Uso de sustancias psicoactivas en estudiantes de escuelas secundarias de Rosario (Argentina) / Psychoactive Drugs Use Among High-School Students In Rosario (Argentina)

Resumen El consumo de Sustancias psicoactivas (SPs) es un problema de salud mundial que afecta particularmente a los adolescentes. Por lo tanto, el conocimiento del contacto que los jóvenes tienen con las SPs, permitirá el desarrollo de políticas de prevención. El objetivo del trabajo fue evaluar el contacto con SPs de estudiantes secundarios de Rosario y alrededores. Entre el 2013 y el 2016, contestaron de forma anónima un cuestionario 1064 estudiantes, observándose un aumento significativo del consumo de SPs en el año 2016. Cuando se excluyen el consumo de tabaco y alcohol (SPs legales) el porcentaje permanece constante. El aumento observado se debe al consumo de SPs tales como alcohol y tabaco. Se observó una disminución de la edad de inicio así como un cambio en los porcentajes y patrones de consumo. La SP más consumida fue el alcohol seguida de tabaco o marihuana. Los cambios observados podrían estar relacionados con las edades y los años de cursado de los estudian tes encuestados.

Abstract. Adolescence is characterized by anxiety, peer-pressure, identity search, etc. All these features contribute to experiment with Psychoactive Drugs (P.D.). P.D. use is a global health problem that has its onset during adolescence. The developing of prevention policies according to a specific population needs the knowledge of the levels and patterns of P.D. use. The goal of the present work was to evaluate P.D.'s level of contact and patterns of use among high school students in Rosario (Argentina). Between 2013 and 2016, a total of 1064 students were surveyed. The results showed that P.D. use (at least once in a lifetime) was significantly higher in 2016 compared to previous years. However, when the use of legal vs illegal P.D. was discriminated we found that such increase was due to higher use of alcohol and tobacco; while the illegal P.D. use remained constant. Moreover, in 2016 we found a decrease in the age of onset as well as a change in the patterns of P.D use. However, all these results must be analyzed taking into account intrinsic differences of the sample.

Exposure to glyphosate during pregnancy induces neurobehavioral alterations and downregulation of Wnt5a-CaMKII pathway.

Glyphosate-based formulations are the most popular herbicide used around the world. These herbicides are widely applied in agriculture to control weeds on genetically modified crops. Although there is much evidence showing that glyphosate-based herbicides induce toxic effect on reproductive and hepatic systems, and also cause oxidative damage on cells, studies from recent years revealed that the nervous system may represent a key target for their toxicity. In the present work, we evaluated the effect of glyphosate (without adjuvants) in neonate rats after gestational exposure. Particularly, we examined whether glyphosate during gestation affected the nervous system function at early development. Pregnant Wistar rats were treated with 24 or 35 mg/kg of pure glyphosate every 48 h and neurobehavioral studies were performed. Our results indicated that gestational exposure to glyphosate induced changes in reflexes development, motor activity and cognitive function, in a dose-dependent manner. To go further, we evaluated whether prenatal exposure to glyphosate affected the Ca+2-mediated Wnt non-canonical signaling pathway. Results indicated that embryos exposed to glyphosate showed an inhibition of Wnt5a-CaMKII signaling pathway, an essential cascade controlling the formation and integration of neural circuits. Taken together, these findings suggest that gestational exposure to glyphosate leads to a downregulation of Wnt/Ca+2 pathway that could induce a developmental neurotoxicity evidenced by deficits at behavioral and cognitive levels in rat pups.

Social Isolation in Male Rats During Adolescence Inhibits the Wnt/ß-Catenin Pathway in the Prefrontal Cortex and Enhances Anxiety and Cocaine-Induced Plasticity in Adulthood.

In adult animals, it is well established that stress has a proactive effect on psychostimulant responses. However, whether only a short period of stress during adolescence can also affect cocaine responses later in life and what mechanisms are involved are unknown. Here, we showed that 5 days of social isolation during rat adolescence had a long-term impact on anxiety-like behaviors, cocaine-induced conditioned place preference, and the expression of sensitization during adulthood. At the molecular level, social isolation decreased the activity of the Wnt/ß-catenin pathway in the prefrontal cortex (PFC). Furthermore, after the expression of cocaine sensitization, isolated rats showed an increase in this pathway in the nucleus accumbens. Together, these findings suggest that, adolescent social isolation by altering the Wnt/ß-catenin pathway in the developing PFC might increase the cocaine responses during adulthood, introducing this pathway as a novel neuroadaptation in the cortical-accumbens connection that may mediate a stress-induced increase in vulnerability to drugs.

Wnt/ß-catenin pathway in the prefrontal cortex is required for cocaine-induced neuroadaptations.

Behavioral sensitization is a progressive and enduring enhancement of the motor stimulant effects elicited by repeated administration of drugs of abuse. It can be divided into two distinct temporal and anatomical domains, termed initiation and expression, which are characterized by specific molecular and neurochemical changes. This study examines the role of the Wnt canonical pathway mediating the induction of cocaine sensitization. We found that ß-catenin levels in the prefrontal cortex (PFC), amygdala (Amyg) and dorsal striatum (CPu) are decreased in animals that show sensitization. Accordingly, GSK3ß activity levels are increased in the same areas. Moreover, ß-catenin levels in nuclear fraction, mRNA expression of Axin2 and Wnt7b are decreased in the PFC of sensitized animals. Then, in order to demonstrate that changes in the PFC are crucial for initiation of sensitization, we either rescue ß-catenin levels with a systemic treatment of a GSK3ß inhibitor (Lithium Chloride) or inhibit Wnt/ß-catenin pathway with an intracerebral infusion of Sulindac before each cocaine injection. As expected, rescuing ß-catenin levels in the PFC as well as CPu and Amyg blocks cocaine-induced sensitization, while decreasing ß-catenin levels exclusively in the PFC exacerbates it. Therefore, our results demonstrate a new role for the Wnt/ß-catenin pathway as a required neuroadaptation in inducing behavioral sensitization.

Role of Wnt/ß-catenin pathway in the nucleus accumbens in long-term cocaine-induced neuroplasticity: a possible novel target for addiction treatment.

Cocaine addiction is a chronic relapsing disorder characterized by the loss of control over drug-seeking and taking, and continued drug use regardless of adverse consequences. Despite years of research, effective treatments for psycho-stimulant addiction have not been identified. Persistent vulnerability to relapse arises from a number of long-lasting adaptations in the reward circuitry that mediate the enduring response to the drug. Recently, we reported that the activity of the canonical or Wnt/ß-catenin pathway in the prefrontal cortex (PFC) is very important in the early stages of cocaine-induced neuroadaptations. In the present work, our main goal was to elucidate the relevance of this pathway in cocaine-induced long-term neuroadaptations that may underlie relapse. We found that a cocaine challenge, after a period of abstinence, induced an increase in the activity of the pathway which is revealed as an increase in the total and nuclear levels of ß-catenin (final effector of the pathway) in the nucleus accumbens (NAcc), together with a decrease in the activity of glycogen synthase kinase 3ß (GSK3ß). Moreover, we found that the pharmacological modulation of the activity of the pathway has long-term effects on the cocaine-induced neuroplasticity at behavioral and molecular levels. All the results imply that changes in the Wnt/ß-catenin pathway effectors are long-term neuroadaptations necessary for the behavioral response to cocaine. Even though more research is needed, the present results introduce the Wnt canonical pathway as a possible target to manage cocaine long-term neuroadaptations.

A dopamine mechanism is implied in the acquisition and expression of amphetamine and stress-induced effects observed in the lymphocyte subpopulations.

Drugs of abuse and stress are associated with changes in circulating cell populations and reductions in cell-mediated immune responses. The main goal of this study was to determine the influence of repeated and acute d-amphetamine treatments on the foot-shock stress-induced effects on the peripheral lymphocyte subpopulations, and the involvement of a dopamine mechanism in the development and expression of this phenomenon. Wistar rats received an acute (5 mg/kg/day i.p.) or a repeated (2 mg/kg/day i.p. during 9 days) amphetamine treatment, and were exposed to a foot-shock stress (1 mA, 3 s) 4 days after the last amphetamine injection. Another group was administered with haloperidol (1 mg/kg/day i.p.) 15 min previous to each daily amphetamine injection or previous to the foot-shock stress session. Then, blood cells stained with monoclonal antibodies against CD3-FITC, CD8-PE and CD4-Cy-Chrome, and against CD161a-FITC, CD3-PE, and CD45RA-Cy-Crhome, were analyzed by multiparameter flow cytometry. The exposure to a foot-shock stress induced a decrease in the absolute number of peripheral lymphocytes, as well as in CD4+ and CD8+ T-cells and B-cells in acute and repeatedly amphetamine-treated rats, whereas the NK-cell population remained unchanged. Haloperidol administration previous to each drug administration or the foot-shock stress session reversed these effects. This study provides strong evidence that dopamine can play a more general role in the influence of amphetamine on the stress-induced effects on the lymphocyte subsets.

A glutamate-dopamine interaction in the persistent enhanced response to amphetamine in nucleus accumbens core but not shell following a single restraint stress.

The administration of psychostimulant drugs or stress can elicit a sensitized response to the stimulating and reinforcing properties of the drug. We previously demonstrated that a single restraint stress session enhanced d-amphetamine (d-AMPH)-induced locomotion the day after the stress session, which lasted up to 8 days. The present experiments were designed to identify the contribution of major dopamine (DA) brain areas in the short- and long-lasting enhancement of d-AMPH-induced locomotion following a single stress, and to test the involvement of N-methyl-D-aspartate (NMDA) receptors in that phenomena. To achieve our goal, 24 h and 8 days after a 2-h restraint stress session either with or without a NMDA receptor blockade, we measured locomotor activity and DA overflow in nucleus accumbens (NAcc) core and shell and caudate putamen (CPu) following a d-AMPH injection (0.5 mg/kg i.p.). The stimulant effect of d-AMPH on DA overflow was enhanced in all nuclei at 24 h after a single stress, while at 8 days the enhanced responsiveness was maintained only in the NAcc core. When the rats were administered with MK-801 (0.1 mg/kg i.p.) 30 min before restraint stress, the d-AMPH-induced enhancement on locomotor activity and DA neurotransmission was prevented in all studied brain areas at both times. These findings show that a glutamate-dopamine link is underlying the short- and long- term d-AMPH-induced enhancement on DA and locomotor activity following stress. The persistent glutamate-dependent DA enhancement in NAcc core highlights the relevance of this region in the long-term proactive effects of stress on vulnerability to drug abuse.

Influence of acute or repeated restraint stress on morphine-induced locomotion: involvement of dopamine, opioid and glutamate receptors.

The development of restraint stress-induced sensitization to the locomotor stimulating effect of morphine (2 mg/kg i.p.) was investigated. In experiment 1, both a single restraint session (2 h) and a repeated restraint stress (2 h per day for 7 days), similarly enhanced the effects of morphine on motor activity. In experiment 2, we observed that this sensitization was prevented by administration of both D(1) and D(2) dopaminergic antagonist [SCH-23390 (0.5 mg/kg i.p.) and (+/-)-sulpiride (60 mg/kg i.p.)] 10 min prior to the stress session. In experiment 3, we showed that an opioid antagonist pretreatment [naltrexone (1 mg/kg i.p.) 10 min prior to stress session, suppressed the stress-induced sensitization after morphine administration. In experiment 4, pretreatment with a non-competitive antagonist of the N-methyl-D-aspartate (NMDA) type of glutamate receptors [(+)-MK-801 (0.1 mg/kg i.p.)], 30 min prior to the acute restraint session, prevented the development of sensitization to morphine. All these results suggest that: (1) sensitization to morphine on stimulating locomotor effect does not depend on the length of exposure to stress (acute vs. repeated); (2) stimulation of both D(1) and D(2) dopaminergic receptors is necessary for the development of restraint stress-induced sensitization to morphine; (3) an opioid system is also involved in this sensitization process; and (4) the stimulation of glutamatergic NMDA receptors is involved in this acute restraint-induced effect.