3,4-Methylenedioxymethamphetamine (MDMA) impairs cognitive function during withdrawal via activation of the arachidonic acid cascade in the hippocampus.

BACKGROUND: The recreational drug ±3,4-methylenedioxymethamphetamine (MDMA; also known as "ecstasy") has unusual subjective prosocial and empathogenic effects, and has exhibited potential as an adjunct to psychotherapy in recent years. However, there has been some concern regarding possible neuropsychiatric symptoms, such as cognitive impairment and dependence, emerging after abstinence. Therefore, this study aimed to evaluate the mechanism underlying cognitive impairment during MDMA withdrawal. To achieve this, we focused on the arachidonic acid cascade, which is related to addiction to some abusive drugs. METHODS: A novel object recognition task was used to investigate cognitive function in mice. Furthermore, we quantified prostaglandin E2 during MDMA withdrawal. RESULTS: The recognition index significantly decreased during withdrawal after repeated administration of MDMA (10mg/kg, i.p., once daily for 7 days), but not following co-administration of diclofenac (10mg/kg, i.p.), a cyclooxygenase inhibitor. On day 1, following repeated MDMA treatment, prostaglandin E2 content significantly increased in the hippocampus but not in the prefrontal cortex and striatum. CONCLUSIONS: Our findings indicate that activation of the arachidonic acid cascade at least in the hippocampus is likely involved in the development of recognition memory impairment during MDMA withdrawal. Therefore, co-use of cyclooxygenase inhibitors with MDMA may reduce concerns regarding MDMA-induced impairment of recognition memory.

Impaired monoamine neural system in the mPFC of SHRSP/Ezo as an animal model of attention-deficit/hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD) is the most common childhood-onset psychiatric disorder. We investigated the effects of systemic administration of monoamine reuptake inhibitors on long-term potentiation (LTP) formation and monoamine release in the medial prefrontal cortex (mPFC) of the stroke-prone spontaneously hypertensive rat (SHRSP)/Ezo, an animal model of ADHD, and its genetic control, Wistar Kyoto (WKY)/Ezo, to elucidate the functional changes in the mPFC monoamine neural system. Methylphenidate (dopamine (DA) and noradrenaline (NA) reuptake inhibitor) and desipramine (NA reuptake inhibitor) improved LTP formation defects in the mPFC of SHRSP/Ezo, suggesting that NA or both DA and NA are required for improvement of impaired LTP. Methylphenidate increased mPFC DA in both WKY/Ezo and SHRSP/Ezo, but the increase was greater in the former. GBR-12909 (DA reuptake inhibitor) increased mPFC DA in WKY/Ezo but had no effect in SHRSP/Ezo. This may be because DA transporter in SHRSP/Ezo is functionally impaired and contributes less to DA reuptake, so its inhibition did not increase DA level. Meanwhile, basal DA levels in the mPFC of SHRSP/Ezo were paradoxically decreased. These results suggest that functional changes in the DA and NA neural system in the frontal lobe are involved in the pathology of ADHD.

Non-target Impact of Dinotefuran and Azoxystrobin on Soil Bacterial Community and Nitrification.

Pesticides to protect crops from pests are subject to rigorous risk assessment before registration in Japan. However, further information needs to be collected regarding the assessment of impacts on the natural environment. In particular, nitrifying bacteria play a role in converting ammonium salts to nitrates in soil. However, there is limited research covering the effects of insecticides on nitrification, despite several fungicides and herbicides have an inhibitory effect on nitrifying bacteria. Therefore, we investigated the effect of pesticides on the nitrification when applied to soil. The application of both pesticides promoted ammonia oxidation, and suppressed nitrite oxidation in a high-concentration treatment of dinotefuran. In addition, it was clarified that the diversity and species richness of soil bacteria was significantly reduced when the pesticides were applied to the soil, and that the specific soil bacteria (Metyhlotenera spp.) dominated the application of the pesticides.

Elevation of endocannabinoids in the brain by synthetic cannabinoid JWH-018: mechanism and effect on learning and memory.

The impairment of learning and memory is a well-documented effect of both natural and synthetic cannabinoids. In the present study, we aimed to investigate the effect of acute administration of JWH-018, a synthetic cannabinoid, on the hippocampal metabolome to assess biochemical changes in vivo. JWH-018 elevated levels of the endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG). The increase of endocannabinoid levels in response to JWH-018 could be inhibited by co-administration of AM251, a CB1 receptor antagonist. Biochemical analyses revealed that this was the result of suppression of two hydrolases involved in endocannabinoid degradation (fatty acid amide hydrolase [FAAH] and monoacylglycerol lipase [MAGL]). Additionally, we showed that JWH-018 causes a reduction in the levels of brain-derived neurotrophic factor (BDNF), which is known to modulate synaptic plasticity and adaptive processes underlying learning and memory. The decrease of BDNF following JWH-018 treatment was also rescued by co-administration of AM251. As both endocannabinoids and BDNF have been shown to modulate learning and memory in the hippocampus, the alteration of their levels in response to JWH-018 may explain the contribution of synthetic cannabinoids to impairment of memory.

Inhibition of Monoacylglycerol Lipase Reduces the Reinstatement of Methamphetamine-Seeking and Anxiety-Like Behaviors in Methamphetamine Self-Administered Rats.

Background: Methamphetamine is a highly addictive psychostimulant with reinforcing properties. Our laboratory previously found that Δ8-tetrahydrocannabinol, an exogenous cannabinoid, suppressed the reinstatement of methamphetamine-seeking behavior. The purpose of this study was to determine whether the elevation of endocannabinoids modulates the reinstatement of methamphetamine-seeking behavior and emotional changes in methamphetamine self-administered rats. Methods: Rats were tested for the reinstatement of methamphetamine-seeking behavior following methamphetamine self-administration and extinction. The elevated plus-maze test was performed in methamphetamine self-administered rats during withdrawal. We investigated the effects of JZL184 and URB597, 2 inhibitors of endocannabinoid hydrolysis, on the reinstatement of methamphetamine-seeking and anxiety-like behaviors. Results: JZL184 (32 and 40 mg/kg, i.p.), an inhibitor of monoacylglycerol lipase, significantly attenuated both the cue- and stress-induced reinstatement of methamphetamine-seeking behavior. Furthermore, URB597 (3.2 and 10 mg/kg, i.p.), an inhibitor of fatty acid amide hydrolase, attenuated only cue-induced reinstatement. AM251, a cannabinoid CB1 receptor antagonist, antagonized the attenuation of cue-induced reinstatement by JZL184 but not URB597. Neither JZL184 nor URB597 reinstated methamphetamine-seeking behavior when administered alone. In the elevated plus-maze test, rats that were in withdrawal from methamphetamine self-administration spent less time in the open arms. JZL184 ameliorated the decrease in time spent in the open arms. Conclusion: We showed that JZL184 reduced both the cue- and stress-induced reinstatement of methamphetamine-seeking and anxiety-like behaviors in rats that had self-administered methamphetamine. It was suggested that a decrease in 2-arachidonoylglycerol in the brain could drive the reinstatement of methamphetamine-seeking and anxiety-like behaviors.

Repeated fluvoxamine treatment recovers early postnatal stress-induced hypersociability-like behavior in adult rats.

Childhood maltreatment is associated with impaired adult brain function, particularly in the hippocampus, and is not only a major risk factor for some psychiatric diseases but also affects early social development and social adaptation in later life. The aims of this study were to determine whether early postnatal stress affects social behavior and whether repeated fluvoxamine treatment reverses these changes. Rat pups were exposed to footshock stress during postnatal days 21-25 (at 3 weeks old: 3wFS). During the post-adolescent period (10-14 weeks postnatal), the social interaction test and Golgi-cox staining of dorsal hippocampal pyramidal neurons were performed. Following exposure to footshock stress, 3wFS rats showed an increase in social interaction time, which might be practically synonymous with hypersociability, and a decrease in spine density in the CA3 hippocampal subregion, but not in CA1. These behavioral and morphological changes were both recovered by repeated oral administration of fluvoxamine at a dose of 10 mg/kg/day for 14 days. These findings suggest that the vulnerability of the hippocampal CA3 region is closely related to social impairments induced by physical stress during the juvenile period and shed some light on therapeutic alternatives for early postnatal stress-induced emotional dysfunction.

A case of small intestinal intussusception caused by anisakiasis diagnosed and treated by upper gastrointestinal endoscopy.

A 35-year-old man attended our hospital with complaining of epigastric pain and vomiting. He was diagnosed with bowel intussusception based on the target sign revealed in the upper jejunum by abdominal computed tomography. However, the cause of the intussusception was not clear. Insertion of an endoscope into the jejunum revealed prominent edema in the upper part of the jejunum, and Anisakis simplex was identified at the site and removed. Symptoms rapidly improved after endoscopic treatment. We report this case because surgery was avoidable and because we are aware of no previous reports of small intestinal intussusception caused by anisakiasis that has been diagnosed and treated endoscopically.

A case of liver abscess caused by appendicitis which was considered to be drained from hepatobronchial fistula.

A 52-year-old man was referred to our hospital complaining of right lower abdominal pain. He was diagnosed with appendicitis complicated with a liver abscess and underwent an appendectomy. After antibiotic treatment following surgery, the liver abscess penetrated the right lung, which was considered to be drained from a hepatobronchial fistula. Due to the effect of drainage, the liver abscess immediately improved and the patient was subsequently discharged.

Neuronal codes for the inhibitory control of impulsive actions in the rat infralimbic cortex.

Poor impulse control is a debilitating condition observed in various psychiatric disorders and could be a risk factor for drug addiction, criminal involvement, and suicide. The rat infralimbic cortex (IL), located in the ventral portion of the medial prefrontal cortex, has been implicated in impulse control. To elucidate the neurophysiological basis of impulse control, we recorded single unit activity in the IL of a rat performing a 3-choiceserial reaction time task (3-CSRTT) and 2-choice task (2-CT), which are animal models for impulsivity. The inactivation of IL neuronal activity with an injection of muscimol (0.1 µg /side) disrupted impulse control in the 3-CSRTT. More than 60% (38/56) of isolated IL units were linked to impulse control, while approximately 30% of all units were linked to attentional function in the 3-CSRTT. To avoid confounding motor-related units with the impulse control-related units, we further conducted the 2-CT in which the animals' motor activities were restricted during recording window. More than 30% (14/44) of recorded IL units were linked to impulse control in the 2-CT. Several types of impulse control-related units were identified. Only 16% of all units were compatible with the results of the muscimol experiment, which showed a transient decline in the firing rate immediately before the release of behavioral inhibition. This is the first study to elucidate the neurophysiological basis of impulse control in the IL and to propose that IL neurons control impulsive actions in a more complex manner than previously considered.

Behavioural effects of monoamine reuptake inhibitors on symptomatic domains in an animal model of attention-deficit/hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous neurobehavioural disorder. Several lines of evidence have implicated monoamine signalling systems, including transporters and receptors, in the pathogenesis of ADHD. We explored the heterogeneity of neural mechanisms that may possibly underlie symptomatic abnormalities in ADHD, by investigating the effects of monoamine reuptake inhibitors with differential spectrums for each monoamine transporter on ADHD-like behaviours in an animal model of ADHD, i.e. juvenile (6-week-old) male stroke-prone spontaneously hypertensive rats (SHRSP/Ezo). The impaired spontaneous alternation performance in a Y-maze task, demonstrated the inattentive features of SHRSP/Ezo, was improved by a selective DA reuptake inhibitor GBR-12909 (1 and 3mg/kg, i.p.). Desipramine (1, 3 and 10mg/kg, i.p.) and milnacipran (30mg/kg, i.p.), which possess a noradrenaline (NA) reuptake inhibitory activity, also ameliorated inattentive behaviour. Increased locomotor activity in open-field apparatus and total arm entries in a Y-maze task, which demonstrate the hyperactive features of SHRSP/Ezo, were improved by desipramine and milnacipran, but impaired by a high dose of GBR-12909 (10mg/kg, i.p.). A selective serotonin (5-HT) reuptake inhibitor fluvoxamine (10 and 30mg/kg, i.p.), did not affect inattention but significantly suppressed hyperactivity at a high dose (30mg/kg, i.p.). Moreover, a low dose of fluvoxamine (3mg/kg, i.p.) ameliorated the increased open arm spent time in an elevated plus-maze without affecting total arm entries, indicating an effect on impulsive features based on the anxiolytic characteristics of SHRSP/Ezo. These behavioural effects of monoamine reuptake inhibitors support the heterogeneity of monoaminergic systems, which are responsible for ADHD-like behaviours in SHRSP/Ezo. These findings may provide pharmacological evidence for the development of ADHD treatments that target more appropriate monoamine transporters.

Milnacipran enhances the control of impulsive action by activating D1-like receptors in the infralimbic cortex.

RATIONALE: Elevated impulsivity is often observed in patients with depression. We recently found that milnacipran, an antidepressant and a serotonin/noradrenaline reuptake inhibitor, could enhance impulse control in rats. However, the neural mechanisms underlying the effects of milnacipran on impulsive action remain unclear. Milnacipran increases not only extracellular serotonin and noradrenaline but also dopamine specifically in the medial prefrontal cortex, which is one of the brain regions responsible for impulsive action. OBJECTIVES: Our goal was to identify whether D(1)- and/or D(2)-like receptors in the infralimbic cortex (IL), the ventral portion of the medial prefrontal cortex, mediates the milnacipran-enhanced impulse control in a three-choice serial reaction time task. METHODS: The rats were bilaterally injected with SCH23390, a selective D(1)-like receptor antagonist (0.3 or 3 ng/side) or eticlopride, a selective D(2)-like receptor antagonist (0.3 or 1 µg/side) into the IL after acute intraperitoneal administration of milnacipran (10 mg/kg). RESULTS: Intra-IL SCH23390 injections reversed the milnacipran-enhanced impulse control, whereas injections of eticlopride into the IL failed to block the effects of milnacipran on impulsive action. CONCLUSIONS: This is the first report that demonstrates a critical role for D(1)-like receptors of the IL in milnacipran-enhanced control of impulsive action.

Peritoneal fibrosis and high transport are induced in mildly pre-injured peritoneum by 3,4-dideoxyglucosone-3-ene in mice.

Peritoneal dialysis (PD) solution contains high concentrations of glucose and glucose degradation products (GDPs). One of several GDPs--3,4-dideoxyglucosone-3-ene (3,4-DGE)--was recently identified as the most reactive and toxic GDP in PD fluids. In vitro, 3,4-DGE has been shown to induce mesothelial cell damage; however, its role in peritoneal fibrosis in vivo remains unclear. In the present study, we intraperitoneally administered chlorhexidine gluconate (CG) for mild peritoneal injury, and we then injected 3,4-DGE [38 µmol/L (low concentration) or 145 µmol/L (high concentration)] 5 times weekly for 4 weeks. Significant thickening of the parietal peritoneal membrane was observed only when treatment with low or high concentrations of 3,4-DGE occurred after CG administration, but not when either CG or 3,4-DGE alone was given. The combination of CG and 3,4-DGE also caused upregulation of messenger RNA expression of transforming growth factor ß1, connective tissue growth factor, fibronectin, collagen type 1 α1 chain, alpha smooth muscle actin (α-SMA), vascular endothelial growth factor 164, NADPH oxidase 1 and 4, p22phox, p47phox, and gp91phox in peritoneal tissue. Treatment with CG alone was sufficient to cause significant F4/80-positive macrophage infiltration, appearance of α-SMA-positive cells, and vessel formation in the submesothelial layer. Addition of 3,4-DGE markedly enhanced those changes and induced apoptosis, mainly in leukocytes. The concentration of 3,4-DGE in the abdominal cavity declined more rapidly in CG-treated mice than in PBS-treated mice. Peritoneal membrane permeability determined by peritoneal equilibration test showed high transport conditions in peritoneum treated with both CG and 3,4-DGE. These results indicate that, when mild peritoneal damage is already present, 3,4-DGE causes peritoneal thickening and fibrosis, resulting in deterioration of peritoneal membrane function.

Anxiolytic effects of yokukansan, a traditional Japanese medicine, via serotonin 5-HT1A receptors on anxiety-related behaviors in rats experienced aversive stress.

ETHNOPHARMACOLOGICAL RELEVANCE: Yokukansan, a traditional Japanese medicine (Kampo), has been reported in the treatment of behavioral and psychological symptoms of dementia (BPSD) such as aggression, anxiety and depression in patients with Alzheimer's disease and other forms of senile dementia. AIMS OF THE STUDY: In the present study, we investigated the anxiolytic effects of yokukansan on anxiety-related behaviors in rats that have experienced aversive stress. MATERIALS AND METHODS: We used male Wistar/ST rats which received an electrical footshock as aversive stress. Yokukansan at a dose of 1.0 g/kg was administered orally once a day for 14 or 16 day before behavioral tests. To evaluate the anxiolytic effects, we used the contextual fear conditioning (CFC) test and elevated plus-maze (EPM) test. And we also investigated effects of yokukansan on locomotor activity in the Open-field (OF) test and on the change in plasma corticosterone after CFC stress, in rats that had experienced footshock stress. RESULTS: In the CFC test, rats that had experienced footshock showed significant freezing behavior on re-exposure to the box 14 day after footshock stress. Yokukansan significantly suppressed freezing behavior in the CFC test. In the EPM test on the 16th day after the CFC test, yokukansan significantly increased the time spent in open arms after footshock stress compared to control rats. However, repeated administration of yokukansan on the 14th day did not affect the decrease in locomotor activity and the increase in plasma corticosterone by re-exposure to the box 14 day after footshock stress in the OF test and determination of serum corticosterone, respectively. These anxiolytic effects by yokukansan were antagonized by WAY-100635, a selective 5-HT(1A) receptor antagonist, in the CFC test, but not the EPM test. Furthermore, 5-HT(1A) receptor agonist buspirone significantly suppressed freezing behavior in the CFC test; however, buspirone induced no change in the time spent in open arms in the EPM test. CONCLUSION: These findings suggested that yokukansan has anxiolytic effects on anxiety-like behaviors induced by both innate fear and memory-dependent fear. In particular, yokukansan produced anxiolytic effects via 5-HT(1A) receptors in memory-dependent fear induced by aversive stress. Furthermore, yokukansan could be useful as one of the therapeutic drugs for the treatment of anxiety disorders and various mental disorders that have comorbid anxiety.

Lithium, but not valproic acid or carbamazepine, suppresses impulsive-like action in rats.

RATIONALE: Higher impulsivity is a pathological symptom in several psychiatric disorders, including bipolar disorder, and is a risk factor for suicide. OBJECTIVES: Our goal was to determine whether major mood-stabilizing drugs used for the treatment of bipolar disorder could suppress impulsive-like action in the three-choice serial reaction time task (3-CSRTT). METHODS: Following training for the 3-CSRTT, rats were acutely administered lithium chloride (LiCl; 0, 3.2, 10, and 32 mg/kg, i.p.), valproic acid (0, 10, 32, and 100 mg/kg, i.p.), or carbamazepine (0, 10, 20, and 30 mg/kg, i.p.). To assess the anorexic effects of lithium, a simple food consumption test was conducted. RESULTS: LiCl dose-dependently decreased the number of premature responses, an index of impulsive-like action. A high dose of LiCl (32 mg/kg) decreased food consumption, but its anorexic effects were not correlated with the effects of LiCl on premature responses. A moderate dose of LiCl (20 mg/kg) significantly reduced the number of premature responses without affecting motivation-related measures in the 3-CSRTT or the amount of food consumption. Although carbamazepine prolonged reward latency, an index of motivation for food, neither valproic acid nor carbamazepine significantly affected premature responses. CONCLUSION: It is likely that lithium has a suppressive effect on impulsive action independent of the anorexic effect. Lithium may suppress impulsive behavior and thereby decrease the risk of suicide. The present results could provide an explanation for the antisuicidal effects of lithium and suggest that lithium could be a beneficial treatment for impulsivity-related disorders.

Regulation of cerebral blood flow in the hippocampus by neuronal activation through the perforant path: relationship between hippocampal blood flow and neuronal plasticity.

Although changes in regional cerebral blood flow (rCBF) have been used as an index of neuronal activity, the effects of long-term potentiation (LTP) in the hippocampus, widely assumed to be an electrophysiological basis of learning and memory, on the changes in rCBF by neuronal activity remain unclear. Hence, to elucidate whether the effects of LTP in the hippocampus reflect in the correlation between neuronal activity and co-occurring changes in rCBF, we investigated the effects of LTP on the responses of hippocampal blood flow (HBF) to the electrical stimulation of the perforant path in vivo. We continuously measured HBF using Laser-Doppler flowmetry, and systemic blood pressure and heart rate were measured from the femoral artery during electrical stimulations in halothane-anesthetized rats. The results showed that the reactivity of HBF to neuronal activation was potentiated by a tetanic stimulation that induces LTP, although the tetanic stimulation did not affect baseline of HBF values. These results suggest that the presence of the plasticity between neuronal activity and the rCBF in the perforant path-dentate pathway, and the neuronal plasticity can be reflected in the transient changes in rCBF when the brain region is activated but not in the steady state.

Inhibition of noradrenaline release by clonidine in the ventral bed nucleus of the stria terminalis attenuates pain-induced aversion in rats.

Pain is an unpleasant sensory and emotional experience. The neural systems underlying the sensory component of pain have been studied extensively, but we are only beginning to understand those underlying the affective component of pain. Previously, we showed the pivotal role of noradrenergic transmission in the ventral part of the bed nucleus of the stria terminalis (vBNST) in the negative affective component of pain using a conditioned place paradigm. In this study, we examined the effect of local administration of clonidine, an α(2)-adrenoceptor agonist, into the vBNST on noradrenaline release and on conditioned place aversion (CPA) induced by an intraplantar formalin injection in male Sprague-Dawley rats. In vivo microdialysis showed that the formalin-induced increase in the extracellular noradrenaline level within the vBNST was significantly suppressed by clonidine (100 µM) perfusion through a microdialysis probe. Bilateral intra-vBNST injections of clonidine (1 and 10 nmol/side) dose-dependently attenuated formalin-induced CPA without reducing nociceptive behaviors. These results suggest that clonidine inhibits noradrenaline release by acting on α(2)-adrenoceptors located in the vBNST and thereby attenuates pain-induced aversion. α(2)-adrenoceptors in the vBNST play a pivotal role in the regulation of negative affective, but not the sensory, component of pain.

Serotonin(1A) receptor-mediated synaptic response in the rat medial prefrontal cortex is altered by early life stress: in vivo and in vitro electrophysiological studies.

Serotonin (5-HT)(1A) receptors play a critical role in the 5-HTergic mechanism associated with fear memory. Previously we showed that adult rats exposed to early postnatal stress, i.e. footshock (FS) stress experienced during the second week (PND 14-18, 2W-FS), exhibited low levels of fear expression. The present study explored whether aversive stress exposure in the second and/or the third week (PND 21-25, 3W-FS) affects the function of cortical 5-HT(1A) receptors, using in vivo and in vitro experiments. A 5-HT(1A) receptor agonist, 8-OH-DPAT (0.5 mg/kg, i.p.), slightly decreased the evoked potential in the mPFC in Non-FS control and 3W-FS group. In contrast, the evoked potential increased after 8-OH-DPAT in the 2W-FS group. The in vitro experiment using patch-clamp recording showed that application of 8-OH-DPAT (10 microM) elicited membrane hyperpolarization of pyramidal neurons in the mPFC in the Non-FS and 3W-FS groups, whereas no changes in membrane potential were observed in the 2W-FS group. These results suggest that synaptic facilitation induced by 8-OH-DPAT resulted from functional changes in cortical 5-HT(1A) receptors. Thus, aversive stress exposure during the second postnatal period appears to cause persistent changes mediated via 5-HT(1A) receptors, presumably involving signal transduction regulating the development of synaptic connectivity underlying fear circuits.