Neonatal Abstinence Syndrome and Corresponding Pharmacotherapy Approaches from 2 University-affiliated Neonatal Intensive Care Units in Puerto Rico (2018-2020).

OBJECTIVE: Neonatal abstinence syndrome (NAS) is a set of drug withdrawal symptoms suffered by neonates exposed to drugs in utero. Several studies have widely described NAS incidence and treatment approach; however, little is known regarding the incidence and manifestations of this disease in Puerto Rico (PR). The principal aim of this study was to describe NAS incidence in the neonatal units of hospitals affiliated with the University of PR in terms of occurrence, clinical manifestations, and treatment approaches. METHODS: Our study evaluated the medical records of NAS babies diagnosed from 2018 through 2020 at 2 hospitals affiliated with the University of PR Medical Sciences Campus. Descriptive and inferential statistics were employed to analyze trends. RESULTS: We identified 12 neonates diagnosed with NAS, 5 with low birthweights (<2500 g); for a NAS incidence of 2 cases per 1000 admitted for the 3 years of recollected data. The urine toxicology results revealed that 9 had experienced intrauterine polydrug exposure. Phenobarbital loading dose were determined on the day of diagnosis (indicated by Finnegan score). The first manifestation of NAS symptoms varied: 8 neonates showed symptoms within 48 hours after birth, whereas 4 had withdrawal symptoms within 72-120 hours of their births. Differences between dosing practices and guidelines were observed, ranging from a 0.69% to a 25% difference during treatment initiation. CONCLUSION: Further research on the incidence of NAS in PR (national level) is needed for a deeper understanding that we hope will lead to the development of enhanced treatment protocols in PR.

Suicide attempt in a dopamine agonist withdrawal syndrome in Parkinson's disease.

Dopamine agonist withdrawal syndrome (DAWS) results from the reduction or suspension of dopamine agonist medications; it encompasses mainly psychiatric symptoms, including suicidal behaviors. In patients with Parkinson's disease (PD), the impact of DAWS can be significant in terms of distress and disability; however, we must take this syndrome into account as a threatening condition because suicidal behaviors could be developing in the context of DAWS. Here we present a brief case of DAWS affecting a young man with PD, whom abruptly discontinued DA treatment and developed psychiatric symptoms within two weeks which led to a suicidal attempt.

Ethanol binge drinking exposure during adolescence displays long-lasting motor dysfunction related to cerebellar neurostructural damage even after long-term withdrawal in female Wistar rats.

Ethanol is one of the psychoactive substances most used by young individuals, usually in an intermittent and episodic manner, also called binge drinking. In the adolescent period, brain structures undergo neuromaturation, which increases the vulnerability to psychotropic substances. Our previous studies have revealed that ethanol binge drinking during adolescence elicits neurobehavioral alterations associated with brain damage. Thus, we explored the persistence of motor function impairment and cerebellum damage in the context of ethanol withdrawal periods (emerging adulthood and adult life) in adolescent female rats. Female Wistar rats (35 days old) received orally 4 cycles of ethanol (3.0 g/kg/day) or distilled water in 3 days on-4 days off paradigm (35th until 58th day of life). Motor behavioral tests (open field, grip strength, beam walking, and rotarod tests) and histological assays (Purkinje's cell density and NeuN-positive cells) were assessed on the 1-, 30-, and 60-days of binge alcohol exposure withdrawal. Our findings demonstrate that the adolescent binge drinking exposure paradigm induced cerebellar cell loss in all stages evaluated, measured through the reduction of Purkinje's cell density and granular layer neurons. The cerebellar tissue alterations were accompanied by behavioral impairments. In the early withdrawal, the reduction of spontaneous movement, incoordination, and unbalance was seen. However, the grip strength reduction was found at long-term withdrawal (60 days of abstinence). The cerebellum morphological changes and the motor alterations persisted until adulthood. These data suggest that binge drinking exposure during adolescence causes motor function impairment associated with cerebellum damage, even following a prolonged withdrawal, in adult life.

Potential of the Blue Calm® food supplement in the treatment of alcohol withdrawal-induced anxiety in adult zebrafish (Danio rerio).

Alcohol use disorder (AUD) is characterized by a set of behavioral, cognitive, nutritional, and physiological phenomena derived from the uncontrolled use of alcoholic beverages. There are cases in which AUD is associated with anxiety disorder, and when untreated, it requires careful pharmacotherapy. Blue Calm® (BC) is a food supplement indicated to aid restorative sleep, which has traces of medicinal plant extracts, as well as myo-inositol, magnesium bisglycinate, taurine, and L-tryptophan as its main chemical constituents. In this context, this study aimed to evaluate the potential of the BC in the treatment alcohol withdrawal-induced anxiety in adult zebrafish (aZF). Initially, BC was submitted to antioxidant activity against 2,2-diphenyl-1-picrylhydrazyl radical. Subsequently, the aZF (n = 6/group) were treated with BC (0.1 or 1 or 10 mg/mL; 20 µL; p.o.), and the sedative effect and acute toxicity (96 h) were evaluated. Then, the anxiolytic-like effect and the possible GABAergic mechanism were analyzed through the Light & Dark Test. Finally, BC action was evaluated for treating alcohol withdrawal-induced anxiety in aZF. Molecular docking was performed to evaluate the interaction of the major chemical constituents of BC with the GABAA receptor. BC showed antioxidant potential, a sedative effect, was not toxic, and all doses of BC had an anxiolytic-like effect and showed potential for the treatment of alcohol withdrawal-induced anxiety in aZF. In addition to the anxiolytic action, the main chemical constituents of BC were confirmed in the molecular docking, thus suggesting that BC is an anxiolytic that modulates the GABAergic system and has pharmacological potential for the treatment of alcohol withdrawal-induced anxiety.

Severe cerebral edema related to oral methadone: A case report and literature review.

Introduction: Opioids are widely used for pain management, and increased intracranial pressure (ICP) has been evidenced in some cases. We reported a patient with severe cerebral edema after initiating methadone and its complete resolution upon discontinuing the medication. Additionally, a review of the literature is made. Case report: A 53-year-old woman patient with a history of systemic lupus erythematosus developed mechanic chronic lower back pain, refractory to conventional treatments. She presented improvement with oxycodone. She withdrew this medication due to a lack of supplies in her country (Colombia) and showed withdrawal symptoms. She consulted the emergency department, where oral methadone was started and symptom control was achieved. Three days after admission, she presented intense headaches and emesis. A brain CT scan was performed in which severe cerebral edema was appreciated. Methadone was discontinued, and neurological symptoms quickly disappeared. A follow-up brain CT scan was performed later, finding full resolution of the edema. Conclusion: A case of severe cerebral edema associated with the initiation of oral methadone and its rapid resolution without neurological sequelae after its withdrawal is presented, clinicians must be attentive to this adverse event.

The Bioavailability of CHF6563, an Ethanol-Free, Sublingual Neonatal Buprenorphine Formulation: A Bridging Study Conducted in Adults.

OBJECTIVE: Sublingual buprenorphine has demonstrated efficacy for treatment of the neonatal opioid withdrawal syndrome (NOWS), but the current formulation used in clinical practice contains 30% ethanol. Ethanol as a pharmacologically active excipient ideally should be removed from neonatal formulations. The objective of this study was to determine the relative bioavailability of a novel ethanol-free -formulation (CHF6563) compared with the commonly used ethanolic solution in a phase I, open-label, 2-period, -single-dose, crossover study in healthy adults. METHODS: Eighteen adult opioid-naïve volunteers were administered one of the formulations in a randomized crossover treatment. After a 10-day washout period, subjects received the other formulation. Serial blood samples were drawn for pharmacokinetic analysis over 48 hours. RESULTS: The geometric mean ratio (90% CIs) of the ethanol-free buprenorphine solution AUC0-last was 0.80 (0.65-0.99) and Cmax was 0.81 (0.66-0.99) compared with reference ethanolic formulation. The -ethanol-free formulation had a greater degree of intersubject variability than the ethanol-containing -reference formulation (coefficient of variation of 59% vs 31.5%, respectively, for AUC0-last). CONCLUSIONS: In an adult population, a novel ethanol-free formulation of buprenorphine containing widely used excipients demonstrated a slight decrease in bioavailability when compared with an ethanolic solution. These results will inform those seeking to develop ethanol-free pediatric drug formulations.

Amelioration of morphine withdrawal syndrome by systemic and intranasal administration of mesenchymal stem cell-derived secretome in preclinical models of morphine dependence.

BACKGROUND: Morphine is an opiate commonly used in the treatment of moderate to severe pain. However, prolonged administration can lead to physical dependence and strong withdrawal symptoms upon cessation of morphine use. These symptoms can include anxiety, irritability, increased heart rate, and muscle cramps, which strongly promote morphine use relapse. The morphine-induced increases in neuroinflammation, brain oxidative stress, and alteration of glutamate levels in the hippocampus and nucleus accumbens have been associated with morphine dependence and a higher severity of withdrawal symptoms. Due to its rich content in potent anti-inflammatory and antioxidant factors, secretome derived from human mesenchymal stem cells (hMSCs) is proposed as a preclinical therapeutic tool for the treatment of this complex neurological condition associated with neuroinflammation and brain oxidative stress. METHODS: Two animal models of morphine dependence were used to evaluate the therapeutic efficacy of hMSC-derived secretome in reducing morphine withdrawal signs. In the first model, rats were implanted subcutaneously with mini-pumps which released morphine at a concentration of 10 mg/kg/day for seven days. Three days after pump implantation, animals were treated with a simultaneous intravenous and intranasal administration of hMSC-derived secretome or vehicle, and withdrawal signs were precipitated on day seven by i.p. naloxone administration. In this model, brain alterations associated with withdrawal were also analyzed before withdrawal precipitation. In the second animal model, rats voluntarily consuming morphine for three weeks were intravenously and intranasally treated with hMSC-derived secretome or vehicle, and withdrawal signs were induced by morphine deprivation. RESULTS: In both animal models secretome administration induced a significant reduction of withdrawal signs, as shown by a reduction in a combined withdrawal score. Secretome administration also promoted a reduction in morphine-induced neuroinflammation in the hippocampus and nucleus accumbens, while no changes were observed in extracellular glutamate levels in the nucleus accumbens. CONCLUSION: Data presented from two animal models of morphine dependence suggest that administration of secretome derived from hMSCs reduces the development of opioid withdrawal signs, which correlates with a reduction in neuroinflammation in the hippocampus and nucleus accumbens.

Immunosuppression-Free Life after Pediatric Liver Transplant: A Case-Control Study from the Society of Pediatric Liver Transplant (SPLIT) Registry.

OBJECTIVE: To compare long-term outcomes of pediatric liver transplant (LT) recipients off immunosuppression (IS) with matched controls on IS using data from the Society of Pediatric Liver Transplant (SPLIT) registry. STUDY DESIGN: This was a retrospective case-control study. SPLIT participants <18 years of age, ≥4 years after isolated LT, and off IS for ≥1 year (cases) were age- and sex-matched 1:2 to patients with the same primary diagnosis and post-LT follow-up duration (controls). Primary outcomes included retransplantation, allograft rejection, IS comorbidities, and prevalence of SPLIT-derived composite ideal outcome (c-IO) achieved at the end of the follow-up period. Differences were compared using multiple linear regression for continuous outcomes and logistic regression for dichotomous data. RESULTS: The study cohort was composed of 33 cases (42.4% male, 60.6% biliary atresia, median age at LT of 0.7 [P25, P75, 0.5, 1.6] years, median IS withdrawal time of 9 [P25, P75, 6, 12] years after LT) and 66 age- and sex-matched controls. No cases required retransplantation. Cases and controls had similar growth parameters, laboratory values, calculated glomerular filtration rates, rates of post-transplant lymphoproliferative disease, graft rejection, and attainment of c-IO. CONCLUSIONS: No differences in allograft rejection rates, IS complications, or c-IO prevalence were seen between SPLIT patients off IS and age- and sex-matched controls remaining on IS. Discontinuation of IS most commonly occurred in the context of rigorously designed IS withdrawal trials. The available sample size was small, affecting generalizability to the broader pediatric LT population.

Ordens de não ressuscitar por pacientes com câncer avançado no Brasil: uma análise bioética / Do not resuscitate orders by advanced cancer patients in Brazil: a bioethical analysis

As Ordens de Não Ressuscitar (ONR) consistem na determinação expressa de não Reanimação Cardiopulmonar (RCP) em pacientes com perda irreversível de consciência ou parada cardíaca não tratável. Embora complexo e multifatorial, o processo decisório das ONR faz parte da rotina dos departamentos de oncologia, que deve se basear em regulações éticas sobre o tema. Portanto, o objetivo do trabalho foi mapear diretrizes sobre ONR para pacientes oncológicos avançados e analisar tais orientações técnicas à luz da bioética. Realizou-se uma revisão integrativa em bases de dados científicas nacionais e internacionais e pesquisa documental nos sites do Conselho Federal de Medicina (CFM) e da Sociedade Brasileira de Oncologia Clínica (SBOC). Das referências selecionadas, constatou-se que: i) os documentos éticos e oncológicos nacionais não mencionam diretamente as ONR; ii) as diretrizes internacionais indicam passos na discussão das ONR com pacientes com câncer avançado, desde a construção de um vínculo de confiança com o paciente/família até a discussão das ONR e a elaboração de um plano de cuidados compartilhado. Conclui-se que, o câncer é um dos principais fatores para que um paciente solicite ONR e a ausência de diretrizes técnicas específicas sobre ONR para pacientes oncológicos avançados no Brasil pode acarretar reanimações cardiorrespiratórias fúteis e/ou gerar conflitos entre médico, pacientes e seus familiares, evidenciando desrespeito aos princípios bioéticos da autonomia, beneficência e não-maleficência.

Do Not Resuscitate (DNR) Orders consist of the explicit determination not to perform Cardiopulmonary Resuscitation (CPR) in patients with irreversible loss of consciousness or untreatable cardiac arrest. Although complex and multifactorial, the decision-making process regarding DNR is part of the routine in oncology departments and should be based on ethical regulations on the subject. Therefore, the aim of this study was to map guidelines on DNR for advanced cancer patients and analyze these technical recommendations in light of bioethics. An integrative review was conducted in national and international scientific databases, as well as a documentary search on the websites of the Federal Council of Medicine (CFM) and the Brazilian Society of Clinical Oncology (SBOC). From the selected references, it was found that: i) national ethical and oncological documents do not directly mention DNR; ii) international guidelines suggest steps in discussing DNR with advanced cancer patients, from building a trusting relationship with the patient/family to discussing DNR and developing a shared care plan. It is concluded that cancer is one of the main factors leading a patient to request DNR, and the lack of specific technical guidelines on DNR for advanced cancer patients in Brazil may result in futile cardiopulmonary resuscitations and/or create conflicts between doctors, patients, and their families, thus highlighting the disrespect for the bioethical principles of autonomy, beneficence, and non-maleficence.

Medication-overuse headache-a review of different treatment strategies.

Medication-overuse headache (MOH) can develop from primary headaches. MOH is usually the result of overuse of symptomatic medications. It is a noteworthy personal and societal burden. The identification and treatment of patients at risk for MOH is an essential component of MOH management. Medication overuse can be modifiable and can advance from episodic to chronic migraine. Treatment for MOH is complex, and experts in the field have varied views on the most appropriate strategy for MOH treatment. The objective of this review is to give a comprehensive synopsis of the literature for the management of MOH. Treatment strategies, such as detoxification and prevention, are the debatable issues. Medication withdrawal is the foundation for management. The available literature suggested abrupt withdrawal with preventive approaches for early management. Bridging therapy could be useful to get relief from withdrawal symptoms. Multidisciplinary choices proved beneficial in supporting withdrawal and preventing relapse. Worldwide, the termination of overused medications has been observed as a standard treatment strategy; however, patient-specific approaches should be taken.

Pharmacologic hyperreactivity of kappa opioid receptors in periaqueductal gray matter during alcohol withdrawal syndrome in rats.

BACKGROUND: Periaqueductal gray matter (PAG) is a brain region rich in kappa-opioid receptors (KOR). KOR in PAG mediates behavioral responses related to pain integration, and panic response, among others. Its participation in the addiction phenomena has been poorly studied. Hence, this preliminary study explored the pharmacological effects of KOR stimulation/blockade in dorsal-PAG (D-PAG) during alcohol withdrawal on anxiety-type behaviors and alcohol intake/preference. METHODS: Juvenile male Wistar rats were unexposed (A-naïve group) or exposed to alcohol for 5 weeks and then restricted (A-withdrawal group). Posteriorly, animals received intra D-PAG injections of vehicle (10% DMSO), salvinorin A (SAL-A; a selective KOR agonist), or 2-Methyl-N-((2'-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl)methyl)propan-1-amine (PF-04455242; a highly selective KOR-antagonist). Subsequently, the defensive burying behavior (DBB) and alcohol intake/preference paradigms were evaluated. RESULTS: SAL-A markedly increased burying time, the height of bedding, and alcohol consumption/preference in A-withdrawal, while slightly increased the height of bedding in A-näive rats. PF-04455242 decreased both burying and immobility duration, whereas increases latency to burying, frequency of rearing, and the number of stretches attempts with no action on alcohol intake/preference in A-withdrawal rats. CONCLUSIONS: In general, stimulation/blockade of KOR in A-withdrawal animals exert higher responses compared to A-naïve ones. SAL-A produced anxiety-like behaviors and increased alcohol consumption/preference, especially/solely in the alcohol-withdrawal condition, while PF-04455242 augmented exploration with no effects on alcohol intake/preference. Our findings suggest a possible pharmacologic hyperreactivity of the KOR in PAG during alcohol withdrawal.

Stress effects on spatial memory retrieval and brain c-Fos expression pattern in adults are modulated by early nicotine exposure.

The cognitive effects of nicotine are linked to persistent modifications in extended neural systems that regulate cognitive and emotional processes, and these changes occur during development. Additionally, acute stress has modulatory effects on cognition that involve broad neural systems and can be influenced by prior environmental challenges. The effects of nicotine and stress may be interconnected, leading to modifications in a network of shared brain substrates. Here, we explored the interaction between nicotine and stress by evaluating the effects of acute stress exposure in spatial memory retrieval for animals pretreated with nicotine during adolescence or adulthood. Adolescent (35 days old) and adult (70 days old) male Wistar rats were treated for 21 days with one daily subcutaneous injection of nicotine 0.14 mg/ml (free base). 30 days after the last injection, rats were trained in the Barnes maze and tested 24 h later, half the rats were tested under regular conditions, and half of them were exposed to 1 h of restraining stress before the retrieval test, and brain samples were collected and c-Fos immunopositive cells were stained. Prolonged nicotine withdrawal or acute stress improved spatial memory retrieval. Acute stress in nicotine pretreated adults impaired spatial memory retrieval. Nicotine exposure during early adulthood resulted in long-lasting brain adaptations that amplified emotional responses to acute stress after prolonged drug withdrawal.

Changes in the autonomic cardiorespiratory activity in parturient women with severe and moderate features of preeclampsia.

Background: Cardiorespiratory coupling (CRC) is a physiological phenomenon that reflects the mutual interaction between the cardiac and respiratory control systems. It is mainly associated with efferent vagal activity from the central autonomic network. Few studies have explored the autonomic changes of CRC in preeclampsia, a critical obstetric complication related to possible autonomic dysfunctions and inflammatory disturbances. This study examined the autonomic mechanisms of CRC in women with severe and moderate preeclampsia and healthy controls by applying nonlinear methods based on information theory, such as mutual information (MI) and Renyi's mutual information (RMI) and the linear and nonlinear analysis of the Pulse-Respiration Quotient (PRQ). Methods: We studied three groups of parturient women in the third trimester of pregnancy with a clinical diagnosis of preeclampsia without severe symptoms (P, 38.5 ± 1.4 weeks of pregnancy, n=19), preeclampsia with severe symptoms (SP, 37.5 ± 0.9 weeks of pregnancy, n=22), and normotensive control women (C, 39.1 ± 1.3 weeks of pregnancy, n=20). 10-minutes of abdominal electrocardiograms (ECG) and respiratory signals (RESP) were recorded in all the participants. Subsequently, we obtained the maternal beat-to-beat (RR) and breath-to-breath (BB) time series from ECG and RESP, respectively. The CRC between RR and BB was quantified by nonlinear methods based on information theory, such as MI and RMI, along with the analysis of the novel index of PRQ. Subsequently, we computed the mean PRQ (mPRQ) and the normalized permutation entropy (nPermEn_PRQ) from the PRQ time series generated from BB and RR. In addition, we examined the vagal activity in the three groups by the logarithm of the median of the distribution of the absolute values of successive RR differences (logRSA). Results: The MI and RMI values were significantly lower (p<0.05) in the preeclamptic groups compared to the control group. However, no significant differences were found between the preeclamptic groups. The logRSA and nPermEn_PRQ indices were significantly lower (p<0.05) in SP compared to C and P. Conclusion: Our data suggest that parturient women with severe and mild preeclampsia may manifest an altered cardiorespiratory coupling compared with normotensive control women. Disrupted CRC in severe preeclampsia could be associated with vagal withdrawal and less complex cardiorespiratory dynamics. The difference in vagal activity between the preeclamptic groups may suggest a further reduction in vagal activity associated with the severity of the disease.

Dependencia y abstinencia de Zolpidem. Reporte de un caso de convulsiones generalizadas

El zolpidem es un agente hipnótico no benzodiacepínico utilizado con suma frecuencia en el tratamiento del insomnio e indicado para emplearlo en el corto plazo. No está indicado para el tratamiento crónico de los trastornos del sueño, pese a lo cual se evidencia en la práctica clínica que gran cantidad de pacientes lo reciben por arios. Si bien se ha descrito que presenta un mejor perfil de efectos adversos que las benzodiacepinas y que genera menos riesgo de dependencia y abstinencia que estas, existen sendos reportes de casos de dependencia y abstinencia de zolpidem. Se presenta el reporte de un caso de convulsiones tónico-clónicas generalizadas por abstinencia a dosis de 300 mg/día de Zolpidem y se realiza una breve revisión de la literatura.

Zolpidem is a non-benzodiazepine hypnotic agent used most frequently in the treatment of insomnia, indicated for short-term use. It is not indicated for the chronic treatment of sleep disorders, despite which there is evidence in clinical practice that a large number of patients receive it for years. Although it has been described that it presents a better profile of adverse effects than benzodiazepines and that it generates a lower risk of dependence and withdrawal than these, there are significant reports of cases of dependence and withdrawal from zolpidem. A report of a case of generalized tonic-clonic seizures due to with drawal at a dose of 300 mg per day of zolpidem is presented and a brief review of the literature is carried out.

Residue Depletion Profile and Estimation of Withdrawal Period for Sulfadimethoxine and Ormetoprim in Edible Tissues of Nile Tilapia (Oreochromis sp.) on Medicated Feed.

Sulfadimethoxine (SDM) and ormetoprim (OMP) are antimicrobials used in combination to treat bacterial infections in fish farming. The use of this drug combination is not yet regulated in some countries, such as Brazil. Due to the lack of regulated drugs for aquaculture in Brazil, this study investigated the residue depletion profile of SDM and OMP in Nile tilapia (Oreochromis sp.) after oral administration. Fish were treated with medicated feed containing a 5:1 ratio of SDM:OMP at the dose of 50 mg kg BW-1 for five consecutive days with an average water temperature of 28 °C. The drugs were incorporated into the feed by using a gelatin coating process which promoted homogeneity in drug concentration and prevented the drug leaching into the water during medication. The SDM and OMP determination in fish fillets (muscle plus skin in natural proportions) was performed using the QuEChERS approach followed by LC-MS/MS quantification. The analytical method was validated according to Brazilian and selected international guidelines. A withdrawal period of 9 days (or 252 °C days) was estimated for the sum of SDM and OMP residues at concentration levels below the maximum residue level of 100 µg kg-1.

Age-dependent memory impairment induced by co-exposure to nicotine and a synthetic cannabinoid in mice.

Co-use of marijuana and tobacco products is the second most common drug combination among adolescents. Nicotine (NIC) and cannabinoid use during adolescence induce similar detrimental changes, raising the hypothesis that simultaneous exposure could result in even more severe outcomes. Thus, we investigated whether the co-exposure to NIC and the synthetic cannabinoid WIN 55,212-2 (WIN) in adolescent mice causes behavioral outcomes different from those observed after exposure to a single drug. Male Swiss mice were exposed twice daily to NIC, WIN, or NIC + WIN during adolescence (PND28-47) or adulthood (PND70-89). Drug combination led to a greater reduction in weight gain in adolescent mice, while NIC-induced weight loss was observed in adults. During administration, NIC provoked hypothermia, and WIN produced hyperlocomotion in adolescent and adult mice. Animals exposed to NIC + WIN presented a profile of changes similar to those exposed to NIC. After drug exposure, changes in locomotion, thigmotaxis, social preference, prepulse inhibition, and working and recognition memory were evaluated. Adolescent but not adult mice exposed to NIC showed withdrawal-related hyperlocomotion unaffected by WIN co-administration. An age-specific impairment in object recognition memory was induced only by drug co-exposure during adolescence, which resolved spontaneously before reaching early adulthood. A transient decrease in hippocampal α7 nAChR subunit and CB1 receptor mRNA levels was induced by NIC exposure, which may be involved but is not enough to explain the memory impairment. Our work confirms the potential of NIC and cannabinoids association to aggravate some of the individual drug effects during critical neurodevelopmental periods.

Effect of chronic unpredictable stress in female Wistar-Kyoto rats subjected to progesterone withdrawal: Relevance for Premenstrual Dysphoric Disorder neurobiology.

Premenstrual Dysphoric Disorder (PMDD) is related to an abrupt drop in progesterone and impairments in the HPA axis that cause anxiety. Suffering persons report higher daily-life stress and anxiety proneness that may contribute to developing PMDD, considered a chronic stress-related disorder. Here, we explored the effect of chronic unpredictable stress (CUS) in rats subjected to progesterone withdrawal (PW) and evaluated gene expression of HPA axis activation in the stress-vulnerable Wistar-Kyoto (WKY) rat strain that is prone to anxiety. Ovariectomized WKY rats were randomly assigned to CUS or Standard-housed conditions (SHC) for 30 days. To induce PW, animals received 2 mg/kg of progesterone on day 25th for 5 days; 24 h later, they were tested using the anxiety-like burying behavior test (BBT). After behavioral completion, rats were euthanized, and brains were extracted to measure Crh (PVN) and Nr3c1 (hippocampus) mRNA. Blood corticosterone and vasopressin levels were determined. Results showed that PW exacerbated anxiety-like behaviors through passive coping in CUS-WKY. PW decreased Crh-PVN mRNA and the Nr3c1-hippocampal mRNA expression in SHC. CUS decreased Crh-PVN mRNA compared to SHC, and no further changes were observed by PW or BBT exposure. CUS reduced Nr3c1-hippocampal gene expression compared to SHC animals, and lower Nr3c1 mRNA was detected due to BBT. The PW increased corticosterone in SHC and CUS rats; however, CUS blunted corticosterone when combined with PW+BBT and similarly occurred in vasopressin concentrations. Chronic stress blunts the response of components of the HPA axis regulation when PW and BBT (systemic and psychogenic stressors, respectively) are presented. This response may facilitate less adaptive behaviors through passive coping in stress-vulnerable subjects in a preclinical model of premenstrual anxiety.

Cannabidiol attenuates the expression of conditioned place aversion induced by naloxone-precipitated morphine withdrawal through the activation of 5-HT1A receptors.

The misuse of and addiction to opioids are serious public health problems in some countries, such as the USA. Drug addiction is a chronic and relapsing medical condition that involves motivational and memory-related processes due to the strong associations between drugs and consuming-related stimuli. These stimuli usually trigger continuous and compulsive use and are associated with relapses after periods of withdrawal. Several factors contribute to relapse, including withdrawal-induced mood changes. Therefore, drugs attenuating withdrawal-induced affective alterations could be useful alternative treatments for relapse prevention. Cannabidiol (CBD), a non-psychotomimetic component from the Cannabis sativa plant, has anti-anxiety and anti-stress properties and has been investigated as an alternative for the treatment of several mental disorders, including drug addiction. Here, we evaluated if CBD administered 30 min prior to test for a conditioned place aversion (CPA) would attenuate the aversion induced by morphine withdrawal precipitated by the opioid receptor antagonist naloxone in male C57BL/6 mice. We also investigated if this effect involves the activation of 5-HT1A receptors, a mechanism previously associated with CBD anti-aversive effects. As expected, morphine-treated mice spent less time exploring the compartment paired with the naloxone-induced withdrawal, indicating a CPA induced by naloxone-precipitated morphine withdrawal. This effect was not observed in animals treated with CBD, at 30 and 60 mg/kg, prior to the CPA test, indicating that CBD attenuated the expression of CPA induced by naloxone-precipitated morphine withdrawal. Pretreatment with the 5-HT1A receptor antagonist WAY100635 (0.3 mg/kg) blocked CBD effects. Our findings suggest that CBD may reduce the expression of a previously established conditioned aversion induced by morphine withdrawal by a mechanism involving the activation of 5-HT1A receptors. Thus, CBD may be a therapeutic alternative for preventing relapse to opioid addiction by decreasing withdrawal-induced negative affective changes.

Atribuciones hacia la timidez y la soledad en niños y niñas de diferentes contextos sociales argentinos / Attributions towards shyness and unsociability in Argentinian children from different social contexts

Resumen Las atribuciones de los niños y las niñas hacia los comportamientos de retraimiento social suelen estar determinadas por el entorno sociocultural particular en el que se desarrollan e influyen en la forma en que reaccionan a las conductas de sus pares durante las interacciones sociales. El objetivo de este trabajo fue comparar dichas atribuciones hacia dos subtipos de retraimiento social (timidez y preferencia por la soledad) referidas por niños y niñas de tres contextos diferentes de Mendoza (Argentina): urbano, urbano-marginado y rural. Se llevó a cabo un estudio con 221 niños y niñas abordando jardines de infantes estatales de cada ámbito (urbano: . = 82, Mmeses= 62.33; urbano-marginado: . = 72, Mmeses= 60.47; rural: . = 67, Mmeses= 63.07). Los escolares fueron entrevistados individualmente con una serie de viñetas gráficas con personajes hipotéticos desplegando conductas sociables, tímidas, solitarias y agresivas frente a las cuales respondieron preguntas sobre sus atribuciones y percepciones en distintos aspectos. Las diferentes pruebas no paramétricas realizadas señalaron que el personaje tímido fue percibido con mayor motivación social y menor intencionalidad en su conducta que el personaje solitario en todos los grupos. No se encontraron diferencias entre los contextos en la atribución de consecuencias sociales negativas para estas conductas, aunque el grupo de escolares rurales reportó mayor preferencia afiliativa y compasión por el personaje tímido en comparación con el grupo urbano. Se discuten estos resultados considerando cómo las expectativas de socialización de cada contexto podrían influir en las percepciones de los escolares hacia el retraimiento social.

Abstract Children's attributions towards withdrawn behaviors are usually determined by the particular social milieu in which they develop and tend to influence their behaviors and reactions. The aim of this work was to compare the attributions towards two subtypes of social withdrawal (shyness and unsociability) referred by children from three different contexts in Mendoza, Argentina: urban, urban-marginalized and rural. Participants were 221 kindergarten children from these contexts (urban: n = 82, Mmonths = 62.33; urban-marginalized: n = 72, Mmonths = 60.47; rural: n = 67, Mmonths = 63.07). Children were individually interviewed with a series of graphic vignettes with hypothetical characters displaying shy and unsociable behaviors, and for comparison purposes were also assessed aggressive and socially competent behaviors. After each vignette, children were asked a series of questions designed to assess their attributions toward each behavior in six dimensions: intentionality, social motivation, affiliative preference, social status, negative impact and sympathy. The results of this study showed that young children in the three contexts were able to distinguish social withdrawal from other types of behaviors (i.e., aggressiveness and sociability). Overall, withdrawn behaviors received more positive attributions (greater affiliative preference, better social position and less negative impact) than aggressive behaviors, although they were also perceived negatively in relation to more socially competent behaviors (the latter were attributed greater affiliative preference and best position within the peer group). Furthermore, it was observed that children from the three contexts made clearly distinctions among the different forms of social withdrawal in terms of intentionality and social motivation. Specifically, they reported that compared with unsociable characters, shy ones are more socially motivated and less intentional in their behavior, evocating greater feelings of compassion. However, some peculiarities can be appreciated in each context. The results indicated that children in the urban group reported greater feelings of sympathy for the shy character in relation to the unsociable, which was not evidenced in the other groups. In addition, children from the rural sample showed a greater preference for interact with the hypothetical shy peer than with the unsociable character and this inclination was also greater when compared with the urban sample. Taken together, these results may suggest that different socialization norms and expectations would evoke different meanings and implications to the socially withdrawn manifestations. It might be possible that in urban contexts children's socialization expectations highlight extraversion and self-affirming behaviors which generate more empathetic reactions in front of passive or fearful manifestations as shyness. On the other hand, rural children may prefer peers who display shy behaviors possibly because it is in line with expectations of social cohesion and modesty that are value in this milieu. Nevertheless, no differences were found between shy and unsociable behaviors in any of the contexts in terms of social position and negative impact that they anticipated for the peer group. These results could provide some support for the idea that social withdrawal tends to be globally perceived as benign at an early age, and especially in the rural context, where it is a frequent and valued behavior. Although it is not possible with the limited variables included in this study to know which are the specific contextual aspects that affect some attributions and through what mechanisms they do so, these findings are an important starting point to continue deepening the socialization processes in urban, urban-marginalized and rural young children. This study is also one of the first to evaluate the knowledge and attributions of Argentinean children from different social context toward social withdrawal and provides new evidence on the differences in the cultural meaning and implications of withdrawn behaviors in early childhood.

Implementation of a brief online skills group of dialectical behaviour therapy for emotional dysregulation in Latinx: a withdrawal experimental single-case design.

BACKGROUND: Dialectical behaviour therapy (DBT) skills groups have shown promise as an effective treatment for clients with emotional dysregulation, especially when combined with individual DBT. However, their efficacy is not well established as an online therapy, or in the Latinx population. AIMS: This study aimed to explore satisfaction, retention and effects of an internet-based DBT group added to individual online sessions. METHOD: An ABAB withdrawal experimental single-case design was conducted to evaluate the effect of a brief online DBT skills group on emotional dysregulation, anxiety and depression for five Latinx participants. DBT skills group (phase B) were compared with placebo group sessions (phase A) and fortnightly individual DBT sessions were offered throughout to manage risk. RESULTS: Visual inspection showed a decrease in level of emotional dysregulation and a large effect size according to the Nonoverlap of All Pairs when comparing group DBT and placebo phases. Although depression symptoms decreased after introducing group DBT, anxiety indicators decreased most during the second round of group placebo sessions. DISCUSSION: Whilst only a pilot, this study suggests that online group DBT in Latinx populations is feasible and effective for changing emotional regulation processes but may not effectively target anxiety. Future research might increase the number of DBT sessions in order to enhance learning opportunities and generalization. Replication with larger sample sizes and diverse modalities is needed.