Brain Monoamine Concentrations Research Articles

Investigation of the Mechanisms of Tramadol-Induced Seizures in Overdose in the Rat.

Tramadol overdose is frequently associated with the onset of seizures, usually considered as serotonin syndrome manifestations. Recently, the serotoninergic mechanism of tramadol-attributed seizures has been questioned. This study’s aim was to identify the mechanisms involved in tramadol-induced seizures in overdose in rats. The investigations included (1) the effects of specific pretreatments on tramadol-induced seizure onset and brain monoamine concentrations, (2) the interaction between tramadol and γ-aminobutyric acid (GABA)A receptors in vivo in the brain using positron emission tomography (PET) imaging and 11C-flumazenil. Diazepam abolished tramadol-induced seizures, in contrast to naloxone, cyproheptadine and fexofenadine pretreatments. Despite seizure abolishment, diazepam significantly enhanced tramadol-induced increase in the brain serotonin (p < 0.01), histamine (p < 0.01), dopamine (p < 0.05) and norepinephrine (p < 0.05). No displacement of 11C-flumazenil brain kinetics was observed following tramadol administration in contrast to diazepam, suggesting that the observed interaction was not related to a competitive mechanism between tramadol and flumazenil at the benzodiazepine-binding site. Our findings do not support the involvement of serotoninergic, histaminergic, dopaminergic, norepinephrine or opioidergic pathways in tramadol-induced seizures in overdose, but they strongly suggest a tramadol-induced allosteric change of the benzodiazepine-binding site of GABAA receptors. Management of tramadol-poisoned patients should take into account that tramadol-induced seizures are mainly related to a GABAergic pathway.

The increasing importance of LNAA supplementation in phenylketonuria at higher plasma phenylalanine concentrations

BackgroundLarge neutral amino acid (LNAA) treatment has been suggested as alternative to the burdensome severe phenylalanine-restricted diet. While its working mechanisms and optimal composition have recently been further elucidated, the question whether LNAA treatment requires the natural protein-restricted diet, has still remained. ObjectiveFirstly, to determine whether an additional liberalized natural protein-restricted diet could further improve brain amino acid and monoamine concentrations in phenylketonuria mice on LNAA treatment. Secondly, to compare the effect between LNAA treatment (without natural protein) restriction and different levels of a phenylalanine-restricted diet (without LNAA treatment) on brain amino acid and monoamine concentrations in phenylketonuria mice. DesignBTBR Pah-enu2 mice were divided into two experimental groups that received LNAA treatment with either an unrestricted or semi phenylalanine-restricted diet. Control groups included Pah-enu2 mice on the AIN-93 M diet, a severe or semi phenylalanine-restricted diet without LNAA treatment, and wild-type mice receiving the AIN-93 M diet. After ten weeks, brain and plasma samples were collected to measure amino acid profiles and brain monoaminergic neurotransmitter concentrations. ResultsAdding a semi phenylalanine-restricted diet to LNAA treatment resulted in lower plasma phenylalanine but comparable brain amino acid and monoamine concentrations as compared to LNAA treatment (without phenylalanine restriction). LNAA treatment (without phenylalanine restriction) resulted in comparable brain monoamine but higher brain phenylalanine concentrations compared to the severe phenylalanine-restricted diet, and significantly higher brain monoamine but comparable phenylalanine concentrations as compared to the semi phenylalanine-restricted diet. ConclusionsPresent results in PKU mice suggest that LNAA treatment in PKU patients does not need the phenylalanine-restricted diet. In PKU mice, LNAA treatment (without phenylalanine restriction) was comparable to a severe phenylalanine-restricted diet with respect to brain monoamine concentrations, notwithstanding the higher plasma and brain phenylalanine concentrations, and resulted in comparable brain phenylalanine concentrations as on a semi phenylalanine-restricted diet.

Caloric restriction modulates the monoaminergic system and metabolic hormones in aged rats

Caloric restriction (CR) can attenuate the general loss of health observed during aging, being one of the mechanisms involved the reduction of hormonal alteration, such as insulin and leptin. This change could also prevent age-specific fluctuations in brain monoamines, although few studies have addressed the effects of CR on peripheral hormones and central neurotransmitters exhaustively. Therefore, the variations in brain monoamine levels and some peripheral hormones were assessed here in adult 4-month old and 24-month old male Wistar rats fed ad libitum (AL) or maintained on a 30% CR diet from four months of age. Noradrenaline (NA), dopamine (DA), serotonin (5-HT) and its metabolites were measured by high-performance liquid chromatography with electrochemical detection (HPLC-ED) in nine brain regions: cerebellum, pons, midbrain, hypothalamus, thalamus, hippocampus, striatum, frontal cortex, and occipital cortex. In addition, the blood plasma levels of hormones like corticosterone, insulin and leptin were also evaluated, as were insulin-like growth factor 1 and other basal metabolic parameters using enzyme-linked immunosorbent assays (ELISAs): cholesterol, glucose, triglycerides, albumin, low-density lipoprotein, calcium and high-density lipoprotein (HDLc). CR was seen to increase the NA levels that are altered by aging in specific brain regions like the striatum, thalamus, cerebellum and hypothalamus, and the DA levels in the striatum, as well as modifying the 5-HT levels in the striatum, hypothalamus, pons and hippocampus. Moreover, the insulin, leptin, calcium and HDLc levels in the blood were restored in old animals maintained on a CR diet. These results suggest that a dietary intervention like CR may have beneficial health effects, recovering some negative effects on peripheral hormones, metabolic parameters and brain monoamine concentrations.

Link between temperament traits, brain neurochemistry and response to SSRI: insights from animal model of social behavior

Dominant-submissive relationships depend upon functionality of the neural circuits involving monoaminergic neurotransmission. Behavioral profiles of selectively bred dominant (Dom) and submissive (Sub) mice have been proposed to mimic hyperthymic- or depressive-like temperaments observed in patients with affective disorders. These mice differentially respond to psychotropic agents and stressful stimuli, however, the mechanisms underlying these differences remain unclear. To address these mechanisms, we analyzed the brain monoamine content and responses to paroxetine (PXT) in Dom and Sub mice. The behavioral effects of PXT (3 mg/kg, single injection) were assessed with the Elevated Plus Maze (EPM) and Forced Swim Test (FST). Monoamine tissue content was analyzed by HPLC-ECD. Compared to Dom, Sub mice had decreased levels of serotonin (5-HT) in the brainstem (BS), reduced levels of norepinephrine (NE) in the prefrontal cortex (PFC), hippocampus (HPC), and striatum (STR) and elevated levels of dopamine (DA) in PFC, HPC, STR and BS. In EPM, PXT administration increased locomotion and exploration in Dom mice, with no effect in Sub mice. In FST, PXT disrupted immobility in Dom mice only. The PXT-produced differences in regional monoamine content were strain-dependent and consistent with the behavioral alterations. Chronic PXT treatment, in vivo monoamine assays and sex-dependent analysis were out of the scope of this study and will be performed in the future in order to provide an in-depth evaluation of the neurochemical mechanisms underlying temperament-dependent responses to SSRIs. Our findings suggest neurochemical mechanisms that underlie temperament-based response to antidepressant treatment.

The Benefit of Large Neutral Amino Acid Supplementation to a Liberalized Phenylalanine-Restricted Diet in Adult Phenylketonuria Patients: Evidence from Adult Pah-Enu2 Mice.

Many phenylketonuria (PKU) patients cannot adhere to the severe dietary restrictions as advised by the European PKU guidelines, which can be accompanied by aggravated neuropsychological impairments that, at least in part, have been attributed to brain monoaminergic neurotransmitter deficiencies. Supplementation of large neutral amino acids (LNAA) to an unrestricted diet has previously been shown to effectively improve brain monoamines in PKU mice of various ages. To determine the additive value of LNAA supplementation to a liberalized phenylalanine-restricted diet, brain and plasma monoamine and amino acid concentrations in 10 to 16-month-old adult C57Bl/6 PKU mice on a less severe phenylalanine-restricted diet with LNAA supplementation were compared to those on a non-supplemented severe or less severe phenylalanine-restricted diet. LNAA supplementation to a less severe phenylalanine-restricted diet was found to improve both brain monoamine and phenylalanine concentrations. Compared to a severe phenylalanine-restricted diet, it was equally effective to restore brain norepinephrine and serotonin even though being less effective to reduce brain phenylalanine concentrations. These results in adult PKU mice support the idea that LNAA supplementation may enhance the effect of a less severe phenylalanine-restricted diet and suggest that cerebral outcome of PKU patients treated with a less severe phenylalanine-restricted diet may be helped by additional LNAA treatment.

Serotonin abnormalities in Dravet syndrome mice before and after the age of seizure onset

Dravet syndrome (DS) is a genetic form of severe epilepsy often associated with mutation of the SCN1A gene encoding the voltage gated sodium channel Nav1.1. Typically refractive to conventional therapy, serotonin neurotransmission may be an innovative target for treatment. To further understand the role of serotonin in this disorder, in this study we examined the state of the endogenous serotonin system in an Scn1a+/– mouse model of DS. Examined at an age before seizures appear, we found the hypothermic effect of 5-HT1A receptor agonist administration was attenuated. HPLC analysis of brain monoamine content revealed modestly reduced serotonin levels in tissue samples of the midbrain that included the dorsal raphe nucleus but no changes elsewhere in the brain. The reduced sensitivity to 5-HT1A agonist administration seen at young ages reversed after the age of seizure development when mice showed an exaggerated hypothermic response. Likewise, adult DS mice showed a pronounced hypersensitivity to a 5-HT2A/2C agonist. As adults however monoamine levels were not detectably altered. Thus there are alterations in the endogenous serotonin system that both precede and follow the appearance of seizure in DS mice, most strikingly in the response to agonist administration.

Cataplexy

Remarkably and almost invariably, the clinical phenomenon of cataplexy results from the loss of around 40 000 hypocretin-containing neurones in the lateral hypothalamus in the context of narcolepsy type 1....

Nicotine exposure of male mice produces behavioral impairment in multiple generations of descendants.

Use of tobacco products is injurious to health in men and women. However, tobacco use by pregnant women receives greater scrutiny because it can also compromise the health of future generations. More men smoke cigarettes than women. Yet the impact of nicotine use by men upon their descendants has not been as widely scrutinized. We exposed male C57BL/6 mice to nicotine (200 μg/mL in drinking water) for 12 wk and bred the mice with drug-naïve females to produce the F1 generation. Male and female F1 mice were bred with drug-naïve partners to produce the F2 generation. We analyzed spontaneous locomotor activity, working memory, attention, and reversal learning in male and female F1 and F2 mice. Both male and female F1 mice derived from the nicotine-exposed males showed significant increases in spontaneous locomotor activity and significant deficits in reversal learning. The male F1 mice also showed significant deficits in attention, brain monoamine content, and dopamine receptor mRNA expression. Examination of the F2 generation showed that male F2 mice derived from paternally nicotine-exposed female F1 mice had significant deficits in reversal learning. Analysis of epigenetic changes in the spermatozoa of the nicotine-exposed male founders (F0) showed significant changes in global DNA methylation and DNA methylation at promoter regions of the dopamine D2 receptor gene. Our findings show that nicotine exposure of male mice produces behavioral changes in multiple generations of descendants. Nicotine-induced changes in spermatozoal DNA methylation are a plausible mechanism for the transgenerational transmission of the phenotypes. These findings underscore the need to enlarge the current focus of research and public policy targeting nicotine exposure of pregnant mothers by a more equitable focus on nicotine exposure of the mother and the father.

Behavioral Symptoms of Anxiety and Depression and Brain Monoamine Contents in Rats after Chronic Intranasal Administration of Interferon-α

The effects of chronic (17 days) intranasal administration of low (50 IU/kg) and intermediate (8000 IU/kg) doses of human interferon-α (IA) on behavioral indicators of anxiety and depression and the monoaminergic system of the brain were studied in rats. Control rats received the same volume of intranasal physiological saline. IA was found to have any ambiguous effects on anxiety levels. Thus, anxiety in the open field test increased after administration of both doses of IA and decreased in the light-dark test and elevated plus maze test after small doses of IA. In the forced swimming test, administration of both doses of IA was followed by an increase in the duration of immobility (a behavioral symptom of depression). Administration of the intermediate (but not the small) dose of IA was followed by increases in the contents of dopamine and its metabolites in the olfactory bulb and decreases in the nucleus accumbens; the noradrenaline content decreased in the prefrontal cortex. It is suggested that these neurochemical changes in the brain may underlie the behavioral symptoms of depression induced by intranasal administration of intermediate doses of IA. Depression-like behavioral symptoms occurring after administration of small doses of IA were evidently not linked with changes in brain monoaminergic systems but could be due to other mechanisms.

Comparison of brain monoamine content in three populations of Lymnaea that correlates with taste-aversive learning ability.

To find a causal mechanism of learning and memory is a heuristically important topic in neuroscience. In the pond snail Lymnaea stagnalis, the following experimental facts have accrued regarding a classical conditioning procedure known as conditioned taste aversion (CTA): (1) one-day food-deprived Dutch snails have superior CTA memory formation; (2) the one-day food-deprived snails have a low monoamine content (e.g., serotonin, dopamine, octopamine) in their central nervous system (CNS); (3) fed or five-day food-deprived snails have poorer CTA memory and a higher monoamine content; (4) the Dutch snails form better CTA memory than the Canadian TC1 strain; and, (5) the F1 cross snails between the Dutch and Canadian TC1 strains also form poor CTA memory. Here, in one-day food-deprived snails, we measured the monoamine content in the CNSs of the 3 populations. In most instances, the monoamine content of the Dutch strain was lower than in the other two populations. The F1 cross snails had the highest monoamine content. A lower monoamine content is correlated with the better CTA memory formation.

Blood phenylalanine reduction corrects CNS dopamine and serotonin deficiencies and partially improves behavioral performance in adult phenylketonuric mice.

Central nervous system (CNS) deficiencies of the monoamine neurotransmitters dopamine and serotonin have been implicated in the pathophysiology of neuropsychiatric dysfunction in human phenylketonuria (PKU). In this study, we confirmed the occurrence of brain dopamine and serotonin deficiencies in association with severe behavioral alterations and cognitive impairments in hyperphenylalaninemic C57BL/6-Pahenu2/enu2 mice, a model of human PKU. Phenylalanine-reducing treatments, including either dietary phenylalanine restriction or liver-directed gene therapy, initiated during adulthood were associated with increased brain monoamine content along with improvements in nesting behavior but without a change in the severe cognitive deficits exhibited by these mice. At euthanasia, there was in Pahenu2/enu2 brain a significant reduction in the protein abundance and maximally stimulated activities of tyrosine hydroxylase (TH) and tryptophan hydroxylase 2 (TPH2), the rate limiting enzymes catalyzing neuronal dopamine and serotonin synthesis respectively, in comparison to levels seen in wild type brain. Phenylalanine-reducing treatments initiated during adulthood did not affect brain TH or TPH2 content or maximal activity. Despite this apparent fixed deficit in striatal TH and TPH2 activities, initiation of phenylalanine-reducing treatments yielded substantial correction of brain monoamine neurotransmitter content, suggesting that phenylalanine-mediated competitive inhibition of already constitutively reduced TH and TPH2 activities is the primary cause of brain monoamine deficiency in Pahenu2 mouse brain. We propose that CNS monoamine deficiency may be the cause of the partially reversible adverse behavioral effects associated with chronic HPA in Pahenu2 mice, but that phenylalanine-reducing treatments initiated during adulthood are unable to correct the neuropathology and attendant cognitive deficits that develop during juvenile life in late-treated Pahenu2/enu2 mice.

Large neutral amino acid supplementation as an alternative to the phenylalanine-restricted diet in adults with phenylketonuria: evidence from adult Pah-enu2 mice

Phenylketonuria treatment mainly consists of a phenylalanine-restricted diet but still results in suboptimal neuropsychological outcome, which is at least partly based on cerebral monoamine deficiencies, while, after childhood, treatment compliance decreases. Supplementation of large neutral amino acids (LNAAs) was previously demonstrated in young phenylketonuria mice to target all three biochemical disturbances underlying brain dysfunction in phenylketonuria. However, both its potential in adult phenylketonuria and the comparison with the phenylalanine-restricted diet remain to be established. To this purpose, several LNAA supplements were compared with a severe phenylalanine-restricted diet with respect to brain monoamine and amino acid concentrations in adult C57Bl/6 Pah-enu2 mice. Adult phenylketonuria mice received a phenylalanine-restricted diet, unrestricted diet supplemented with several combinations of LNAAs or AIN-93M control diet for 6 weeks. In addition, adult wild-type mice on AIN-93M diet served as controls. The severe phenylalanine-restricted diet in adult phenylketonuria mice significantly reduced plasma and brain phenylalanine and restored brain monoamine concentrations, while brain concentrations of most nonphenylalanine LNAAs remained subnormal. Supplementation of eight LNAAs was similarly effective as the severe phenylalanine-restricted diet to restore brain monoamines, while brain and plasma phenylalanine concentrations remained markedly elevated. These results provide biochemical support for the effectiveness of the severe phenylalanine-restricted diet and showed the possibilities of LNAA supplementation being equally effective to restore brain monoamines in adult phenylketonuria mice. Therefore, LNAA supplementation is a promising alternative treatment to phenylalanine restriction in adult phenylketonuria patients to further optimize neuropsychological functioning.

Neuroendocrine and Immune Responses Undertake Different Fates following Tryptophan or Methionine Dietary Treatment: Tales from a Teleost Model

Methionine and tryptophan appear to be fundamental in specific cellular pathways involved in the immune response mechanisms, including stimulation of T-regulatory cells by tryptophan metabolites or pro-inflammatory effects upon methionine supplementation. Thus, the aim of this study was to evaluate the immunomodulatory effect of these amino acids on the inflammatory and neuroendocrine responses in juveniles of European seabass, Dicentrarchus labrax. To achieve this, goal fish were fed for 14 days methionine and tryptophan-supplemented diets (MET and TRP, respectively, 2× dietary requirement level) or a control diet meeting the amino acids requirement levels (CTRL). Fish were sampled for immune status assessment and the remaining fish were challenged with intraperitoneally injected inactivated Photobacterium damselae subsp. piscicida and sampled either 4 or 24 h post-injection. Respiratory burst activity, brain monoamines, plasma cortisol, and immune-related gene expression showed distinct and sometimes opposite patterns regarding the effects of dietary amino acids. While neuroendocrine intermediates were not affected by any dietary treatment at the end of the feeding trial, both supplemented diets led to increased levels of plasma cortisol after the inflammatory insult, while brain monoamine content was higher in TRP-fed fish. Peripheral blood respiratory burst was higher in TRP-fed fish injected with the bacteria inoculum but only compared to those fed MET. However, no changes were detected in total antioxidant capacity. Complement factor 3 was upregulated in MET-fed fish but methionine seemed to poorly affect other genes expression patterns. In contrast, fish fed MET showed increased immune cells numbers both before and after immune challenge, suggesting a strong enhancing effect of methionine on immune cells proliferation. Differently, tryptophan effects on inflammatory transcripts suggested an inhibitory mode of action. This, together with a high production of brain monoamine and cortisol levels, suggests that tryptophan might mediate regulatory mechanisms of neuroendocrine and immune systems cooperation. Overall, more studies are needed to ascertain the role of methionine and tryptophan in modulating (stimulate or regulate) fish immune and neuroendocrine responses.

Changes in Brain Monoamines Underlie Behavioural Disruptions after Zebrafish Diet Exposure to Polycyclic Aromatic Hydrocarbons Environmental Mixtures.

Zebrafish were exposed through diet to two environmentally relevant polycyclic aromatic hydrocarbons (PAHs) mixtures of contrasted compositions, one of pyrolytic (PY) origin and one from light crude oil (LO). Monoamine concentrations were quantified in the brains of the fish after six month of exposure. A significant decrease in noradrenaline (NA) was observed in fish exposed to both mixtures, while a decrease in serotonin (5HT) and dopamine (DA) was observed only in LO-exposed fish. A decrease in metabolites of 5HT and DA was observed in fish exposed to both mixtures. Several behavioural disruptions were observed that depended on mixtures, and parallels were made with changes in monoamine concentrations. Indeed, we observed an increase in anxiety in fish exposed to both mixtures, which could be related to the decrease in 5HT and/or NA, while disruptions of daily activity rhythms were observed in LO fish, which could be related to the decrease in DA. Taken together, these results showed that (i) chronic exposures to PAHs mixtures disrupted brain monoamine contents, which could underlie behavioural disruptions, and that (ii) the biological responses depended on mixture compositions.

L-Ornithine is a potential acute satiety signal in the brain of neonatal chicks

Recently, we observed that neonatal chicks exhibit feeding behavior characterized by frequent food intake and short resting intervals, with changes detected in the brain amino acid and monoamine concentrations. In this study, we aimed to clarify further the relationship between the appetite of neonatal chicks and brain amino acid metabolism. In Experiment 1, changes were investigated in free amino acids in the brain under conditions of regulated appetite induced by fasting and subsequent short-term re-feeding. Chicks (5days old) were distributed into four treatment groups — namely, fasting for 3h, and fasting for 3h followed by re-feeding for 10, 20 or 30min. Brain samples were collected after treatment to analyze free amino acid concentrations. Amino adipic acid and proline in all brain parts as well as arginine and ornithine in all brain parts – except mesencephalic arginine and cerebellar ornithine – were increased in a time-dependent manner following re-feeding. In Experiment 2, we further examined the effect of exogenous administration of some amino acids altered in association with feeding behavior in Experiment 1. We chose l-arginine and its functional metabolite, l-ornithine, to analyze their effects on food intake in chicks. Intracerebroventricular injection (2μmol) of l-ornithine, but not l-arginine, significantly inhibited food intake in neonatal chicks. In Experiment 3, we found that central injection of l-ornithine (2, 4, and 6μmol) dose-dependently suppressed food intake in chicks. These results suggested that l-ornithine may have an important role in the control of food intake as an acute satiety signal in the neonatal chick brain.

VEGF-induced antidepressant effects involve modulation of norepinephrine and serotonin systems

Throughout life, we are exposed to a variety of stresses, which may be inevitable and noxious sometimes. During evolution, animals must have acquired some physiological means to counteract stress. Vascular endothelial growth factor (VEGF) is an angiogenic and neurogenic factor, which has been shown to elicit antidepressant-like effects in response to different external stimuli, potentially functioning as an anti-stress molecule. However, it remains largely unknown how VEGF modulates mood-related behaviors. To investigate molecular correlates, we analyzed monoaminergic systems of VEGF transgenic mice that display antidepressant-like behavior. Immunostaining showed that overall morphologies of monoaminergic nuclei and their processes were normal. However, we found imbalances in brain monoamine contents, in which the levels of norepinephrine and serotonin, but not dopamine, were decreased exclusively in the regions where VEGF was expressed. The turnover of norepinephrine showed a marked increase and serotonin turnover showed a modest reduction, whereas dopamine turnover was not affected. The protein levels of tyrosine hydroxylase and tryptophan hydroxylase, the rate-limiting enzymes of catecholamine and serotonin synthesis, remained constant. The mRNA levels of monoamine receptors were generally similar but adrenergic receptors of ADRα1A and ADRβ1 were down-regulated. Behavioral tests showed that serotonin- or norepinephrine-selective antidepressant drugs failed to additively enhance antidepressant-like behaviors, whereas monoamine depleting drugs attenuated VEGF-mediated antidepressant-like effect. These data suggest that VEGF-induced antidepressant-like effects involve modulation of norepinephrine and serotonin systems.

Toxicological study of Zaleplon (Anxiolytic drug) in experimental animals.

Anxiety disorders are among the most prevalent mental disorders in the general population. Nearly 30 million persons are affected in the United States, with women affected nearly twice as frequently as men. These disorders are frequently treated using benzodiazepines (Diazepam) and non-benzodiazepines (Zaleplon). Non-benzodiazepines have replaced the benzodiazepines for anxiety treatment due to low risk of dependence and CNS effects encouraging drug abuse. This work was designed to investigate the toxicological overdose effect of zaleplon and diazepam on behavior, blood pressure, heart rate, brain neurotransmitter content and liver & kidney functions in rats. Rats were divided into five groups: 1% Tween 80, p.o. (control), diazepam (1 & 4 mg/kg, p.o.) and zaleplon (1 & 4 mg/kg, p.o.). All groups were injected daily for four weeks to perform the following: behavioral study (assessment of motor co-ordination and anxiety performance), measurement of blood pressure & heart rate, determination of the free amino acid and monoamine contents in the whole brain, determination of serum aminotransferases activity, total protein, total and direct billirubin, creatinine & blood urea nitrogen of experimental rats. Zaleplon decreased motor co-ordination, blood pressure and heart rate with extent lesser than diazepam. However, it decreased anxiety performance and brain monoamine content with extent more than diazepam. While, diazepam increased brain amino acid content, serum aminotransferases activity, total protein, total & direct billirubin, creatinine and blood urea nitrogen by magnitude more than zaleplon.

Mechanism of the histamine H3 receptor-mediated increase in exploratory locomotor activity and anxiety-like behaviours in mice

Histaminergic neurons are activated by histamine H3 receptor (H3R) antagonists, increasing histamine and other neurotransmitters in the brain. The prototype H3R antagonist thioperamide increases locomotor activity and anxiety-like behaviours; however, the mechanisms underlying these effects have not been fully elucidated. This study aimed to determine the mechanism underlying H3R-mediated behavioural changes using a specific H3R antagonist, JNJ-10181457 (JNJ).First, we examined the effect of JNJ injection to mice on the concentrations of brain monoamines and their metabolites. JNJ exclusively increased Nτ-methylhistamine, the metabolite of brain histamine used as an indicator of histamine release, suggesting that JNJ dominantly stimulates the release of histamine release but not of other monoamines.Next, we examined the mechanism underlying JNJ-induced behavioural changes using open-field tests and elevated zero maze tests. JNJ-induced increase in locomotor activity was inhibited by α-fluoromethyl histidine, an inhibitor of histamine synthesis, supporting that H3R exerted its effect through histamine neurotransmission. The JNJ-induced increase in locomotor activity in wild-type mice was preserved in H1R gene knockout mice but not in histamine H2 receptor (H2R) gene knockout mice. JNJ-induced anxiety-like behaviours were partially reduced by diphenhydramine, an H1R antagonist, and dominantly by zolantidine, an H2R antagonist. These results suggest that H3R blockade induces histamine release, activates H2R and elicits exploratory locomotor activity and anxiety-like behaviours.

Cryptic and biochemical responses of young cuttlefish Sepia officinalis exposed to environmentally relevant concentrations of fluoxetine

Antidepressants released in the environment have the potential to generate neural disrupting effects in non-target organisms, yet their putative effects on behaviors have never been studied in cephalopod molluscs. This study assessed the impact of the antidepressant fluoxetine (FLX) on the efficiency of cryptic behaviors (body patterns on uniform, checkerboard and sandy substrates), locomotor activity, and brain chemistry in young cuttlefish exposed to environmental concentrations (1 and 100ngL−1 of FLX) during the perinatal period. Behavioral responses of cuttlefish were monitored at hatching and two weeks later, and brain monoamine contents were quantified at one month of age. FLX significantly altered the camouflage efficiencies on uniform and sandy backgrounds only at the lowest concentration, but not at 100ngL−1. Hatchlings exposed to 1ngL−1 of FLX exhibited a duration exposure-dependent decrease in the uniform camouflage. They also showed a significant increase of the frequency of sand digging behaviors which might make them highly visible to predators in nature. When tested again two weeks later, cuttlefish seemed to have recovered and no more behavioral alterations were observed showing a transitory effect of the antidepressant. FLX did not affect the levels of serotonin, norepinephrine and their metabolites; however, it seemed to influence dopaminergic activity between the two FLX-exposed groups. The results show for the time that environmentally realistic concentrations of a single SSRI significantly impair the cryptic performances of newly hatched cuttlefish, and may ultimately reduce their chance for survival.

Sex-dependent effects of maternal separation on plasma corticosterone and brain monoamines in response to chronic ethanol administration

Prolonged and repeated periods of maternal separation produce behavioral phenotype of increased vulnerability to neuropsychiatric disorders and drug abuse. Most of the changes in behavior, corticosterone (CORT) and monoamine levels induced by long maternal separation (LMS) are observed after a challenge, but not in basal conditions. LMS increases ethanol-induced locomotor response and self-administration, possibly due to changes in CORT release and/or monoamine concentrations. This study examined the effects of LMS in association with chronic ethanol treatment on plasma CORT and brain monoamine concentrations in male and female Swiss mice, which were kept undisturbed (animal facility rearing – AFR) or separated from their mothers for 3h/day, from 2 to 14days of age (LMS). As adults, one set of male and female mice received no drug treatment to assess the effect of LMS per se. Another set of animals received saline injections for 20days and one ethanol injection (2.2g/kg, i.p.) on day 21 (acute) or ethanol for 21days (chronic). Locomotor activity, plasma CORT levels and monoamines in the frontal cortex, striatum and hippocampus of AFR and LMS mice were evaluated in non-treated, acute and chronic ethanol-treated animals. In non-treated mice, no differences were found in CORT or locomotor activity, with small changes in monoamines content. In LMS females, chronic ethanol increased dopamine and serotonin concentrations in the frontal cortex, relative to acute ethanol LMS and to chronic ethanol-treated AFR groups (p<0.05). In LMS males, chronic ethanol increased hippocampal noradrenaline, dopamine, serotonin and metabolites when compared to respective AFR controls, as well as acute LMS. Moreover, chronic ethanol treatment resulted in higher CORT concentrations in LMS than in AFR males. Overall, these results indicate that LMS mice were more susceptible to the effects of chronic ethanol administration on CORT and brain monoamine concentrations, and that these effects were sex-dependent.