Sex differences in the effects of N-ethylpentylone in young CD1 mice: Insights on behaviour, thermoregulation and early gene expression.

BACKGROUND AND PURPOSE: New psychoactive substances such as N-ethylpentylone (NEP) are continuously emerging in the illicit drug market, and knowledge of their effects and risks, which may vary between sexes, is scarce. Our present study compares some key effects of NEP in male and female mice. EXPERIMENTAL APPROACH: Psychostimulant, rewarding and reinforcing effects were investigated by tracking locomotor activity, conditioned place preference (CPP) paradigm and through a self-administration (SA) procedure, respectively, in CD1 mice. Moreover, the expression of early genes (C-fos, Arc, Csnk1e, Pdyn, Pp1r1b and Bdnf in addiction-related brain areas) was assessed by qPCR. Finally, serum and brain levels of NEP were determined by UHPLC-MS/MS. KEY RESULTS: NEP-treated males experimented locomotor sensitisation and showed higher and longer increases in locomotion as well as higher hyperthermia after repeated administration than females. Moreover, while preference score in the CPP was similar in both sexes, extinction occurred later, and reinstatement was more easily established for males. Female mice self-administered more NEP than males at a higher dose. Differences in early gene expression (Arc, Bdnf, Csnk1e and Ppp1r1b) were found, but the serum and brain NEP levels did not differ between sexes. CONCLUSION AND IMPLICATIONS: Our results suggest that male mice are more sensitive to NEP psychostimulant and rewarding effects. These differences may be attributed to different early gene expression but not to pharmacokinetic factors. Moreover, males appear to be more vulnerable to the hyperthermic effects of NEP, while females might be more prone to NEP abuse.

3,4-Methylenedioxy methamphetamine, synthetic cathinones and psychedelics: From recreational to novel psychotherapeutic drugs.

The utility of classical drugs used to treat psychiatric disorders (e.g., antidepressants, anxiolytics) is often limited by issues of lack of efficacy, delayed onset of action or side effects. Psychoactive substances have a long history of being used as tools to alter consciousness and as a gateway to approach the unknown and the divinities. These substances were initially obtained from plants and animals and more recently by chemical synthesis, and its consumption evolved toward a more recreational use, leading to drug abuse-related disorders, trafficking, and subsequent banning by the authorities. However, these substances, by modulation of certain neurochemical pathways, have been proven to have a beneficial effect on some psychiatric disorders. This evidence obtained under medically controlled conditions and often associated with psychotherapy, makes these substances an alternative to conventional medicines, to which in many cases the patient does not respond properly. Such disorders include post-traumatic stress disease and treatment-resistant depression, for which classical drugs such as MDMA, ketamine, psilocybin and LSD, among others, have already been clinically tested, reporting successful outcomes. The irruption of new psychoactive substances (NPS), especially during the last decade and despite their recreational and illicit uses, has enlarged the library of substances with potential utility on these disorders. In fact, many of them were synthetized with therapeutic purposes and were withdrawn for concrete reasons (e.g., adverse effects, improper pharmacological profile). In this review we focus on the basis, existing evidence and possible use of synthetic cathinones and psychedelics (specially tryptamines) for the treatment of mental illnesses and the properties that should be found in NPS to obtain new therapeutic compounds.

Characterization of monoaminergic neurochemicals in cortex and striatum of mouse brain.

Monoamine neurochemicals regulate most of the physiological and behavioural processes in the vertebrate brain. Mice and rats are the preferred species in scientific research, specifically in biomedical research, due to their anatomical, genetic and physiological similarity to human. Moreover, the interest in monitoring the changes in the central nervous system (CNS) produced by neuroactive compounds is constantly growing. In this study, we have evaluated the performance of liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) for the multiresidue determination of multi-class monoamine neurotransmitters in the main areas of mouse brain (prefrontal cortex and striatum). The best performance was obtained with a BEH amide column, which permitted the separation of 9 compounds in only 10 min. Moreover, the performance of LC-MS/MS was evaluated in terms of linearity, sensitivity, intraday precision and overall robustness. Finally, catecholamine neurochemicals reported significant differences in the concentration levels between prefrontal cortex and striatum, while serotonergic neurochemicals didn't report any significant differences.

Repeated administration of N-ethyl-pentedrone induces increased aggression and impairs social exploration after withdrawal in mice.

N-ethyl-pentedrone (NEPD, 2-(ethylamino)-1-phenyl-1-pentanone) is one of the latest synthetic cathinone derivatives that emerged into the illicit drug market. This drug has psychostimulant properties and has been related with several intoxications and even fatalities. However, information about the consequences of its acute and repeated consumption is lacking. Thus, the aim of our study was to investigate the behavioral effects after both acute and repeated NEPD exposure as well as the neurochemical changes. Male OF1 mice were treated with an acute dose (1, 3 or 10 mg/kg, i.p.) or received repeated injections of these doses (twice/day, 5 days) of NEPD. Shortly after drug-exposure or during drug-withdrawal, anxiety-like behavior, aggressiveness, social interaction, depressive-like symptoms, body weight and temperature were assessed. Also, monoamine synthesis enzymes, levels of neurotransmitters and their precursors and main metabolites, as well as ΔFosB, were determined in striatum and prefrontal cortex from post-mortem tissue. Acute administration of NEPD induced anxiolytic effects and reduced social exploration whereas during withdrawal after repeated administration the anxiolytic effect had vanished, and the reduced social exploration was still present and accompanied with increased aggressive behavior. Moreover, NEPD (10 mg/kg) induced slight hyperthermia and reduced weight gain during the repeated administration, whereas increased locomotor activity and lack of depressive symptoms were found during withdrawal. This was accompanied by increased plasma corticosterone and decrease in striatal dopamine. Finally, the long-lasting and robust increase in ΔFosB levels found in striatum after NEPD chronic exposure suggests a high risk of dependence. The increased aggressivity and locomotor activity, together with this potential of inducing dependence justify a warning about the risks of consumption of NEPD if translated to humans.

Behavioural and neurochemical effects after repeated administration of N-ethylpentylone (ephylone) in mice.

N-ethyl-pentylone (NEP), also known as 'ephylone' and N-ethylnorpentylone, has been identified as one of the most recent novel psychostimulants to emerge into the illicit drug market and it has been associated with some intoxications and even fatalities. However, little is known about the consequences of its repeated consumption as well as the role of the monoaminergic system in such consequences. Thus, the aim of our study was to investigate the neurochemical profile and the behavioural effects after both acute and repeated NEP exposure. Male OF1 mice were acutely (1, 3, 10 mg/kg, i.p.) or repeatedly (1, 3, 10 mg/kg, i.p., 5 days, twice/day) exposed to NEP, and anxiety-like behaviour, aggressiveness, social interaction, depressive-like symptoms, body temperature, changes in monoaminergic enzymes and neurotransmitters levels as well as ΔFosB in striatum and prefrontal cortex (PFC) from post-mortem tissue were analysed short after drug-exposure or during drug-withdrawal. Acute administration of NEP induced anxiolytic effects but also an aggressive behaviour and social exploration deficits in mice, which persist during NEP-withdrawal. Moreover, NEP induced hyperthermia as well as depressive-like symptoms after repeated administrations that may be related to the decrease in serotonin and noradrenaline levels observed in striatum and PFC. Finally, the long-term increase in ΔFosB levels in striatum after NEP chronic exposure points to a high risk of dependence. Altogether indicates that NEP consumption induces different neurological and neuropsychiatric disorders accompanied by changes in the monoaminergic system, posing a threat to public health.

Structure-Activity Relationship of Novel Second-Generation Synthetic Cathinones: Mechanism of Action, Locomotion, Reward, and Immediate-Early Genes.

Several new synthetic cathinones, which mimic the effect of classical psychostimulants such as cocaine or MDMA, have appeared in the global illicit drug market in the last decades. In fact, the illicit drug market is continually evolving by constantly adding small modifications to the common chemical structure of synthetic cathinones. Thus, the aim of this study was to investigate the in vitro and in vivo structure-activity relationship (SAR) of six novel synthetic cathinones currently popular as recreational drugs, pentedrone, pentylone, N-ethyl-pentedrone (NEPD), N-ethyl-pentylone (NEP), 4-methyl-pentedrone (4-MPD), and 4-methyl-ethylaminopentedrone (4-MeAP), which structurally differ in the absence or presence of different aromatic substituents and in their amino terminal group. Human embryonic kidney (HEK293) cells expressing the human isoforms of SERT and DAT were used for the uptake inhibition and release assays. Moreover, Swiss CD-1 mice were used to investigate the psychostimulant effect, rewarding properties (3, 10, and 30 mg/kg, i.p.), and the induction of immediate-early genes (IEGs), such as Arc and c-fos in the dorsal striatum (DS) and ventral striatum (VS) as well as bdnf in the medial prefrontal cortex (mPFC), of the test compounds. Our results demonstrated that all tested synthetic cathinones are potent dopamine (DA) uptake inhibitors, especially the N-ethyl analogs, while the ring-substituted cathinones tested showed higher potency as SERT inhibitors than their no ring-substituted analogs. Moreover, unlike NEP, the remaining test compounds showed clear "hybrid" properties, acting as DAT blockers but SERT substrates. Regarding the locomotion, NEP and NEPD were more efficacious (10 mg/kg) than their N-methyl analogs, which correlates with their higher potency inhibiting the DAT and an overexpression of Arc levels in the DS and VS. Furthermore, all compounds tested induced an increase in c-fos expression in the DS, except for 4-MPD, the least effective compound in inducing hyperlocomotion. Moreover, NEP induced an up-regulation of bdnf in the mPFC that correlates with its 5-HTergic properties. Finally, the present study demonstrated for the first time that NEP, 4-MPD, and 4-MeAP induce reward in mice. Altogether, this study provides valuable information about the mechanism of action and psychostimulant and rewarding properties as well as changes in the expression of IEGs related to addiction induced by novel second-generation synthetic cathinones.

Ganancia de peso gestacional como factor de riesgo para desarrollar complicaciones obstétricas / Gestational weight gain as a risk factor for developing obstetric complications

La ganancia de peso gestacional es un fenómeno complejo influenciado no sólo por cambios fisiológicos y metabólicos maternos, sino también por el metabolismo placentario. Las mujeres que durante el embarazo tienen un índice de masa corporal (IMC) normal y una ganancia de peso adecuada, presentan una mejor evolución gestacional y del parto. Las mujeres con una ganancia de peso gestacional mayor a la recomendada presentan un incremento en el riesgo de tener hipertensión, diabetes mellitus, varices, coledocolitiasis, embarazos prolongados, retardo en el crecimiento intrauterino, mayor porcentaje de complicaciones al nacimiento, complicaciones trombóticas, anemia, infecciones urinarias y desórdenes en la lactancia. Por una parte, existe una relación entre el peso de la placenta y el volumen del líquido amniótico y, por la otra, el peso del recién nacido, probablemente también exista una relación con el tamaño del útero. Existen diferentes factores que dificultan que la ganancia de peso sea la adecuada, entre los que se encuentra una edad mayor o igual a 40 años. La ganancia excesiva de peso que se puede mantener, e incluso aumentar después del embarazo, dificulta que la mujer regrese a su peso ideal. En el primer trimestre, en la dieta (1,800 calorías) se debe incluir ingredientes saludables. En el segundo trimestre, el feto dobla su talla (a 2,500 calorías), al inicio del cuarto mes, hay que ir aumentando progresivamente las calorías hasta llegar a las 2,500 recomendadas por la OMS. Durante el tercer trimestre (2,750 calorías), en los últimos meses de gestación, se debe aportar a la dieta unas 2,750 calorías diarias y contener sólo unos 100 gramos de proteínas. La comprensión de los determinantes de la ganancia de peso durante el embarazo es esencial para el diseño de las intervenciones clínicas y de la salud de la madre y el bebé.

Gain of gestational weight is a complex phenomenon, not only influenced by maternal physiologic and metabolic changes, but also for the placental metabolism. The women that have a normal body weight index (BWI) and a gain of weight adapted during the gestation to the moment to be pregnancy present a better evolution in pregnancy and childbirth that those women with a gain of more weight to the one recommended. The women with a gain of gestational weight bigger than the increase the risk of having obstetric complications like hypertension, diabetes, coledocolitiasis, prolonged pregnancy, intra-uterine low growth, bigger percentage of complications to the birth, infections before and after the childbirth, thrombotic complications, anemia, bladder infections and disorder in the nursing. A relationship exists between the weight of the placenta and the volume the amniotic liquid, on one hand and the weight of the newly born one for other and that it probably exists also a relationship among the size of the uterus. Different types of complications exist when the gain of weight is not the appropriate one, among those that are the oldest age or similar to 40 years where a bigger risk of obstetric complications exists, this way the excessive gain of weight that can stay and even to increase after the pregnancy being therefore very difficult so that the woman to return to its ideal weight. In the first trimester (1,800 calories) should begin to include healthy ingredients. Second trimester, the fetus bends its size, to the beginning of the fourth month it is necessary to go increasing the calories intake progressively until arriving at the 2,500. Third trimester recommends an intake of 2,750 calories and to contain about 100 grams of proteins. The understanding of the determinant of the gain of weight during the pregnancy is essential for the design of the clinical interventions and of the mother's health and the baby.

Complicaciones obstétricas de la diabetes gestacional: criterios de la IADPSG y HAPO / Obstetric complications of gestational diabetes: criteria of the HAPO and IADPSG

La diabetes mellitus gestacional (DMG) se define como una intolerancia a los carbohidratos, de severidad variable, que se diagnostica por primera vez durante el embarazo. Los síntomas más comunes asociados con la diabetes mellitus gestacional son hambre y sed extremas, además de visión borrosa y aumento de peso excesivo. El origen étnico y la edad son factores de riesgo, al igual que el índice de masa corporal. Estudios como el de Hyperglycemia and Adverse Pregnancy Outcome (HAPO, Hiperglucemia y Resultado Adverso del Embarazo) se han llevado a cabo con el objetivo de clarificar el riesgo de desenlaces adversos asociados con varios grados de intolerancia a la glucosa materna. La International Association of Diabetes and Pregnancy Study Groups (IADPSG, Asociación Internacional de Grupos de Estudio de Diabetes y Embarazo) ha propuesto criterios para el diagnóstico y la clasificación de la hiperglucemia en el embarazo. El estudio HAPO reportó un alto porcentaje de complicaciones perinatales de la diabetes mellitus gestacional, por lo que actualmente se proponen 92 mg/dL de glucemia como punto de corte para el diagnóstico de la diabetes mellitus gestacional. En este momento están en proceso varios estudios para evaluar si el realizar intervenciones terapéuticas a partir del punto de corte señalado reduce la incidencia de complicaciones perinatales. El tratamiento de la diabetes mellitus gestacional consiste en una dieta limitada en carbohidratos que se debe administrar en pequeñas porciones, pero de manera más frecuente que la dieta habitual para mantener los niveles de glucosa estables.

Gestational diabetes is defined as an intolerance to carbohydrates not caused by the lack of insulin, but by contraregulation hormones that block insulin effects; this condition is named "resistance to insulin", and has generally its onset at > 20 weeks of gestation. The ethnic origin, the age and the body mass index have been identified as risk factors. The studies of diverse ethnic groups have demonstrated frequencies of 0.4% in Caucasian races, l.5% in blacks, 3.5 to 7.3% in Asian and up to 16% in Native American. Regarding the mothers' age, it has been pointed out that the incidence is of 0.4 to 0.5% in those younger than 25 years old and of 4.3 to 5.5% in those older than that age. These women have a greater probability of developing gestational diabetes in their next pregnancy and type 2 diabetes in the future. 95 mg/dL was previously considered as the limit in fasting glucose to diagnose gestational diabetes; however, the Hyperglycemia and Adverse Pregnancy Outcome study reported a high percentage of perinatal complications, so now 92 mg/dL is used as the glucose cutoff; studies are underway to evaluate if complications diminish in a significant way. The treatment has the objective of diminishing the risk of perinatal complications; a proportion of women requires intensive treatment of prenatal insulin. A diet limited in sweets and carbohydrates, with small snacks between meals is advisable to maintain the levels of glucose stable.