Incipient Parallel Evolution of SARS-CoV-2 Deltacron Variant in South Brazil.

With the coexistence of multiple lineages and increased international travel, recombination and gene flow are likely to become increasingly important in the adaptive evolution of SARS-CoV-2. These processes could result in genetic introgression and the incipient parallel evolution of multiple recombinant lineages. However, identifying recombinant lineages is challenging, and the true extent of recombinant evolution in SARS-CoV-2 may be underestimated. This study describes the first SARS-CoV-2 Deltacron recombinant case identified in Brazil. We demonstrate that the recombination breakpoint is at the beginning of the Spike gene. The 5' genome portion (circa 22 kb) resembles the AY.101 (Delta), and the 3' genome portion (circa 8 kb nucleotides) is most similar to the BA.1.1 (Omicron). Furthermore, evolutionary genomic analyses indicate that the new strain emerged after a single recombination event between lineages of diverse geographical locations in December 2021 in South Brazil. This Deltacron, AYBA-RS, is one of the dozens of recombinants described in 2022. The submission of only four sequences in the GISAID database suggests that this lineage had a minor epidemiological impact. However, the recent emergence of this and other Deltacron recombinant lineages (XD, XF, and XS) suggests that gene flow and recombination may play an increasingly important role in the COVID-19 pandemic. We explain the evolutionary and population genetic theory that supports this assertion, concluding that this stresses the need for continued genomic surveillance. This monitoring is vital for countries where multiple variants are present, as well as for countries that receive significant inbound international travel.

Increased responsiveness to punishment of cocaine self-administration after experience with high punishment.

One behavioral feature of drug addiction is continued drug use despite awareness that this causes negative consequences. Attempts to model this feature in animals typically involve punishing drug self-administration with electrical footshock to identify individuals whose drug use is differently suppressed by punishment. Here we sought to further study individual responsiveness of drug use to punishment in rats self-administering intravenous cocaine. Rats were first trained during several weeks to self-administer cocaine under a fixed-ratio 3 schedule of reinforcement. Then, their self-administration behavior was punished with increasing intensity of footshock (i.e., from 0.1 mA to 0.9 mA, every 30 min). With increasing intensity of punishment, rats first continued to self-administer cocaine before eventually stopping near completely. When retested, however, drug use became more responsive to punishment and was suppressed by a low and initially ineffective footshock intensity (i.e., 0.1 mA). This increase in responsiveness to punishment was seen in all individuals tested, albeit with varying degrees, and was acquired after one single experience with an intensity of punishment that near completely suppressed drug self-administration. Mere passive, non-contingent exposure to the same intensity, however, had no such effect. Once acquired, increased responsiveness to punishment persisted during at least one month when rats were tested every week, but not every day. Finally, increased responsiveness to punishment was not observed after exposure to a non-painful form of punishment (i.e., histamine). Overall, this study reveals that initial responsiveness of drug use to punishment can change rapidly and persistently with experience. We discuss several possible mechanisms that may account for this change in punishment responsiveness and also draw some of the implications and future perspectives for research on animal models of compulsion-like behavior.

Effects of neonatal dopaminergic lesion on oral cocaine self-administration in rats: Higher female vulnerability to cocaine consumption.

The dopaminergic system is associated with cocaine-seeking behaviors, being influenced by other neurotransmitters such as GABA and deregulated by chronic cocaine self-administration. Administration of 6-hydroxydopamine (6-OHDA) to neonatal rats produces a depletion of brain dopamine, mainly, that results in behavioral alterations in adulthood. This model can be applied to better understanding of the role of the dopaminergic system in cocaine use and how its behavioral effects can modulate drug intake. Though there are well-established sex differences in the pattern of drug use, there are no published studies investigating sex-dependent effects of neonatal lesions with 6-OHDA on cocaine self-administration nor regarding GABAA receptor (GABAAR) subunits expression. Herein, neurotoxic lesion was induced in male and female neonatal rats by intracisternal injection of 6-OHDA at PND 4, and locomotion was evaluated before and after cocaine self-administration. Cocaine was diluted in a sweet solution (sucrose 1.5%) and offered for 27 consecutive 3-h daily sessions via a dispenser for oral intake, in an operant chamber under a fixed-ratio 1 (FR1) schedule. The 6-OHDA lesion reduced oral cocaine self-administration in male and female rats. Female rats, independent of dopaminergic condition, consumed more cocaine-containing solution than sucrose-only solution. Furthermore, as expected, 6-OHDA-lesioned animals presented a higher basal locomotor activity when compared to sham rats. We evaluated GABAAR subunit expression and found no statistically significant differences between rats that self-administered a sucrose-only solution and those that self-administered a cocaine-containing solution. Even when the reward system is depleted, some behavioral differences remain in females, providing more data that highlight the female vulnerability to cocaine consumption.

Social distancing and changes in drug use: Results from a cross-sectional study during the COVID-19 pandemic in Brazil.

Background: The outbreak of coronavirus disease 19 has led to measures of social distancing and quarantine worldwide. This stressful period may lead to psychological problems, including changes in substance use. In addition, sociodemographic factors are linked to changed levels of drug use and abuse observed during the COVID-19 pandemic, which are also associated with increased anxiety, depression, and other disorders. Thus, the aim of the study was to investigate (i) changes in drug use during the COVID-19 pandemic associated with social distancing, and (ii) to verify factors associated with those changes. Methods: A web-based cross-sectional observational survey was completed by a self-selected adult general population in Brazil (N = 2,435) during September/October 2020 (first wave) before and throughout the pandemic. Key outcomes: social distancing, self-reported drug use (ASSIST), and emotional states (DASS-21). Results: High social distancing was associated with fewer chances (prevalence ratio) of increased drug use for alcohol (0.71, CI95%: 0.64-0.80), tobacco (0.72; CI95%: 0.60-0.87), cannabis (0.65; CI95%: 0.55-0.78), and others. Low social distancing presented a higher DASS-21 score for anxiety (P = 0.017). Concerning covariates analysis by a general linear model, men (alcohol: 1. 71; cannabis: 3.86), younger age (alcohol: 0.97), less education (alcohol, tobacco, cannabis and cocaine/crack comparing several lower schooling categories vs. higher education), lower income (alcohol: 0.42; tobacco: 0.47; and cannabis: 0.36), and higher depression DASS-21 score (alcohol: 1.05; tobacco: 1.08; cannabis: 1.07; and cocaine/crack: 1.07) were associated with higher use prevalence of several drugs. Conclusions: Individuals reporting low social distancing increased the use of most drugs during the pandemic, while high social distancing significantly decreased drug use. Anxiety and depressive states and several sociodemographic factors (men; lower income; less education) were associated with higher drug use patterns.

Elevated GABA levels in the medial prefrontal cortex and lower estrogen levels abolish cocaine sensitization behavior in ovariectomized female rats.

Animal models show that cocaine sensitization, a behavioral marker of addiction, is more significant in intact gonadal female than male rats and ovariectomy suppress this behavior in female rats. However, few studies explore changes in neurotransmission related to this phenomenon. Here we investigated the in vivo changes on GABA, glutamate, and taurine levels in the medial prefrontal cortex (mPFC) of gonadal intact or ovariectomized female rats after a cocaine challenge administration. Adult female rats were bilaterally ovariectomized (OVX), or sham-operated (SHAM) and randomly assigned to control (CTR), acute (ACT), or repeated (RPT) cocaine administration groups. In the challenge day, after eight days of daily cocaine (15 mg/kg) or saline administration and ten days of washout and stereotaxic surgery, RPT and ACT groups received cocaine, and the CTR group received saline. Horizontal locomotion was monitored concomitantly with microdialysate collection to determine extracellular GABA, glutamate, and taurine levels. Hormonal determination in blood samples confirmed the lower hormonal status of the OVX. Cocaine sensitization occurred in SHAM-RPT female rats after the challenge administration. Non-sensitized OVX-RPT rats showed a peak of GABA at 30 min after cocaine administration, with no change on glutamate and taurine levels. Therefore, elevated GABA levels in the mPFC and lower serum estrogen levels abolish cocaine sensitization behavior in ovariectomized female rats. We discuss some possible implications of these finding for future models of cocaine sensitization research lighting in the female hormonal influence.

The effects of caffeine on alcohol oral self-administration behavior in rats.

Caffeine and alcohol are some of the most commonly used psychoactive substances in the world, and are often used concomitantly. However, little is known about the effect of caffeine on alcohol consumption. Here, our aim was to investigate the co-exposure of alcohol mixed with caffeine in self-administration. Thirty-two male and thirty-two female Wistar rats were randomly divided into the following groups: control, caffeine (0.25 mg/mL), alcohol (10% v/v) and alcohol mixed with caffeine. After one week of training, the animals underwent self-administration for 21 days (1 h per day) in a fixed ratio of 1 (FR1). The forced swimming test (FST) was performed before the training phase and 24 h after the last self-administration session to verify abstinence-induced depressive-like behaviors. Our results showed that all rats consumed a lower volume of alcohol-containing solution than control solution, and that the presence of caffeine did not influence this parameter. Females consumed less volume of alcohol solution than males but the average dose was similar. Females that self-administered alcohol mixed with caffeine presented a higher immobility in the FST than males that self-administered the same solution. These results support the conclusion that moderate doses of caffeine such as the ones from our study (approximately 7-8 mg/kg/day) do not influence alcohol consumption. Additionally, females might be more susceptible than males to depressive-like effects caused by the abstinence of the use of these substances in combination.

Role of Parenting Styles in Adolescent Substance Use Cessation: Results from a Brazilian Prospective Study.

BACKGROUND: This study aims to identify the association between parenting styles and behavioral changes among adolescents regarding the consumption of alcohol, tobacco, cannabis, cocaine/crack. METHODS: A group of ninety-nine adolescents (39 girls and 60 boys), aged 14 to 19 years (17.05 ± 1.51), who called in to a call center that provides counseling to substance users, was followed-up for 30 days. Data collection occurred between March 2009 and October 2015. The adolescents answered questions regarding parental responsiveness and demanding nature on a scale to assess parental styles and provided sociodemographic data, substance abuse consumption characteristics, and the Contemplation Ladder scale score. RESULTS: The parental styles most reported by the adolescents were authoritative (30%) and indulgent (28%). Children who perceived their mothers as having an indulgent style and who had absent fathers presented more difficulties in making behavioral changes to avoid alcohol and cocaine/crack consumption. CONCLUSION: The study found that parent-child relationships were associated with a lack of change in the adolescent regarding substance use behavior, particularly the consumption of alcohol and cocaine/crack.

Pre-trial cocaine biases choice toward cocaine through suppression of the nondrug option.

Being under the influence during choice between drug and nondrug options can have a dramatic effect on choice outcomes. When rats face a choice between cocaine and sweet water and are not under the influence, they prefer sweet water. In contrast, when they are under the influence of cocaine, this causes them to shift their choice to cocaine nearly exclusively. Here we sought to characterize the behavioral mechanisms underlying the influence of cocaine on choice. In theory, rats under the influence of cocaine should be in a mixed motivational state, at least temporarily, with both their motivation for cocaine and their motivation for the nondrug option suppressed by the drug satiating and anorexic effects of cocaine, respectively. For this mixed state to shift choice to cocaine, the satiated motivation for cocaine should recover before the suppressed motivation for the preferred nondrug option. The goal of the present study was to test this prediction in rats that expressed a preference for sweet water after extended access to cocaine self-administration. We measured their choice and response latencies to each option after pre-trial, passive administration of cocaine to estimate the duration of its drug satiating and anorexic effects. As expected, pre-trial cocaine caused most rats to shift their choice to cocaine. Though this shift was not simply due to a longer latency to respond for sweet water than for cocaine after pre-trial cocaine, it nevertheless occurred while rats' motivation for the nondrug option was still partially suppressed. Thus, cocaine seems to bias choice toward more cocaine mainly via suppression of the nondrug option.

Environmental enrichment reduces cocaine neurotoxicity during cocaine-conditioned place preference in male rats.

Environmental enrichment (EE) has a neuroprotective role and prevents the development of cocaine addiction behavior in rats. Studies showing the role of EE in cocaine toxicity are nonexistent. We hypothesized that rats exposed to EE are protected from cocaine-induced changes in the redox profile and DNA damage after undergoing conditioned place preference (CPP). Ten male Wistar rats were placed in EE cages equipped with toys, a ladder and tunnels, and ten were provided clean, standard laboratory housing (non-EE). EE and non-EE rats were randomly allocated to the classical CPP cocaine vs. saline (COC/Saline) group, where cocaine (15 mg/kg; i.p.) was tested alternately with saline. Afterwards, intracellular reactive species and antioxidant enzymes were evaluated and the comet essay was performed in the prefrontal cortex and hippocampus of rats. As expected, EE rats spent less time in the cocaine-paired chamber, and as a new result, less cocaine-induced DNA damage was observed in the two brain structures. Altogether, our results demonstrate that EE decreases neurotoxicity in brain regions linked to cocaine addiction but does not extinguish it completely.

Acute intraperitoneal administration of taurine decreases the glycemia and reduces food intake in type 1 diabetic rats.

Taurine, an amino acid with antioxidant and osmoregulatory properties, has been studied for its possible antidiabetic properties in type 1 and type 2 diabetic animals. In type 2 diabetic mice, taurine decreases blood glucose through increased insulin secretion and insulin receptor sensitization. However, insulin is absent in type 1 diabetic individuals. The aim of this study was to evaluate the effects of taurine on parameters related to the energy balance that could explain the metabolic action of this amino acid in type 1 diabetic rats. Control and streptozotocin-induced diabetic rats received saline or taurine (100 mg/kg/day), intraperitoneally, for 30 days. Parameters such as palatable food intake, gastrointestinal transit rate, serum glucose, insulin, leptin, and glucagon levels were measured 60 min after the last taurine administration. Liver, kidneys, heart, and retroperitoneal fat were dissected and weighted. Glycogen levels were measured in the liver and soleus muscle. Our results showed that acute taurine administration decreased glycemia. It also decreased food intake in diabetic rats, without affecting other metabolic parameters. Altogether, our results suggest that in type 1 diabetic rats, taurine decreases blood glucose by a non-insulin-dependent mechanism. Due to the safety profile of taurine, and its effect on glycemia, this amino acid may help to design new drugs to add benefit to insulin therapy in type 1 diabetic individuals.

Non-medical use of methylphenidate: a review.

INTRODUCTION: Methylphenidate is a psychostimulant medication used for the treatment of attention deficit hyperactivity disorder and narcolepsy. However, it has also been used for non-medical purposes, e.g. to produce euphoria, to increase self-esteem, and to achieve the so-called neurocognitive enhancement, decreasing the feeling of tiredness and increasing focus and attention. OBJECTIVE: To describe, from theoretical and contextual points of view, the potential for abuse and non-medical use of methylphenidate. METHOD: The PubMed, SciELO and Cochrane databases were searched using the following keywords in Portuguese: metilfenidato, transtorno do déficit de atenção com hiperatividade, facilitadores dos processos cognitivos or agentes nootrópicos, and abuso de substâncias; and in English: methylphenidate, attention deficit disorder with hyperactivity, cognitive enhancement or nootropic agents, and substance abuse. Studies published between 1990 and 2010 were selected for review. RESULTS: Non-medical use of methylphenidate is a relevant topic that raises important ethical and scientific questions in several areas, e.g. pharmacological and neurobiological characteristics, evidence of methylphenidate use, forms of non-medical use of methylphenidate, mechanisms of action, and therapeutic application of methylphenidate. According to the review, methylphenidate can generally influence performance as a result of its stimulatory effect. Notwithstanding, evidence does not support the conclusion that it can enhance cognitive performance. CONCLUSION: Health professionals need to acquire expert knowledge and inform patients and their families on the methylphenidate potential for abuse when used with non-medical purposes.

Uso não terapêutico do metilfenidato: uma revisão / Non-medical use of methylphenidate: a review

INTRODUCTION: Methylphenidate is a psychostimulant medication used for the treatment of attention deficit hyperactivity disorder and narcolepsy. However, it has also been used for non-medical purposes, e.g. to produce euphoria, to increase self-esteem, and to achieve the so-called neurocognitive enhancement, decreasing the feeling of tiredness and increasing focus and attention. OBJECTIVE: To describe, from theoretical and contextual points of view, the potential for abuse and non-medical use of methylphenidate. METHOD: The PubMed, SciELO and Cochrane databases were searched using the following keywords in Portuguese: metilfenidato, transtorno do déficit de atenção com hiperatividade, facilitadores dos processos cognitivos or agentes nootrópicos, and abuso de substâncias; and in English: methylphenidate, attention deficit disorder with hyperactivity, cognitive enhancement or nootropic agents, and substance abuse. Studies published between 1990 and 2010 were selected for review. RESULTS: Non-medical use of methylphenidate is a relevant topic that raises important ethical and scientific questions in several areas, e.g. pharmacological and neurobiological characteristics, evidence of methylphenidate use, forms of non-medical use of methylphenidate, mechanisms of action, and therapeutic application of methylphenidate. According to the review, methylphenidate can generally influence performance as a result of its stimulatory effect. Notwithstanding, evidence does not support the conclusion that it can enhance cognitive performance. CONCLUSION: Health professionals need to acquire expert knowledge and inform patients and their families on the methylphenidate potential for abuse when used with non-medical purposes.

INTRODUÇÃO: O metilfenidato é um medicamento psicoestimulante usado no tratamento do transtorno de déficit de atenção e hiperatividade e da narcolepsia. No entanto, a droga também vem sendo utilizada com fins não terapêuticos, por exemplo para produzir euforia, aumentar a autoestima e obter o chamado aprimoramento neurocognitivo, diminuindo a sensação de cansaço e aumentando o foco e a atenção. OBJETIVO: Descrever, sob o ponto de vista teórico e contextual, o potencial de abuso do metilfenidato quando usado com fins não terapêuticos. MÉTODO: Foi realizada uma pesquisa nos bancos de dados PubMed, SciELO e Cochrane, utilizando os seguintes termos em português: metilfenidato, transtorno do déficit de atenção com hiperatividade, facilitadores dos processos cognitivos or agentes nootrópicos e abuso de substâncias; e, em inglês: methylphenidate, attention deficit disorder with hyperactivity, cognitive enhancement or nootropic agents e substance abuse. Foram selecionados estudos publicados entre 1990 e 2010. RESULTADOS: O uso não terapêutico do metilfenidato é um tema relevante e que suscita questões científicas e éticas importantes sob diversos aspectos, por exemplo características farmacológicas e neurobiológicas, evidência de uso da droga, formas não terapêuticas de uso, mecanismos de ação e aplicação terapêutica do metilfenidato. De acordo com a revisão o metilfenidato pode, em geral, influenciar o desempenho como resultado de seu efeito estimulatório. No entanto, independentemente disso, as evidências não apoiam a conclusão de que ele possa promover um melhor desempenho cognitivo. CONCLUSÃO: É importante que profissionais da saúde tenham conhecimento e informem os pacientes e suas famílias sobre o potencial de abuso do metilfenidato quando usado com fins não terapêuticos.

A eficácia das intervenções farmacológicas e psicossociais para o tratamento do tabagismo: revisão da literatura / Efficacy of pharmacological and no-pharmacological treatments for smoking cessation

A cessação do tabagismo traz benefícios à saúde, pois indivíduos que param de fumar evitam a maioria das doenças associadas ao tabaco. Objetiva-se revisar as características fundamentais e eficácia das intervenções farmacológicas e psicossociais para o tratamento dos tabagistas, apresentando dados de revisões tipo meta-análises e de ensaios clínico randomizados. Intervenções farmacológicas como a terapia de reposição de nicotina e a bupropiona e intervenções psicossociais como a terapia cognitivo-comportamental e a intervenção motivacional face a face e por telefone demonstram eficácia. A farmacoterapia aumenta a chance de abstinência em 2 vezes e as intervenções psicossociais face a face ou por telefone em 1,5 a 2,5 vezes em relação a tabagistas recebendo intervenções controles. Estes dados fornecem subsídios para profissionais de saúde decidirem qual o melhor tratamento para o tabagista, informando as intervenções disponíveis, sua eficácia e o benefício de sua utilização.

Smoking cessation is associated to health benefits, because individuals who stop smoking will avoid most tobacco-related disorders. Our aim was to review the most important characteristics and the efficacy of the pharmacological and psychossocial treatments available for tobacco smokers, presenting meta-analysis and randomized clinical trials fundamental conclusions. Pharmacological interventions involving nicotine replacement and antidepressant use, with bupropion as the first line agent, and psychossocial interventions involving cognitive behavioral therapies and face-to-face or phone-based motivational interventions are proving to be efficacious. Pharmacotherapies increase two-fold the chance of abstinence and face-to-face or phone-based psychosocial interventions increase the chance of quitting smoking in 1.5 to 2.5 times in comparison to individuals who try to quit smoking by themselves. These data support health professionals to decide the most effective treatment for individual smokers, according to the available interventions tested, their efficacy and the benefits of use.

Aconselhamento telefônico reativo para cessação do consumo do tabaco: relato de caso / Reactive telephone counseling for cessation of the consumption of the tobacco: case study

Este estudo teve por objetivo descrever o modelo de aconselhamento telefônico reativo para tabagistas, utilizado pelo VIVAVOZ. Discute-se a importância do aconselhamento telefônico reativo no processo de cessação do consumo de tabaco. O estudo baseia-se em relato de caso de uma tabagista que procurou o VIVAVOZ – Serviço Nacional de Informações e Orientações sobre Drogas – para auxiliá-la na mudança de seu comportamento dependente. Os instrumentos aplicados na avaliação incluíram o Questionário de Tolerância de Fagerstrõm, História Tabagística, Avaliação do Consumo e as escalas URICA e Ladder. O modelo apresentado demonstrou resultados positivos, neste caso específico, no processo de motivação para cessação do consumo de tabaco, aumentando o período de abstinência e as tentativas de parada.