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Abstract: Many psychiatric patients do not respond to conventional therapy. There is a vast effort to investigate possible mechanisms involved in treatment resistance, trying to provide better treatment options, and several data points toward a possible involvement of inflammatory mechanisms. Microglia, glial, and resident immune cells are involved in complex responses in the brain, orchestrating homeostatic functions, such as synaptic pruning and maintaining neuronal activity. In contrast, microglia play a major role in neuroinflammation, neurodegeneration, and cell death. Increasing evidence implicate microglia dysfunction in neuropsychiatric disorders. The mechanisms are still unclear, but one pathway in microglia has received increased attention in the last 8 years, i.e., the NLRP3 inflammasome pathway. Stress response and inflammation, including microglia activation, can be attenuated by Cannabidiol (CBD). CBD has antidepressant, anti-stress, antipsychotic, anti-inflammatory, and other properties. CBD effects are mediated by direct or indirect modulation of many receptors, enzymes, and other targets. This review will highlight some findings for neuroinflammation and microglia involvement in stress-related psychiatric disorders, particularly addressing the NLRP3 inflammasome pathway. Moreover, we will discuss evidence and mechanisms for CBD effects in psychiatric disorders and animal models and address its potential effects on stress response via neuroinflammation and NLRP3 inflammasome modulation.

The endocannabinoid system is an important regulator of the hormonal and behavioral stress responses, which critically involve corticotropin-releasing factor (CRF) and its receptors. While it has been shown that CRF and the cannabinoid type 1 (CB1) receptor are co-localized in several brain regions, the physiological relevance of this co-expression remains unclear. Using double in situ hybridization, we confirmed co-localization in the piriform cortex, the lateral hypothalamic area, the paraventricular nucleus, and the Barrington's nucleus, albeit at low levels. To study the behavioral and physiological implications of this co-expression, we generated a conditional knockout mouse line that selectively lacks the expression of CB1 receptors in CRF neurons. We found no effects on fear and anxiety-related behaviors under basal conditions nor after a traumatic experience. Additionally, plasma corticosterone levels were unaffected at baseline and after restraint stress. Only acoustic startle responses were significantly enhanced in male, but not female, knockout mice. Taken together, the consequences of depleting CB1 in CRF-positive neurons caused a confined hyperarousal phenotype in a sex-dependent manner. The current results suggest that the important interplay between the central endocannabinoid and CRF systems in regulating the organism's stress response is predominantly taking place at the level of CRF receptor-expressing neurons.

Post-traumatic stress disorder (PTSD) is a chronic disease caused by traumatic incidents. Numerous studies have revealed grey matter volume differences in affected individuals. The nature of the disease renders it difficult to distinguish between a priori versus a posteriori changes. To overcome this difficulty, we studied the consequences of a traumatic event on brain morphology in mice before and 4 weeks after exposure to brief foot shocks (or sham treatment), and correlated morphology with symptoms of hyperarousal. In the latter context, we assessed hyperarousal upon confrontation with acoustic, visual, or composite (acoustic/visual/tactile) threats and integrated the individual readouts into a single Hyperarousal Score using logistic regression analysis. MRI scans with subsequent whole-brain deformation-based morphometry (DBM) analysis revealed a volume decrease of the dorsal hippocampus and an increase of the reticular nucleus in shocked mice when compared to non-shocked controls. Using the Hyperarousal Score as regressor for the post-exposure MRI measurement, we observed negative correlations with several brain structures including the dorsal hippocampus. If the development of changes with respect to the basal MRI was considered, reduction in globus pallidus volume reflected hyperarousal severity. Our findings demonstrate that a brief traumatic incident can cause volume changes in defined brain structures and suggest the globus pallidus as an important hub for the control of fear responses to threatening stimuli of different sensory modalities.

Diversas evidências sugerem o envolvimento de citocinas pró-inflamatórias em pacientes psiquiátricos e modelos animais de transtornos mentais. Interleucina-1β (IL-1β), amplamente descrita como agente neuroinflamatório, apresenta-se elevada em pacientes depressivos, ansiosos e com transtorno de estresse pós-traumático (PTSD). A via de NFkB e o inflamassoma de NLRP3 medeiam a transcrição e função de IL-1β, induzindo a ativação do sistema imune inato e inflamação. A ativação deste complexo tem sido amplamente relacionada à transtornos mentais. O canabidiol (CBD) possui inúmeros efeitos terapêuticos já descritos. Entretanto, a interação entre CBD e sistema imunológico, além do envolvimento de mecanismos imunológicos sobre os efeitos comportamentais da droga, ainda são pouco conhecidos. Desse modo, este trabalho objetivou avaliar o envolvimento do inflamassoma de NLRP3 no mecanismo pelo qual o CBD previne ou reverte alterações comportamentais e neuroimunoendócrinas em modelos animais. Para isso, machos C57BL/6 adultos foram expostos aos protocolos: estresse crônico imprevisível (21 dias), estresse por restrição (6h) ou 2 choques inescapáveis nas patas (1,5mA). Adicionalmente, usou-se modelo animal de ansiedade baseado no acasalamento seletivo. Os resultados obtidos através do modelo de estresse crônico imprevisível evidenciaram que os animais estressados apresentam redução do peso corpóreo, aumento do tempo de imobilidade no teste do nado forçado e hipolocomoção no teste do campo aberto em comparação com animais controle. Entretanto, no teste de supressão da alimentação pela novidade, os animais não apresentavam a supressão da alimentação apenas pela neofobia, mas sim de modo geral. O teste de preferência pela sacarose não nos forneceu dados robustos. O CBD não alterou os efeitos comportamentais do estresse. Diante da baixa reprodutibilidade dos resultados obtidos com este modelo, decidimos utilizar o modelo de estresse por restrição por 6 horas. Esse modelo diminuiu o tempo de permanência e o número de entradas nos braços abertos do labirinto em cruz elevado (LCE) 24 h e 7 dias após o estresse. Não houveram alterações no teste de suspensão pela cauda e peso corpóreo. O tratamento repetido com o CBD 30 mg/kg preveniu o estabelecimento das consequências comportamentais do estresse nos animais estressados, porém induziu efeito tipo-ansiogênico per se nos animais não estressados. Durante o doutorado sanduíche, foram utilizados camundongos com comportamentos extremos relacionados a ansiedade de modo inato (HAB) e seus respectivos controles (NAB). Os animais HAB apresentaram comportamentos relacionados à ansiedade no teste do LCE e beetle mania task quando comparados aos NAB. No teste de medo condicionado ao som, os animais HAB são capazes de extinguir a memória aversiva, porém não são capazes de consolidar a extinção e possuem recuperação espontânea das respostas de medo, quando comparados aos animais NAB. O tratamento com o CBD (15 e 30 mg/kg) não induziu alterações em comparação com o grupo veículo nos animais HAB em nenhum dos testes utilizados. Diante da ausência de efeitos agudos do CBD, decidimos trocar para um modelo animal de PTSD. Três semanas após o trauma, o tratamento diário teve início: veículo ou CBD (10 a 30 mg/kg, 1 injeção i.p.). Depois de uma semana de tratamento, os animais foram testados para generalização e efeitos de longa duração dos choques e, 24 horas depois, os animais foram testados para expressão e recuperação do medo. O estresse aumentou o tempo de congelamento e diminuir o número de rearings em ambos os testes. O tratamento repetido com o CBD não reverteu as alterações induzidas pelo modelo. Não houve efeito do estresse e/ou do tratamento nos animais submetidos ao trauma e testados no beetle mania task. Em geral, as inúmeras limitações enfrentadas dificultaram o andamento do projeto. Os resultados obtidos com o modelo de estresse único por restrição evidenciam que esse protocolo induz alterações que viabilizam estudos pré-clínicos de transtorno mentais e que o tratamento repetido com o CBD, na dose de 30 mg/kg, induz um efeito dual que depende da condição prévia de estresse do animal. Já os estudos com a linhagem HAB evidenciam que esses animais possuem o fenótipo relacionado à ansiedade de modo inato, porém que o CBD não possui efeito agudo nesses animais. Por fim, o modelo animal de PTSD, induziu alterações comportamentais robustas e duradouras. Apesar de o CBD não alterar os efeitos do estresse, este resultado pode sugerir que este fitocanabinoide não seja efetivo em pacientes com o quadro de TEPT já estabelecido após um longo período do trauma; uma vez que estudos prévios de nosso grupo e de outros grupos evidenciaram que o composto pode prevenir as consequências comportamentais em outros modelos animais de TEPT, quando administrado logo após o trauma ou após um novo estresse - reminder. Several pieces of evidence suggest the involvement of proinflammatory cytokines in psychiatric patients as well as in animal models of mental disorders. Interleukin-1β (IL- 1β) levels, widely described as neuroinflammatory agent, is increased in patients with depression, anxiety and post-traumatic stress disorder (PTSD). NFkB and NLRP3 inflammasome pathway mediate IL-1β transcription and function. The activation of this complex has been related to mental disorders. Cannabidiol (CBD) has several therapeutical effects already described. However, the interaction between CBD and immune system, as well as the involvement of immunological mechanisms mediating behavioral effects of this drug, are still poorly understood. This work aimed to evaluate the involvement of NLRP3 inflammasome pathway on the mechanisms by which CBD can prevent of reverse behavioral and neuroimmunoendocrine alterations in animal models. Adult male C57Bl/6 mice were exposed to the following protocols: chronic unpredictable stress (CUS; 21 days), restraint stress (RS; 6h) or 2 inescapable foot shocks (PTSD; 1.5mA). Additionally, an animal model of anxiety, based on selective breeding, was used. Results obtained with CUS model showed a reduction on the body weight, increase in immobility time on the forced swim test as well as hipolocomotion on the open field test of stressed mice in comparison with control. However, on the novelty suppressed feeding test, animals showed that the feeding was generally suppressed and not just by neophobia. Sucrose preference test wasn\'t able to give us reliable results. CBD wasn\'t able to alter behavioral effects induced by stress. Considering the low reproducibility of the results obtained with this model, we decided to use RS. Six hours of RS decreased the time spent and number of entries in the open arms of the elevated plus maze (EPM) 24h and 7 days after stress. There were no changes on the tail suspension test and body weight. Repeated treatment with CBD (30 mg/kg) prevents behavioral consequences of stress in stressed mice, despite induced an anxiogenic-like effect per se in controls. During the abroad internship in Germany, we used mice with high-anxiety trait (HAB) and their respective controls (NAB). HAB mice showed an increase in anxiety related behaviors in the EPM and beetle mania task when compared to NAB. In the auditory fear conditioning test, HAB mice did extinguish aversive memory, however were not able to consolidate extinction memory and spontaneously recovered fear responses when compared to NAB. CBD treatment (15 and 30 mg/kg) did not show any improvement in comparison with vehicle in HAB mice. In the absence of acute CBD effects, we decided to use an animal model of PTSD. Three weeks after the trauma, daily treatment with vehicle or CBD (10-30 mg/kg, 1 injection i.p.) started. After one week of treatment, animals were tested for generalization and long-lasting consequences of shocks. Twenty for hours later, mice were tested for fear expression and recovery. Stress increased freezing time and decreased number of rearings in both tests. Repeated treatment with CBD did not revert the alterations induced by this model. In the same way, there was no effect of stress and/or treatment of mice submitted to trauma and tested in the beetle mania task. In general, the difficulties faced hindered the progress of the project. Results obtained with CUS suggest that this protocol induce changes that makes possible preclinical studies of mental disorders and that repeated treatment with CBD, 30 mg/kg, induce a dual effect that depends on the previous stress condition of the animal. The experiment with HAB lineage evidence that these mice did present innate anxiety-related phenotype, despite CBD had no acute effect. Finally, PTSD model is able to induce robust and long-lasting behavioral alterations in mice. Although CBD wasn\'t able to ameliorate these stress\' effects, this result can suggest that this phytocannabinoid is not effective in patients with PTSD already installed after a long period of trauma; since previous studies by our and other groups have shown that the compound can prevent behavioral consequences in other animal models of PTSD, when administered shorly after the trauma or a new stressor - reminder.

It was evaluated the effects of maternal treatment with the Trichilia catigua (ExTc) crude extract on the antibodies’ production by their offspring. Female rats received ExTc or saline from the first day of pregnancy until the twenty-first day after the birth of the pups, when the pups were weaned. All pups were inoculated with two doses of 50 μg of IgY diluted in aluminium hydroxide/PBS on days 26 and 40 of life. Antibody levels were analysed by ELISA. Our results show an increase in levels of IgG1 and IgG2a anti-IgY in female offspring of mothers treated with ExTc compared to female offspring of untreated mothers. Furthermore, ExTc treatment suppressed the production of IgG2a anti-IgY antibodies in males. The data show that maternal exposure to ExTc can modulate the production of antibodies in the offspring.

Background: The dorsal hippocampus has a central role in modulating cardiovascular responses and behavioral adaptation to stress. The dorsal hippocampus also plays a key role in stress-associated mental disorders. The endocannabinoid system is widely expressed in the dorsal hippocampus and modulates defensive behaviors under stressful conditions. The endocannabinoid anandamide activates cannabinoid type 1 receptors and is metabolized by the fatty acid amide hydrolase enzyme. Aims: We sought to verify whether cannabinoid type 1 receptors modulate stress-induced cardiovascular changes, and if pharmacological fatty acid amide hydrolase inhibition in the dorsal hippocampus would prevent the cardiovascular responses and the delayed anxiogenic-like behavior evoked by restraint stress in rats via cannabinoid type 1 receptors. Methods: Independent groups received intra-dorsal-hippocampal injections of N-(piperidin-1yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-hpyrazole-3-carboxamide (AM251; cannabinoid type 1 receptor antagonist/inverse agonist, 10–300 pmol) and/or cyclohexyl carbamic acid 3′-carbamoyl-biphenyl-3-yl ester (URB597; fatty acid amide hydrolase inhibitor, 10 pmol) before the restraint stress session. Cardiovascular response during restraint stress or later behavioral parameters were evaluated. Results: Acute restraint stress altered the cardiovascular response, characterized by increased heart rate and mean arterial pressure, as well as decreased tail cutaneous temperature. It also induced a delayed anxiogenic-like effect, evidenced by reduced open arm exploration in the elevated plus maze 24 h after stress. AM251 exacerbated the stress-induced cardiovascular responses after injection into the dorsal hippocampus. In contrast, local injection of URB597 prevented the cardiovascular response and the delayed (24 h) behavioral consequences of restraint stress, effects attenuated by pretreatment with AM251. Conclusion: Our data corroborate previous results indicating that the hippocampal endocannabinoid system modulates the outcome of stress exposure and suggest that this could involve modulation of the cardiovascular response during stress exposure.

Made available in DSpace on 2018-11-26T16:48:04Z (GMT). No. of bitstreams: 0 Previous issue date: 2016-07-01 Depression is one of the most prevalent disorders in the world and may occur during pregnancy and postpartum periods. Fluoxetine (FLX) has been widely prescribed for use during depression in pregnancy and lactation. This study aimed to investigate if in utero and lactational exposure to FLX could compromise reproductive parameters in female offspring. Wistar rats received, by daily gavage, FLX 5 mg/kg or 0.3 ml of water (control group) from the first gestational day until weaning (21 days). Assessments in the female offspring included: body weight, anogenital distance, vaginal opening, first estrus, estrous cycle, reproductive organs weight, uterine morphometric analyses, ovarian follicle and corpora lutea counting, estradiol plasmatic concentration, sexual behavior, maternal behavior and fertility test. Exposure to FLX delayed the puberty onset in female pups. The present study demonstrated that developmental exposure to FLX can deregulate the neuroendocrine hormonal control of female offspring during prepubertal and pubertal periods. (C) 2016 Elsevier Inc. All rights reserved. Univ Estadual Londrina, Dept Physiol Sci, BR-86051980 Londrina, Parana, Brazil Univ Sao Paulo, Dept Morphol Estomatol & Physiol, Ribeirao Preto, SP, Brazil Sao Paulo State Univ, Dept Physiol, Botucatu, SP, Brazil Univ Estadual Londrina, Dept Biol, BR-86051980 Londrina, Parana, Brazil Sao Paulo State Univ, Dept Physiol, Botucatu, SP, Brazil

O Canabidiol (CBD), principal composto não-psicotomimético da Cannabis sativa, possui diversas propriedades farmacológicas, incluindo a indução de efeitos tipoantidepressivos e ansiolíticos em roedores após administração sistêmica. O isolamento social aumenta comportamentos agressivos em camundongos, condição denominada agressão induzida pelo isolamento social ou agressão territorial. Drogas ansiolíticas e antidepressivas podem atenuar comportamentos agressivos. Desse modo, o objetivo do presente trabalho foi avaliar se o CBD atenuaria comportamentos agressivos induzidos pelo isolamento social em camundongos. Camundongos Suíços machos (7-8 semanas de idade no dia do isolamento, 30-40 g no dia do teste) foram mantidos isolados (camundongos residentes) para indução dos comportamentos agressivos. Paralelamente, camundongos co-específicos (camundongos intrusos) foram mantidos agrupados (oito por caixa). Neste modelo, um camundongo intruso da mesma linhagem, sexo e idade foi colocado na caixa moradia do residente. As interações entre os camundongos residente e intruso foram gravadas por 20 min e a latência para a primeira mordida contra o intruso, o número de ataques e o tempo total de ataques foram analisados por um observador cego aos grupos experimentais. Após 10 dias de isolamento social, foi testado se a administração aguda (i.p.) de CBD (5, 15, 30 ou 60 mg/kg), 30 min antes do teste, atenuaria comportamentos agressivos dos camundongos residentes contra os intrusos. Para avaliar a participação de receptores 5-HT1A e CB1 nos efeitos do CBD, grupos independentes de animais receberam 1 injeção prévia de WAY 100635 (antagonista dos receptores 5-HT1A, 0,3 mg/kg) ou AM251 (antagonista dos receptores CB1, 1 mg/kg), 30 min antes do CBD (15 mg/kg). Para controlar possíveis efeitos motores da droga, grupos independentes de animais tratados com doses efetivas de CBD ou não efetivas de WAY100635 ou AM251 foram submetidos ao actímetro para avaliação da atividade locomotora total. O CBD (15 mg/kg) aumentou a latência para o residente atacar o intruso e este efeito foi atenuado tanto pela administração prévia de AM251 (VEI+VEI: 186,62±83,16; VEI+CBD: 956,25±150,77; AM+VEI: 271,71±156,18; AM+CBD: 395,86±208,24; p=0,030) quanto WAY100635 (VEI+VEI: 116,33±29,38; VEI+CBD: 860,87±177,36; WAY+VEI: 305,12±159,16; WAY+CBD: 302,57±154,68; p=0,011). Além disso, o CBD reduziu o número de ataques em todas as doses testadas (VEI: 23,00±3,66; CBD 5: 12,25±2,43; CBD 15: 6,62±2,43; CBD 30: 7,71±3,24; CBD 60: 8,16±2,36; p=0,002) e as doses intermediárias (15 e 30 mg/kg) foram capazes de diminuir o tempo total de ataques (VEI: 114,37±22,65; CBD 5: 80,87±23,83; CBD 15: 40,00±14,58; CBD 30: 25,86±12,88; CBD 60: 54,67±9,68; p=0,018), ambos os efeitos sendo atenuados pelo AM251 (Número de ataques - VEI+VEI: 19,25±2,56; VEI+CBD: 3,25±2,36; AM+VEI: 22,86±4,97; AM+CBD: 14,14±4,10; p=0,028; Tempo total de ataques - VEI+VEI: 66,62±9,19; VEI+CBD: 11,75±9,56; AM+VEI: 118,86±31,00; AM+CBD: 58,71±17,45; p=0,049) e WAY100635 (Número de ataques - VEI+VEI: 30,83±6,77; VEI+CBD: 7,87±4,68; WAY+VEI: 22,50±5,06; WAY+CBD: 23,57±6,74; p=0,059; Tempo total de ataques - VEI+VEI: 151,17±32,65; VEI+CBD: 16,75±10,88; WAY+VEI: 113,75±24,66; WAY+CBD: 76,29±21,36; p=0,002). Não foi observado efeito motor do CBD em nenhuma das doses testadas, bem como do WAY100635 e AM251. Esses resultados evidenciam que o CBD atenua comportamentos agressivos em camundongos e nos permitem sugerir um mecanismo misto, visto que há o envolvimento de receptores CB1 e 5-HT1A. Desse modo, este fitocanabinoide poderia ser uma alternativa terapêutica para tratar comportamentos agressivos associados a transtornos psiquiátricos Cannabidiol (CBD), a major non-psychotomimetic compound from Cannabis sativa plant, induces anxiolytic- and antidepressant-like effects in rodents after systemic administration. Long-term individual housing increases aggressive behavior in mice, a condition named isolation-induced aggression or territorial aggression, which can be attenuated by anxiolytic and antidepressant drugs. Thus, the aim of the present study was to verify whether CBD would attenuate the aggressive behavior induced by social isolation. Male Swiss mice (7-8 weeks of age on the isolation day, 30-40 g on the test day) were individually housed (resident mice) to induce aggressive behavior, while conspecific mice (intruder mice) were grouped housed (eight per cage). In this model, an intruder mouse of the same strain, sex and age is placed in the resident home cage. The resident-intruder interactions were videotaped for 20 min and the latency to the first bite against the intruder, the number of attacks and the total duration of aggressive encounters were recorded and later analyzed by an observer blind to the treatment groups. After 10 days of social isolation, we tested if acute intraperitoneal CBD administration (5, 15, 30 and 60 mg/kg) to the resident mice 30 min prior to the test would attenuate aggressive-like behavior towards the intruder animal. To evaluate the involvement of 5-HT1A and CB1 receptors in the CBD effects, independent groups of animals were injected with WAY100635 (0.3 mg/kg) or AM251(1 mg/kg) 30 min prior to CBD (15 mg/kg). To control possible motor effects, independent animals treated with effective doses of CBD or ineffective doses of WAY100635 or AM251 were submitted to the actimeter to evaluate the total locomotor activity. CBD (15 mg/kg) increased latency to attack the intruder and this effect was attenuated by the prior administration of AM251 (VEI+VEI: 186.62±83.16; VEI+CBD: 956.25±150.77; AM+VEI: 271.71±156.18; AM+CBD: 395.86±208.24; p=0.030) or WAY100635 (VEI+VEI: 116.33±29.38; VEI+CBD: 860.87±177.36; WAY+VEI: 305.12±159.16; WAY+CBD: 302.57±154.68; p=0.011). Moreover, CBD reduced the number of attacks in all tested doses (VEI: 23.00±3.66; CBD 5: 12.25±2.43; CBD 15: 6.62±2.43; CBD 30: 7.71±3.24; CBD 60: 8.16±2.36; p=0.002) as well as the duration of aggressive behavior encounters in the intermediary doses (15 and 30 mg/kg; VEI: 114.37±22.65; CBD 5: 80.87±23.83; CBD 15: 40.00±14.58; CBD 30: 25.86±12.88; CBD 60: 54.67±9.68; p=0.018), both effects were attenuated by AM251 (Number of attacks - VEI+VEI: 19.25±2.56; VEI+CBD: 3.25±2.36; AM+VEI: 22.86±4.97; AM+CBD: 14.14±4.10; p=0.028; Total time of attacks - VEI+VEI: 66.62±9.19; VEI+CBD: 11.75±9.56; AM+VEI: 118.86±31.00; AM+CBD: 58.71±17.45; p=0.049) and WAY100635 (Number of attacks - VEI+VEI: 30.83±6.77; VEI+CBD: 7.87±4.68; WAY+VEI: 22.50±5.06; WAY+CBD: 23.57±6.74; p=0.059; Total time of attacks - VEI+VEI: 151.17±32.65; VEI+CBD: 16.75±10.88; WAY+VEI: 113.75±24.66; WAY+CBD: 76.29±21.36; p=0.002). CBD, in all tested doses, as well as WAY100635 and AM251, did not induce locomotor changes. These findings suggest that CBD decreases aggressive behaviors in mice and allow us to suggest that this effect involves CB1 and 5-HT1A receptors. Therefore, this phytocannabinoid may be therapeutically useful to treat aggressive behaviors that are usually associated with psychiatric disorders

Ethnopharmacological relevance Trichilia catigua is broadly used in folk medicine due to its mental and physical tonic activities and stimulant effects. In animal models, its antidepressant-like effects have been associated with the dopaminergic (DA) system modulation, which has an important role on maternal behavior and male offspring reproductive development. Aim of the study Since little is known about the adverse effects of the exposure to T. catigua crude extract (CAT) in rats, specially regarding maternal homeostasis and offspring development, the aim of the present study was to evaluate whether CAT exposure may influence maternal toxicity parameters and behavior or disrupt male offspring physical and reproductive development. Material and methods Dams were treated daily (by gavage) with 400 mg/kg of CAT or vehicle (control=CTR) throughout pregnancy and lactation. Fertility and maternal behavior tests were conducted in dams. Male offspring reproductive and behavioral parameters were analyzed. Results Dams exposed to CAT showed increased pre- and post-implantation losses rates when compared to CTR group. No significant changes regarding maternal behavior or male offspring parameters were observed. Conclusion In conclusion, maternal exposure to CAT interfered with implantation during the initial phases of pregnancy but did not induce changes on maternal behavior or male offspring reproductive and behavioral parameters.

Long-term single housing increases aggressive behavior in mice, a condition named isolation-induced aggression or territorial aggression, which can be attenuated by anxiolytic, antidepressant, and antipsychotic drugs. Preclinical and clinical findings indicate that cannabidiol (CBD), a non-psychotomimetic compound from Cannabis sativa, has anxiolytic, antidepressant, and antipsychotic properties. Few studies, however, have investigated the effects of CBD on aggressive behaviors. Here, we investigated whether CBD (5, 15, 30, and 60 mg/kg; i.p.) could attenuate social isolation-induced aggressive behavior in the resident-intruder test. Male Swiss mice (7–8 weeks) were single-housed for 10 days (resident mice) to induce aggressive behaviors, while conspecific mice of same sex and age (intruder mice) were group-housed. During the test, the intruder was placed into the resident's home-cage and aggressive behaviors initiated by the resident, including the latency for the first attack, number of attacks, and total duration of aggressive encounters, were recorded. The involvement of 5-HT1A and CB1 receptors (CB1R) in the effects of CBD was also investigated. All tested CBD doses induced anti-aggressive effects, indicated by a decrease in the number of attacks. CBD, at intermediary doses (15 and 30 mg/kg), also increased latency to attack the intruder and decreased the duration of aggressive encounters. No CBD dose interfered with locomotor behavior. CBD anti-aggressive effects were attenuated by the 5-HT1A receptor antagonist WAY100635 (0.3 mg/kg) and the CB1 antagonist AM251 (1 mg/kg), suggesting that CBD decreases social isolation-induced aggressive behaviors through a mechanism associated with the activation of 5-HT1A and CB1 receptors. Also, CBD decreased c-Fos protein expression, a neuronal activity marker, in the lateral periaqueductal gray (lPAG) in social-isolated mice exposed to the resident-intruder test, indicating a potential involvement of this brain region in the drug effects. Taken together, our findings suggest that CBD may be therapeutically useful to treat aggressive behaviors that are usually associated with psychiatric disorders.

Dopaminergic receptor antagonists may be used as galactagogues because they increase serum prolactin (PRL) by counteracting the inhibitory influence of dopamine on PRL secretion. The antipsychotic drug sulpiride (SUL) is documented to be effective as a galactagogue, but it is transferred through milk to the neonates. The aim of the present study was to evaluate if maternal exposure to SUL during lactation could disrupt maternal care and/or male offspring reproductive development. The dams were treated daily (gavage) with SUL 2.5mg/kg or 25mg/kg during lactation. Maternal behavior was analyzed on lactational days 5 and 10. In offspring, reproductive and behavioral parameters were analyzed at different time points. SUL treatment did not impair maternal care, but caused testicular damage in male offspring. At postnatal day 90, a reduction in testis weight, volume of seminiferous tubule and histopathological alterations such as an increased percentage of abnormal seminiferous tubules were observed. Data shows that maternal exposure to SUL during lactation may impact the reproductive development of male rats and the testes seem to be the main target organ at adulthood.

Fluoxetine (FLX) is a selective serotonin reuptake inhibitor (SSRI) antidepressant commonly prescribed during pregnancy and lactation. Pre- and post-partum depression, as well as SSRI treatment during these periods, may change maternal care, interfering with offspring development. Moreover, it is known that SSRIs may alter testes structure and function in offspring. The present study investigated the effects of maternal FLX exposure on maternal behaviour and testes function in offspring. Female Wistar rats were treated with 7.5 mg kg–1 FLX or tap water (control group) by gavage from the Day 1 of pregnancy until 21 days after birth (postnatal Day (PND) 21). Maternal behaviour was evaluated and morphofunctional analyses of offspring testes were conducted on PND 21 and 50. There were no significant differences between the FLX-treated and control groups regarding maternal behaviour. Nor did maternal treatment with FLX have any effect on bodyweight gain, anogenital distance, day of preputial separation, testis weight and the gonadosomatic index in male offspring. However, there was a decreased number of Sertoli cells at both PND 21 and 50 in FLX-exposed male offspring. The findings of the present study demonstrate that maternal exposure to FLX can impair testicular function in weanling and pubertal animals.

Sodium stearate has no effect upon the bacteriological condition of a wound, but the addition of 4 parts per 1,000 of chloramine-T renders it antiseptic. Experiment I enabled us to compare the action of sodium stearate alone with that of sodium stearate containing 4 parts per 1,000 of chloramine-T. Wounds which had been previously sterilized could be maintained in an aseptic condition by 4 parts per 1,000 of chloramine-T, although in some cases reinfection occurred (Experiments 2, 3, and 5). For this reason the concentration of chloramine-T was increased. Surface wounds, deep-seated wounds, and osseous cavities, which had previously been either completely or almost completely sterilized, could be maintained for days and even weeks in a condition of surgical asepsis by the use of a paste containing 7 and 10 parts per 1,000 of chloramine-T. Experiments 7, 8, 9, 10, and 12 are examples of this. Slightly infected wounds (Experiments 9, II, and 12) were sterilized in the same manner. Next, it was attempted to sterilize wounds which were suppurating and more or less infected, and in some cases accompanied by fracture. This attempt was probably successful because the wounds used for the experiments showed but slight quantities of secretions and only a shallow layer of necrotic tissue. It is useless to attempt to sterilize severely infected wounds with a paste, for the volume of chloramine-T that can be applied is too limited. A large volume of an active substance is required to sterilize a wound which secretes great quantities of pus, for owing, on the one hand, to the dilution of this substance with the secretions, and, on the other, to its combination with the proteins contained in the pus, the concentration of the antiseptic is rapidly diminished. For these reasons it is essential that the antiseptic solution should be constantly renewed, so that the concentration may be sufficiently strong to effect the destruction of the bacteria. Therefore, the chloramine-T paste cannot sterilize a severely infected wound. The concentration of the active substance contained in a paste must at the same time be sufficiently weak to be innocuous to the tissues. We have seen that it should not exceed 15 parts per 1,000. Thus, it is evident that if the secretions from the wounds are abundant, the substance could exert its action upon the microorganisms for the space of only a few hours. For this reason the chloramine paste should only be applied under the conditions specified in our experiments; that is, in connection with moderately infected wounds which have been carefully washed with sodium oleate, and possess but slight quantities of secretion. Under these conditions, the chloramine paste effects the complete disappearance of the bacteria and maintains the sterility thus secured for as long a time as may be wished. If the technique followed in the dressing is not exactly as above described, reinfection will occur. If applied in this manner the chloramine paste is not injurious to the tissues, for the cicatrization curves of the wounds thus treated show but slight modification from the calculated curves. Chloramine paste makes it possible, therefore, to keep wounds sufficiently free from microorganisms so that the effect of substances which are believed to influence cicatrization can be studied.