 %. The quantity of methylene chloride in the lyophilizate correspond to the requirements for residual solvent content. The reconstitution time of lyophilizate into a primary emulsion was 3–5 seconds. The reconstituted dispersion was yellow, odorless, and did not break within 2 days during storage. The pH of the reconstituted emulsion was 7,34. The average particle size was (164,7 ± 6,4) nm, the zeta potential was –32 mV.Conclusion. The developed dosage form is stable according to its physicochemical and pharmaceutical characteristics and is suitable for experimental study on models as a neuroprotective and neurorehabilitation agent.

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.

Garcinia cambogia extract alters anxiety, sociability, and dopamine turnover in male Swiss albino mice

Obesity is a global concern, closely allied with somatic and psychosomatic disorders. Herbal drugs are available in modern medicine to treat obesity. Garcinia camobogia being used by so many people trying to lose weight produces various systemic side effects. The study was conducted to assess its effect on anxiety, sociability, and dopamine turnover in male mice. Twenty-one male Swiss albino mice of either were divided into three groups with seven mice in each group. Control group was given distilled water (0.5 ml p.o.) and the other two groups received Garcinia cambogia extract at two different doses, a low and a higher dose (100 mg/kg and 500 mg/kg. p.o.) Each animal received a single oral dose daily, which was administered using an oral gavage for fourteen consecutive days. Effect of test drugs on anxiety was evaluated using open field test. Sociability and social novelty were evaluated using three chambers test. Results (mean ± SD) were analyzed using one-way ANOVA test followed by Tukey’s test. Garcinia cambogia extract significantly increased the time spent in the corners in the open field test, significantly reduced sociability and social novelty in the three-chamber test, significantly reduced dopamine turnover in the brain with a significant decrease in dopamine metabolite homovanillic acid (HVA) and increased D2 receptor expression in ventral tegmental area. Garcinia cambogia extract have significant anxiogenic effect along with reduced sociability and social novelty in male mice. Moreover, these effects could be related to the altered dopamine turnover and D2 receptor expression in mice brain.Article HighlightsChronic used of alcoholic extract of Garcinia campbogia lead to a significant increase in anxiety that was manifested by the reduced time in the center zone and increased immobility in the open field test.Garcinia camobogia chronic administration has a profound impact on sociability and social novelty with a significant decrease in both behavioral patterns compared to the control group.These effects could be attributed to the noticed change in the dopamine turnover in the brain with a significant decrease in dopamine metabolite (HVA) and an upward expression of D2 receptors in return.

Effects of Terazosin, Silodosin and Alfuzosin on Depression and Anxiety in Mice

Aims: Benign prostatic hyperplasia (BPH) is common urological disease, is characterized by lower urinary tract syndrome, usually associated with sexual dysfunctions. The aim of present study is to investigate the effects of terazosin, silodosin and alfuzosin which are the main treatment options for BPH on depression and anxiety to understand whether these drugs may be effective in BPH caused mood disorders.
 Study Design: All the drugs were given intraperitoneally (i.p.) in a volume of 0.1 ml per 10 g body weight of mice. Drugs were given 30 min before the experiment. We investigated the effects of terazosin, silodosin and alfuzosin on depression and anxiety, in mice.
 Place and Duration of Study: Sample: Department of Pharmacology and Department of Urology, Sakarya University, Animal Research Center, between June 2019 and September 2020.
 Methodology: Here, we examined the effects of terazosin (0.5, 1, 2 mg/kg), silodosin silodosin (1, 3, 10 mg/kg) and alfuzosin (3, 6 and 9 mg/kg) on depression and anxiety by using forced swimming test and elevated plus maze test, respectively, in mice (n:96). Additionally, the locomotor activity was evaluated by open field test.
 Results: All doses of terazosin, alfuzosin and silodosin significantly increased immobility time, compared to saline group. Silodosin and alfuzosin prolonged the time spent in open arms but terazosin decreased the time spent in open arms compared to saline group. Terazosin, silodosin (1 and 3 mg/kg) and alfuzosin (3 and 6 mg/kg) did not have any effect on the number of entries into the open arms while silodosin (10 mg/kg) and alfuzosin (9 mg/kg) increased the number of entries into open arms.
 Conclusion: We found that silodosin and alfuzosin had antidepressant and anxiolytic-like effects, while terazosin had depressant and anxiogenic effects. Patients with BPH who need antidepressant and anxiolytic treatment can be treated with a single drug instead of multiple medications.

TNF signaling pathway-mediated microglial activation in the PFC underlies acute paradoxical sleep deprivation-induced anxiety-like behaviors in mice

Acute sleep deprivation is a common condition in modern life and increases anxiety symptoms in healthy individuals. The neuroinflammatory response induced by microglial activation could be an important contributing factor, but its underlying molecular mechanisms are still unclear. In the present study, we first found that acute paradoxical sleep deprivation (PSD) induced by the modified multiple platform method (MMPM) for 6 h led to anxiety-like behavior in mice, as verified by the open field test, elevated plus maze test, light–dark box test, and marble burying test. In addition, bioinformatic analysis suggested an important relationship between acute sleep deprivation and brain inflammatory signaling pathways. Key genes enriched in the TNF signaling pathway were confirmed to be altered during acute PSD by qPCR and Western blot analyses, including the upregulation of the prostaglandin-endoperoxide synthase 2 (Ptgs2) and suppressor of cytokine signaling 3 protein (Socs3) genes and the downregulation of the cysteine-aspartic acid protease 3 (Casp3) gene. Furthermore, we found that microglial cells in the prefrontal cortex (PFC) were activated with significant branch structure changes and that the cell body area was increased in the PSD model. Finally, we found that minocycline, a tetracycline with anti-inflammatory properties, may ameliorate the anxiogenic effect and microglial activation. Our study reveals significant correlations of anxiety-like behavior, microglial activation, and inflammation during acute PSD.

High and fluctuating levels of ovarian hormones induce an anxiogenic effect, which can be modulated under stress conditions: Evidence from an assisted reproductive rodent model

Elevated levels of endogenous ovarian hormones are conditions commonly experienced by women undergoing assisted reproductive technologies (ART). Additionally, infertility-associated stress and treatment routines are factors that together may have a highly negative impact on female emotionality, which can be aggravated when several cycles of ART are needed to attempt pregnancy. This study aimed to investigate the effect of high and fluctuating levels of gonadal hormones induced by repeated ovarian stimulation on the stress response in rodents. To mimic the context of ART, female rats were exposed to an unpredictable chronic mild stress (UCMS) paradigm for four weeks. During this time, three cycles of ovarian stimulation (superovulation) (150 IU/Kg of PMSG and 75 IU/Kg of hCG) were applied, with intervals of two estrous cycles between them. The rats were distributed into four groups: Repeated Superovulation/UCMS; Repeated Superovulation/No Stress; Saline/UCMS; and Saline/No Stress. Anxiety-like and depressive-like behaviors were evaluated in a light-dark transition box and by splash test, respectively. Corticosterone, estradiol, progesterone, and biometric parameters were assessed. Data were analyzed using a two-way Generalized Linear Model (GzLM). Our results showed that repeated ovarian stimulation exerts by itself an expressive anxiogenic effect. Surprisingly, when high and fluctuating levels of ovarian hormones were combined with chronic stress, anxiety-like behavior was no longer observed, and a depressive-like state was not detected. Our findings suggest that females subjected to emotional overload induced by repeated ovarian stimulation and chronic stress seem to trigger the elaboration of adaptive coping strategies.

Synergistic effect between quinpirole and L-NAME as well as sulpiride and L-arginine on the modulation of anxiety and memory processes in the 6-OHDA mouse model of Parkinson's disease: An isobologram analysis

We evaluated interactions between dopamine D2 receptor and nitric oxide (NO) actions on the regulation of anxiety and memory in the 6-hydroxydopamine (6-OHDA) mouse model of Parkinson's disease (PD). A unilateral guide cannula was stereotaxically implanted over the right striatum. Elevated plus-maze test (EPM) test–retest protocol was employed to evaluate anxiety and memory in mice. The results revealed that injection of L-NAME (9 mg/kg) induced anxiolytic and amnesic effects, while L-arginine (9 mg/kg) produced anxiogenic and memory-improvement effects in the 6-OHDA mouse model of PD. Administration of sulpiride (20 mg/kg) induced anxiogenic and memory-improvement effects, whereas quinpirole (20 mg/kg) caused anxiolytic and amnesic effects in PD mice. Co-injection of sulpiride (5, 10, and 20 mg/kg) plus L-NAME (3 mg/kg) induced anxiolytic and amnesic effects. Co-injection of sulpiride (20 mg/kg) plus L-arginine (3 mg/kg) induced anxiogenic and memory-improvement effects. Co-administrations of quinpirole (20 mg/kg) and L-NAME (3 mg/kg) induced anxiolytic effect, but co-administration of quinpirole (20 mg/kg) plus L-arginine (3 mg/kg) caused anxiogenic and memory-improvement effects. The isobologram analysis revealed that there is a synergistic effect between sulpiride and L-arginine as well as quinpirole and L-NAME upon induction of anxiogenic and anxiolytic effects, respectively in PD mice. Our results suggested: (1) NO and dopamine D2 receptor mechanisms affect anxiety and memory in PD mice; (2) L-NAME reversed anxiogenic and memory-improvement effect induced by sulpiride; (3) Anxiolytic and amnesic effects induced by quinpirole reversed by L-arginine; (4) There is a synergistic effect between dopamine D2 receptor and NO systems on the modulation of anxiety and memory.

Acute effects of oral delta-9-tetrahydrocannabinol (THC) on autonomic cardiac activity and their relation to subjective and anxiogenic effects.

Cannabis is the most commonly used psychotropic drug in the United States, after alcohol. Despite its apparent sedative and calming effects, cannabis and its main psychoactive constituent, ∆9 -tetrahydrocannabinol (THC) can produce serious adverse effects including tachycardia and anxiety. These effects can be especially pronounced in women, who remain underrepresented in clinical cannabinoid research. The present study is one of the first to characterize the effects of single doses of oral THC on autonomic nervous system function in healthy adult women. Occasional female cannabis users participated in three laboratory sessions in which they received oral THC (7.5 and 15mg) and placebo. Autonomic measures included heart rate (HR), blood pressure (BP), pre-ejection period (PEP) a measure of cardiac sympathetic functioning, and high frequency heart rate variability (HF-HRV) a measure of parasympathetic cardiac control. Autonomic responses were examined in relation to subjective drug effects. THC dose-dependently increased HR, decreased HF-HRV, and increased ratings of feeling a drug effect, cannabis-like intoxication, and anxiety. Although the drug did not significantly affect BP or PEP, HR was negatively related to both PEP and HF-HRV. HF-HRV, the measure of parasympathetic activity, was significantly negatively related to subjective measures of cannabis intoxication (but not anxiety) at the 15mg dose only. PEP was not significantly related to any subjective measure. These results extend our knowledge of the autonomic effects of THC in relation to subjective drug experience. This and future studies will help us to understand risk factors related to cannabis use.

Specific sub-regions of the longitudinal axis of the hippocampus mediate behavioural responses to chronic psychosocial stress

Accumulating evidence suggests that the hippocampus is functionally segregated along its longitudinal axis into a dorsal (dHi) sub-region, shown to play roles in learning & memory and a ventral sub-region (vHi), involved in anxiety and antidepressant action. Recent studies also suggest that the intermediate hippocampus (iHi) might be functionally independent, but it has received relatively little attention. We recently found that the iHi is involved in the behavioural effects of chronic treatment with the antidepressant fluoxetine in the forced swim test. However, the roles of specific sub-regions of the longitudinal axis of the hippocampus in the response to chronic stress, a risk factor for depression and anxiety disorders, has not yet been investigated. Therefore, we used excitotoxic lesions of the dHi, iHi or vHi in male C57BL/6 mice to investigate the roles of these sub-regions in the behavioural (anxiety, anhedonia, depression) responses to chronic psychosocial stress. We found that stress-induced increases in anxiety in the novelty-induced hypophagia and marble burying tests were prevented by each of the sub-region lesions, but only vHi lesions attenuated stress-induced anxiety in the open field test. Stress-induced anhedonia was reduced in dHi- and vHi- but not iHi-lesioned mice. In stressed mice, only vHi lesions induced an antidepressant-like effect in the forced swim test and prolonged latency to adopt a defeat posture during social defeat, suggesting an increase in stress resilience. Interestingly, iHi lesions increased stress-induced social avoidance in the social interaction test. In summary, we found that all hippocampal sub-regions are involved in the anxiogenic effects of chronic stress but that the iHi plays a predominant role in stress-induced social avoidance and the vHi has a predominant role in active coping behaviours and antidepressant-like behaviour following chronic stress.

Anticompulsive effects of novel derivatives of coumarin in rats

BACKGROUND: Until now, the neurotropic effect, in particular the effect on the emotional behavior of oxy-coumarins, has not been adequately studied. There are only few data on their central action. Currently, research is underway on the synthesis of new compounds based on natural oxy-coumarins, which will potentially have a higher biological activity.
 AIM: Was to study the central action of new oxycoumarin-based compounds IEM-2886, LVM-99, LVM-S144, in particular, on compulsive behavior in rats.
 MATERIALS AND METHODS: To assess the behavior of Wistar rats, the Marble-test and Elevated plus maze methods were used. Oxycoumarin derivatives (IEM-2886, LVM-99, LVM-S144) were injected intraperitoneally at doses of 1, 10 and 25 mg/kg. The effectiveness of the drugs was judged by the number of balls buried in the Marble test and by the duration of staying in the open and closed sleeves of the Elevated plus maze. Results. It was shown that in the Marble test, oxycoumarin-based compounds (IEM-2886, LVM-99, LVM-S144) caused a decrease in the number of buried balls, which shows their anti-compulsive effect. After administration of IEM-2886, LVM-99, LVM-S144 (125 mg / kg) compounds, dose-dependent effects were observed (p 0.05). The elevated plus maze test did not show the anxiolytic effect typical for tranquilizers. Moreover, after the administration of IEM-2886 and LVM-S144 at a dose of 25 mg / kg, an increase in the time spent in the closed sleeve of the maze (p 0.05) was observed, i.e. an anxiogenic effect.
 CONCLUSION: Thus, oxy-coumarin-based compounds are selective for the assessment of anticompulsive effects.

Peripubertal Bisphenol A Exposure Imparts Detrimental Age-Related Changes in Body Composition, Cognition, and Hydrogen Sulfide Production Capacities.

Aims:Peripubertal endocrine disruption has immediate and lifelong consequences on health, cognition, and lifespan. Disruption comes from dietary, environmental, and pharmaceutical sources. The plasticizer Bisphenol A (BPA) is one such endocrine disrupting chemical. However, it is unclear whether peripubertal BPA exposure incites long-lasting physiological, neuro-cognitive, and/or longevity-related metabolic impairments. Catabolism of cysteine via transsulfuration enzymes produces hydrogen sulfide (H2S), a redox-modulating gasotransmitter causative to endocrine and metabolic homeostasis and improved cognitive function with age. As thyroid hormone (TH) regulates hepatic H2S production and BPA is a TH receptor antagonist, we hypothesized that BPA exposure during peripubertal development impairs metabolic and neuro-cognitive/behavioral endpoints in aged mice, in part, due to altered peripheral and/or localized H2S production and redox status.Results:To test this, male C57BL/6J mice at 5 weeks of age were orally exposed daily for 5 weeks to 250 μg BPA/kg, defined as low dose group (LD BPA), or 250 mg BPA/kg, defined as high dose group (HD BPA). Both LD and HD BPA exposure decreased lean mass and increased fat mass accompanied by decreased serum total TH at advanced ages. In addition, LD BPA had an anxiogenic effect whereas HD BPA caused cognitive deficits. Notably, HD BPA disrupted tissue-specific H2S production capacities and/or protein persulfidation, with the former negatively correlated with memory deficits and oxidative stress.Innovation and Conclusion:These findings provide a potential mechanism of action for acute and long-term health impacts of BPA-induced peripubertal endocrine disruption and bolster the need for improved monitoring and limitation of adolescent BPA exposure. Antioxid. Redox Signal. 36, 1246–1267.