Chronic ingestion of soy peptide supplementation reduces aggressive behavior and abnormal fear memory caused by juvenile social isolation.

Juvenile loneliness is a risk factor for psychopathology in later life. Deprivation of early social experience due to peer rejection has a detrimental impact on emotional and cognitive brain function in adulthood. Accumulating evidence indicates that soy peptides have many positive effects on higher brain function in rodents and humans. However, the effects of soy peptide use on juvenile social isolation are unknown. Here, we demonstrated that soy peptides reduced the deterioration of behavioral and cellular functions resulting from juvenile socially-isolated rearing. We found that prolonged social isolation post-weaning in male C57BL/6J mice resulted in higher aggression and impulsivity and fear memory deficits at 7 weeks of age, and that these behavioral abnormalities, except impulsivity, were mitigated by ingestion of soy peptides. Furthermore, we found that daily intake of soy peptides caused upregulation of postsynaptic density 95 in the medial prefrontal cortex and phosphorylation of the cyclic adenosine monophosphate response element binding protein in the hippocampus of socially isolated mice, increased phosphorylation of the adenosine monophosphate-activated protein kinase in the hippocampus, and altered the microbiota composition. These results suggest that soy peptides have protective effects against juvenile social isolation-induced behavioral deficits via synaptic maturation and cellular functionalization.

Single administration of a psychedelic [(R)-DOI] influences coping strategies to an escapable social stress.

Psychedelic compounds have potentially rapid, long-lasting anxiolytic, antidepressive and anti-inflammatory effects. We investigated whether the psychedelic compound (R)-2,5-dimethoxy-4-iodoamphetamine [(R)-DOI], a selective 5-HT2A receptor partial agonist, decreases stress-related behavior in male mice exposed to repeated social aggression. Additionally, we explored the likelihood that these behavioral changes are related to anti-inflammatory properties of [(R)-DOI]. Animals were subjected to the Stress Alternatives Model (SAM), an escapable social stress paradigm in which animals develop reactive coping strategies - remaining in the SAM arena (Stay) with a social aggressor, or dynamically initiated stress coping strategies that involve utilizing the escape holes (Escape) to avoid aggression. Mice expressing these behavioral phenotypes display behaviors like those in other social aggression models that separate animals into stress-vulnerable (as for Stay) or stress-resilient (as for Escape) groups, which have been shown to have distinct inflammatory responses to social stress. These results show that Stay animals have heightened cytokine gene expression, and both Stay and Escape mice exhibit plasma and neural concentrations of the inflammatory cytokine tumor necrosis factor-α (TNFα) compared to unstressed control mice. Additionally, these results suggest that a single administration of (R)-DOI to Stay animals in low doses, can increase stress coping strategies such as increasing attention to the escape route, promoting escape behavior, and reducing freezing during socially aggressive interaction in the SAM. Lower single doses of (R)-DOI, in addition to shifting behavior to suggest anxiolytic effects, also concomitantly reduce plasma and limbic brain levels of the inflammatory cytokine TNFα.

Systemic histone deacetylase inhibition ameliorates the aberrant responses to acute stress in socially isolated male mice.

Adverse experiences in early life can induce maladaptive responses to acute stress in later life. Chronic social isolation during adolescence is an early life adversity that can precipitate stress-related psychiatric disorders. We found that male mice after 8 weeks of adolescent social isolation (SI) have markedly increased aggression after being exposed to 2 h of restraint stress (RS), which was accompanied by a significant increase of AMPA receptor- and NMDA receptor-mediated synaptic transmission in prefrontal cortex (PFC) pyramidal neurons of SIRS males. Compared to group-housed counterparts, SIRS males exhibited a significantly decreased level of histone H3 acetylation in PFC. Systemic administration of class I histone deacetylase inhibitors, romidepsin or MS-275, ameliorated the aggressive behaviour, as well as general social interaction deficits, of SIRS males. Electrophysiological recordings also found normalization of PFC glutamatergic currents by romidepsin treatment of SIRS male mice. These results revealed an epigenetic mechanism and intervention avenue for aggression induced by chronic social isolation. KEY POINTS: Adolescent chronic social isolation can precipitate stress-related psychiatric disorders. A significant increase of glutamatergic transmission is found in the prefrontal cortex (PFC) of socially isolated male mice exposed to an acute stress (SIRS). Treatment with class I histone deacetylase (HDAC) inhibitors ameliorates the aggressive behaviour and social interaction deficits of SIRS males, and normalizes glutamatergic currents in PFC neurons. It provides an epigenetic mechanism and intervention avenue for aberrant stress responses induced by chronic social isolation.

Real-World Evidence of Antipsychotic Monotherapy Versus Polypharmacy in the Treatment of Schizophrenia Spectrum Disorders.

PURPOSE/BACKGROUND: It is still not well known whether antipsychotic monotherapy versus polypharmacy differs in terms of efficacy in the emergency department (ED) utilization, presentation with agitation/aggression, and rehospitalization in schizophrenia spectrum disorders (SSD) patients. This study aimed to determine the effectiveness of antipsychotic monotherapy and polypharmacy for these outcomes in the real world. METHODS/PROCEDURES: The study was conducted with electronic health records of 669 SSD patients admitted to the ED. Patients were evaluated in 4 groups according to antipsychotic use at the first admission to ED: antipsychotic noncompliance for more than 90 days, antipsychotic noncompliance for 15 to 90 days, antipsychotic monotherapy, and polypharmacy. All patients followed up for at least 1 year after index admission. The primary outcomes determined an association between antipsychotic monotherapy versus polypharmacy and all-cause psychiatric hospitalization between the groups after index admission in the SSD. FINDINGS/RESULTS: The groups, including patients with antipsychotic noncompliance, had higher ED visits, more hospitalizations, and more admissions with agitation/aggression compared with antipsychotic monotherapy or polypharmacy. However, no differences were found between monotherapy and polypharmacy groups regarding these outcomes. In addition, there was no difference in the risk of hospitalization in monotherapy antipsychotic users compared with polypharmacy users. Patients discharged with monotherapy or polypharmacy also had similar rehospitalization rates at follow-up. IMPLICATIONS/CONCLUSIONS: There is no positive evidence that recommending polypharmacy over antipsychotic monotherapy is superior with regard to the resulting frequency of ED visits, ED admissions with agitation/aggression, hospitalization, and rehospitalization. In this context, antipsychotic monotherapy may be preferred over polypharmacy in patients who are not resistant to treatment.

On an association between fear-induced aggression and striatal-enriched protein tyrosine phosphatase (STEP) in the brain of Norway rats.

Striatal-enriched protein tyrosine phosphatase (STEP) is a signal transduction protein involved in the pathogenesis of neuropathologies. A STEP inhibitor (TC-2153) has antipsychotic and antidepressant effects. Here, we evaluated the role of STEP in fear-induced aggression using Norway rats selectively bred for 90 generations for either high aggression toward humans (aggressive rats) or its absence (tame rats). We studied the effects of acute administration of TC-2153 on behavior and STEP expression in the brain of these animals and the influence of chronic treatment with TC-2153 on the behavior and STEP expression in aggressive rats in comparison with classic antidepressant fluoxetine, which is known to exert antiaggressive action. Acute TC-2153 administration decreased the aggressive reaction to humans in aggressive rats, while having no impact on the friendly behavior of tame rats. Moreover, in the elevated plus-maze test, the drug had an anxiolytic effect on both aggressive and tame rats. Aggressive rats demonstrated elevated levels of a STEP isoform (STEP46) as compared to tame animals, whereas acute TC-2153 administration significantly reduced STEP46 protein concentration in the brain of aggressive rats. Chronic treatment of aggressive rats with either TC-2153 or fluoxetine attenuated fear-induced aggression. Chronic administration of fluoxetine enhanced the exploratory activity in the elevated plus-maze test and decreased the STEP46 protein level in aggressive rats' hippocampus, whereas chronic TC-2153 administration did not affect these parameters. Thus, STEP46 can play an important role in the mechanisms of aggression and may mediate antiaggressive effects of TC-2153 and fluoxetine.

Inhibition of boldenone-induced aggression in rats by curcumin: Targeting TLR4/MyD88/TRAF-6/NF-κB pathway.

The illicit abuse of anabolic steroids is associated with brutal aggression, which represents a serious health hazard and social threat. Boldenone is commonly used for doping by athletes and adolescents for esthetic purposes and to enhance performance and endurance during competitions. However, the mechanistic pathways underlying boldenone-induced behavioral deviations and neuronal toxicity have not yet been elucidated. On the other hand, the natural polyphenol curcumin is appreciated for its relative safety, potent antioxidant activity, and anti-inflammatory properties. Therefore, the present study was initiated to explore the signaling pathways underlying boldenone-induced anxiety and aggression in rats, and the protective effects of curcumin. To achieve this aim, male Wistar albino rats were randomly distributed into control, curcumin (100 mg/kg in sesame oil, p.o., once daily), boldenone (5 mg/kg, intramuscular, once weekly), and combination groups. Rats were challenged across the open field, irritability, defensive aggression, and resident-intruder tests. The prefrontal cortex was used to assess serotonin level, oxidative stress markers, and mRNA expression of myeloid differentiation primary response gene (MyD88), TNFR-associated factor 6 (TRAF-6), tumor necrosis factor α (TNF-α), interleukin-1ß (IL-1ß), protein expression of toll-like receptor 4 (TLR4), and phosphorylated nuclear factor-κB transcription factor (NF-κB p65). Unprecedented, the current results showed that boldenone elicited aggression in rats accompanied by depleted serotonin, enhanced oxidative stress, and exaggerated inflammatory response via upregulation of TLR4/MyD88/TRAF-6/NF-κB pathway. Interestingly, curcumin mitigated boldenone-induced neurobehavioral disturbances in rats, normalized the oxidant/antioxidant balance, and suppressed TLR4/MyD88/TRAF-6/NF-κB pathway and its downstream proinflammatory signaling molecules TNF-α and IL-1ß.

Estrogen signaling modulates behavioral selection toward pups and amygdalohippocampal area in the rhomboid nucleus of the bed nucleus of the stria terminalis circuit.

Gonadal steroid hormone influences behavioral choice of adult animals toward pups, parental or aggressive. We previously reported that long-term administration of 17ß-estradiol (E2) to male mice during sexual maturation induces aggressive behavior toward conspecific pups, which is called "infanticide," and significantly enhanced excitatory synaptic transmission in the rhomboid nucleus of bed nucleus of the stria terminalis (BSTrh), which is an important brain region for infanticide. However, it is unclear how estrogen receptor-dependent signaling after sexual maturity regulates neural circuits including the BSTrh. Here we revealed that E2 administration to gonadectomized mice in adulthood elicited infanticidal behavior and enhanced excitatory synaptic transmission in the BSTrh by increasing the probability of glutamate release from the presynaptic terminalis. Next, we performed whole-brain mapping of E2-sensitive brain regions projecting to the BSTrh and found that amygdalohippocampal area (AHi) neurons that project to the BSTrh densely express estrogen receptor 1 (Esr1). Moreover, E2 treatment enhanced synaptic connectivity in the AHi-BSTrh pathway. Together, these results suggest that reinforcement of excitatory inputs from AHi neurons into the BSTrh by estrogen receptor-dependent signaling may contribute to the expression of infanticide.

Eventos adversos em uma unidade de internação psiquiátrica / Eventos adversos en una unidad de hospitalización psiquiátrica / Adverse events in a psychiatric hospitalization unit

RESUMO Objetivo descrever os eventos adversos presentes na internação psiquiátrica, analisando-os à luz da teoria do erro humano. Método pesquisa qualitativa, realizada em 2018 em um hospital psiquiátrico. Os dados foram coletados por entrevistas semiestruturadas com 15 profissionais de saúde da equipe multidisciplinar. A análise foi lexical por meio do software Alceste. Resultados evidenciaram-se eventos adversos medicamentosos por erros de administração ou por reações adversas a medicamentos, que produzem danos como impregnação, reações extrapiramidais associadas aos riscos de queda e broncoaspiração pela sonolência e/ou sedação. Outros danos relacionam-se à agressividade do paciente, que produz lesões corporais a si ou a outro, como durante uma tentativa de suicídio ou uso de violência como comportamento de fuga ou defesa. Considerações finais e implicações para a prática existem eventos adversos mais comuns nos ambientes de internação psiquiátrica que precisam ser de conhecimento da equipe de saúde mental porque demandam ações de mitigação por meio do fortalecimento dos sistemas de segurança do paciente. Os dados subsidiam ações para o fortalecimento dos sistemas de segurança nos ambientes de internação psiquiátrica e contribuem à reflexão do conceito de segurança do paciente na psiquiatria.

RESUMEN Objetivo describir los eventos adversos presentes en la hospitalización psiquiátrica, analizándolos a la luz de la teoría del error humano. Método investigación cualitativa, realizada en 2018 en un hospital psiquiátrico. Los datos se recolectaron a través de entrevistas semiestructuradas con 15 profesionales de la salud del equipo multidisciplinario. Se llevó a cabo el análisis léxico por medio del software Alceste. Resultados se evidenciaron eventos adversos por errores de administración o reacciones adversas al fármaco, que producen daños como impregnación y reacciones extrapiramidales asociadas al riesgo de caídas y broncoaspiración por somnolencia y / o sedación. Otros daños se relacionan con agresividad por parte del paciente, que produce daño corporal a sí mismo o a otro, como durante un intento de suicidio o uso de violencia como conducta de fuga o defensa. Conclusión e implicaciones para la práctica hay eventos adversos más comunes en entornos de hospitalización psiquiátrica que deben ser conocidos por el equipo de salud mental porque exigen acciones de mitigación a través del fortalecimiento de los sistemas de seguridad del paciente. Los datos reflejan la necesidad de implementar acciones para fortalecer los sistemas de seguridad en entornos de hospitalización psiquiátrica y contribuyen a la reflexión del concepto de seguridad del paciente en psiquiatría.

ABSTRACT Objective to describe the adverse events found in psychiatric hospitalization, analyzing them in the light of the human error theory. Method a qualitative research study, carried out in 2018 in a psychiatric hospital. The data were collected through semi-structured interviews with 15 health professionals from the multidisciplinary team. Analysis was of the lexical type using the Alceste software. Results adverse drug events were evidenced due to administration errors or adverse drug reactions, which produce harms such as impregnation and extrapyramidal reactions associated with the risks for falls and bronchoaspiration due to drowsiness and/or sedation. Other harms are related to the patient's aggressiveness, which produce bodily self-harm or harms to another person, such as during a suicide attempt or use of violence as an escape or defense behavior. Conclusion and implications for the practice some adverse events are more frequent in psychiatric hospitalization settings; such events need to be known by the mental health team, as they require mitigation actions through the strengthening of patient safety systems. The data subsidize actions for strengthening safety systems in psychiatric hospitalization settings and contribute to reflecting on the concept of patient safety in Psychiatry.

Effect of Central Administration of Brain-Derived Neurotrophic Factor (BDNF) on Behavior and Brain Monoamine Metabolism in New Recombinant Mouse Lines Differing by 5-HT1A Receptor Functionality.

Experiments were carried out on recombinant B6.CBA-D13Mit76C (B6-M76C) and B6.CBA-D13Mit76B (B6-M76B) mouse lines created by transferring a 102.73-118.83 Mbp fragment of chromosome 13, containing the 5-HT1A receptor gene, from CBA or C57BL/6 strains to a C57BL/6 genetic background, correspondingly. We have recently shown different levels of 5-HT1A receptor functionality in these mouse lines. The administration of BDNF (300 ng/mouse, i.c.v.) increased the levels of exploratory activity and intermale aggression only in B6-M76B mice, without affecting depressive-like behavior in both lines. In B6-M76B mice the behavioral alterations were accompanied by a decrease in the 5-HT2A receptor functional activity and the augmentation of levels of serotonin and its main metabolite, 5-HIAA (5-hydroxyindoleacetic acid), in the midbrain. Moreover, the levels of dopamine and its main metabolites, HVA (homovanillic acid) and DOPAC (3,4-dihydroxyphenylacetic acid), were also elevated in the striatum of B6-M76B mice after BDNF treatment. In B6-M76C mice, central BDNF administration led only to a reduction in the functional activity of the 5-HT1A receptor and a rise in DOPAC levels in the midbrain. The obtained data suggest the importance of the 102.73-118.83 Mbp fragment of mouse chromosome 13, which contains the 5-HT1A receptor gene, for BDNF-induced alterations in behavior and the brain monoamine system.

Acute cannabidiol treatment attenuates ethanol-induced place preference and reduces aggressivity in group-housed male rats.

Alcohol abuse is a widespread cause of aggressive and impulsive behaviors that impact the users as well as their entourage. However, only a few medications are effective. Recently, cannabidiol has been reported to improve mood disorders and recovery from substance abuse, yet the psychopharmacologic effects of cannabidiol in ethanol-induced drug reward and aggressivity remain unexplored. In the present study, we investigated the effects of cannabidiol on ethanol-induced place preference and aggressivity in individually and group-housed male rats using the conditioned place preference test, and intruder evoc aggression test, respectively. The obtained results showed that ethanol significantly increased locomotor activity, induced conditioned place preference in all animals, and, specifically, increased aggressivity in individually housed rats. These behavioural impairments induced by ethanol were associated with decreased glucocorticoid and mineralocorticoid receptors transcription in the prefrontal cortex. Notwithstanding, cannabidiol at a dose of 10 mg/kg significantly inhibited Et-OH-induced place preference in group-housed, but not in individually housed rats, and markedly inhibited the aggressive behaviour. These findings suggest that ethanol-induced behavioural impairments are dependent on the housing condition that may affect corticosterone receptors expression and subsequently the animal responsivity to cannabidiol treatment.

Pharmacological and philosophical considerations for the around-the-clock use of scheduled melatonin to promote sedation and reduce aggression in individuals with serious mental illness: a case report.

Melatonin, the endogenous hormone that helps maintain circadian rhythm, has been used exogenously for both primary and secondary sleep disorders. While the effects of melatonin given prior to planned sleep and to restore normal circadian sleep phases have been well studied, there is little information on the use of melatonin as a pharmacotherapeutic intervention for around-the-clock sedation to prevent agitation and aggressive patient behaviors. This is the first case report to our knowledge of melatonin used throughout the day, as a scheduled dose for prolonged treatment duration, to reduce aggression in a patient with severe mental illness.

Blockade of GPR55 in dorsal periaqueductal gray produces anxiety-like behaviors and evocates defensive aggressive responses in alcohol-pre-exposed rats.

GPR55 is a receptor expressed in several central nervous system areas, including the periaqueductal gray (PAG). Current knowledge of GPR55 physiology in PAG only covers pain integration, but it is involved in other actions such as anxiety, panic, motivated behaviors, and alcohol intake. In the present study, juvenile male Wistar rats were unexposed (alcohol-naïve group; A-naïve) or exposed to alcohol for 5 weeks (alcohol-pre-exposed group; A-pre-exposed). Posteriorly, animals received intra dorsal-PAG (D-PAG) injections of vehicle (10% DMSO), LPI (1 nmol/0.5 µl) and ML-193 (1 nmol/0.5 µl, a selective GPR55 antagonist). Finally, defensive burying behavior (DBB) paradigm and alcohol preference were evaluated. Compared to the A-naïve group, the A-pre-exposed vehicle group had higher (p < 0.05): (i) time of immobility; (ii) latency to and duration of burying; and (iii) alcohol consumption. In both groups (i.e., A-naïve and A-pre-exposed) treatment with LPI: (i) decreased duration of burying (p < 0.05); (ii) suppressed time of immobility; and (iii) increased alcohol intake (p < 0.05). On the other hand, treatment with ML-193: (i) decreased duration of immobility in A-pre-exposed (but not in A-naïve rats); (ii) promoted an aggressive response against the shock-probe in A-pre-exposed rats (p < 0.05); and (iii) increased alcohol intake (p < 0.05). Our results suggest that blockade of GPR55 in D-PAG is associated with anxiety-like behaviors, defensive aggressive behaviors, and higher alcohol intake, whereas LPI in D-PAG produced anxiolytic-like effects (probably GPR55-mediated), but not prevention of alcohol intake.

Chemogenetic modulation of histaminergic neurons in the tuberomamillary nucleus alters territorial aggression and wakefulness.

Designer receptor activated by designer drugs (DREADDs) techniques are widely used to modulate the activities of specific neuronal populations during behavioural tasks. However, DREADDs-induced modulation of histaminergic neurons in the tuberomamillary nucleus (HATMN neurons) has produced inconsistent effects on the sleep-wake cycle, possibly due to the use of Hdc-Cre mice driving Cre recombinase and DREADDs activity outside the targeted region. Moreover, previous DREADDs studies have not examined locomotor activity and aggressive behaviours, which are also regulated by brain histamine levels. In the present study, we investigated the effects of HATMN activation and inhibition on the locomotor activity, aggressive behaviours and sleep-wake cycle of Hdc-Cre mice with minimal non-target expression of Cre-recombinase. Chemoactivation of HATMN moderately enhanced locomotor activity in a novel open field. Activation of HATMN neurons significantly enhanced aggressive behaviour in the resident-intruder test. Wakefulness was increased and non-rapid eye movement (NREM) sleep decreased for an hour by HATMN chemoactivation. Conversely HATMN chemoinhibition decreased wakefulness and increased NREM sleep for 6 h. These changes in wakefulness induced by HATMN modulation were related to the maintenance of vigilance state. These results indicate the influences of HATMN neurons on exploratory activity, territorial aggression, and wake maintenance.

Intranasal oxytocin drives coordinated social approach.

Coordinated responses to challenge are essential to survival for bonded monogamous animals and may depend on behavioral compatibility. Oxytocin (OT) context-dependently regulates social affiliation and vocal communication, but its role in pair members' decision to jointly respond to challenge is unclear. To test for OT effects, California mouse females received an intranasal dose of OT (IN-OT) or saline after bonding with males either matched or mismatched in their approach response to an aggressive vocal challenge. Pair mates were re-tested jointly for approach response, time spent together, and vocalizations. Females and males converged in their approach after pairing, but mismatched pairs with females given a single dose of IN-OT displayed a greater convergence that resulted from behavioral changes by both pair members. Unpaired females given IN-OT did not change their approach, indicating a social partner was necessary for effects to emerge. Moreover, IN-OT increased time spent approaching together, suggesting behavioral coordination beyond a further increase in bonding. This OT-induced increase in joint approach was associated with a decrease in the proportion of sustained vocalizations, a type of vocalization that can be associated with intra-pair conflict. Our results expand OT's effects on behavioral coordination and underscore the importance of emergent social context.

Chronic intranasal oxytocin reverses stress-induced social avoidance in female prairie voles.

Social anxiety disorder (SAD) is a prevalent mental illness in both men and women, but current treatment approaches with selective serotonin reuptake inhibitors (SSRI) have limited success. The neuropeptide oxytocin (OXT) has become a therapeutic target due to its prosocial and anxiolytic effects. Nevertheless, no research has focused on the impact of chronic OXT treatment in animal models of SAD. Social defeat stress is an animal model of social conflict that reliably induces a social avoidance phenotype, reflecting symptoms observed in individuals suffering from SAD. Here, we used the socially monogamous prairie vole, which exhibits aggressive behavior in both sexes, to examine the effects of OXT and SSRI treatment following social defeat stress in males and females. Defeated voles became avoidant in unfamiliar social situations as early as one day after defeat experience, and this phenotype persisted for at least eight weeks. OXT receptor (OXTR) binding in mesocorticolimbic and paralimbic regions was reduced in defeated females during the eight-week recovery period. In males, serotonin 1A receptor binding was decreased in the basolateral amygdala and dorsal raphe nucleus starting at one week and four weeks post-defeat, respectively. Chronic intranasal treatment with OXT had a negative effect on sociability and mesolimbic OXTR binding in non-defeated females. However, chronic intranasal OXT promoted social engagement and increased mesolimbic OXTR binding in defeated females but not males. SSRI treatment led to only modest effects. This study identifies a sex-specific and stress-dependent function of intranasal OXT on mesolimbic OXTR and social behaviors.

Effects of GnRH agonists on testosterone and testosterone-stimulated parameters for contraception and aggression reduction in male lion-tailed Macaques (Macaca silenus).

Managing social groups in zoos requires controlling reproduction in individuals that do not have a current breeding recommendation, while simultaneously maintaining social harmony and animal well-being. Contraceptives, such as gonadotropin releasing-hormone (GnRH) agonists, that suppress testosterone production, offer a potential solution. They achieve infertility by interrupting spermatogenesis and may ameliorate androgen-induced aggression. This study investigated the effects of two GnRH agonists, histrelin and deslorelin, on testosterone, testis size, body weight and sperm production in male lion-tailed macaques, along with subjective observations of aggressive behavior. Five trials at three institutions with 14 males demonstrated that 100 mg histrelin or 9 to 12 mg of deslorelin could at least temporarily reduce testosterone, but a lower 6 mg dose was ineffective. However, ability of deslorelin to produce azoospermia varied among males, even at the highest dose. In general, a higher dose was needed (1) to achieve than to maintain suppression of any measured parameter and (2) to suppress sperm production than testosterone concentration. Testosterone production was also more likely than sperm production to recover, suggesting possible damage to seminiferous tubules but not to Leydig cells. Aggressive behavior was reduced in all but the group receiving the lowest dose. This allowed social groups to be maintained for many years despite recovery of testosterone in some males, suggesting that new social roles had been learned and become independent of androgen influence.

Kamishoyosan (a Japanese traditional herbal formula), which effectively reduces the aggressive biting behavior of male and female mice, and potential regulation through increase of Tph1, Tph2, and Esr2 mRNA levels.

Kamishoyosan (KSS), a Japanese traditional herbal formula, is used to treat symptoms related to the autonomic nervous system in men and women; it is especially known for improving the symptoms of irritability (e.g., bad temper and persistent anger). Although clinical and ethological studies of KSS have been conducted, its efficacy in reducing irritability remains to be validated. In the present study, male and female ddY-strain mice were isolation-reared for 8 weeks (from the third postnatal week) to induce pathologically aggressive biting behavior (ABB), which was used as an indicator of irritability. The ABB of mice toward metal rods was measured using the Aggressive Response Meter. An intraperitoneal administration of KSS (100 mg/kg) effectively reduced ABB in male and female mice at 2 h after the administration; however, this effect was canceled by prior administration of WAY-100635 [a 5-hydroxytryptoamine (5-HT)-1A receptor antagonist; 0.5 mg/kg] and bicuculline (a type-A gamma-aminobutyric acid receptor antagonist; 1.0 mg/kg). Additionally, tamoxifen, ICI-182780, and G-15 (all estrogen receptor antagonists) inhibited the action of KSS in a dose-dependent manner. Furthermore, gene expression of tryptophan hydroxylase (Tph) 1 and Tph2 were increased and 5-HT immunofluorescence was slightly increased in the dorsal raphe nucleus (DRN) of isolation-reared mice administered with KSS. Collectively, these results indicate that KSS effectively reduces ABB in isolation-reared male and female mice through stimulation of 5-HT production in the DRN. Our findings also suggest that gene expression of estrogen receptor (Esr) 2 increased in the DRN might be associated with the reduction of ABB.

An open label pilot study of the safety and tolerability of perampanel in amyotrophic lateral sclerosis.

INTRODUCTION/AIMS: Perampanel, a selective noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) antagonist, is capable of slowing the progression of the amyotrophic lateral sclerosis (ALS) phenotype and increasing the number of anterior horn cells in transgenic mice. Trials of perampanel in epilepsy showed a favorable tolerability profile. In this study we aimed to determine the tolerability and safety of perampanel in patients with ALS. METHODS: Enrolled subjects were started on 2 mg/day of perampanel and the dose was increased by 2 mg/day every week to a maximum dose of 8 mg/day. Our primary outcome measure was tolerability, which was evaluated by monitoring adverse events. The secondary outcome measure was clinical progression, assessed using the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) and spirometry. RESULTS: Six participants were enrolled. All had adverse events, mostly behavioral. Two completed the trial and the other four withdrew due to adverse events. All participants reported resolution of these events after discontinuation of the drug. The trial was halted due to the large number of adverse events. DISCUSSION: The use of perampanel in this study of ALS was limited by its poor tolerability.

Ethanol as a stimulus to risky and auto-aggressive behaviour.

According to the World Health Organization (WHO), ethyl alcohol occupies the third place among health risks for the general population, causing damage to health as well as social damage. Ethanol is also considered the greatest risk factor in injuries. Both alcohol and its main metabolite, acetaldehyde, are directly toxic to tissues and lead to several systemic pathologies. Alcohol abuse may also lead to mental health disorders. Although one-in-eight adult Poles abstains from drinking alkohol, 10-20% of adult Poles drink alcohol regularly. It is estimated that this group includes about 900,000 addicts, and over 2,000,000 people who drink alcohol at a risky or harmful level. It affects their occurrence and their consequences Drink- driving is one of the problems most often raised, although alcohol is a documented risk factor in pedestrian accidents. It is also an important risk factor for suicidal behaviour with people under the influence of alcohol choosing more radical and effective methods of committing suicide, such as hanging or 'throwing themselves under a moving vehicle.' Only properly selected and consistently taken preventive actions can improve the tragic statistics related to ethanol stimulating risky and auto-aggressive behaviours. It is also necessary to improve the system for reporting such events because only reliable statistics enable proper assessment of the scale of the problem, and the effectiveness of these activities.