Dopamine D3 Receptor Modulates Akt/mTOR and ERK1/2 Pathways Differently during the Reinstatement of Cocaine-Seeking Behavior Induced by Psychological versus Physiological Stress.

Stress triggers relapses in cocaine use that engage the activity of memory-related nuclei, such as the basolateral amygdala (BLA) and dentate gyrus (DG). Preclinical research suggests that D3 receptor (D3R) antagonists may be a promising means to attenuate cocaine reward and relapse. As D3R regulates the activity of the Akt/mTOR and MEK/ERK1/2 pathways, we assessed the effects of SB-277011-A, a D3R antagonist, on the activity of these kinases during the reinstatement of cocaine-induced conditioned place preference (CPP) induced by psychological (restraint) and physiological (tail pinch) stress. Both stimuli reactivated an extinguished cocaine-CPP, but only restrained animals decreased their locomotor activity during reinstatement. Cocaine-seeking behavior reactivation was correlated with decreased p-Akt, p-mTOR, and p-ERK1/2 activation in both nuclei of restrained animals. While a D3R blockade prevented stress-induced CPP reinstatement and plasma corticosterone enhancement, SB-277011-A distinctly modulated Akt, mTOR, and ERK1/2 activation depending on the stressor and the dose used. Our data support the involvement of corticosterone in the SB-277011-A effects in restrained animals. Additionally, the ratios p-mTOR/mTOR and/or p-ERK1/2 /ERK1/2 in the BLA during stress-induced relapse seem to be related to the locomotor activity of animals receiving 48 mg/kg of the antagonist. Hence, our study indicates the D3R antagonist's efficacy to prevent stress-induced relapses in drug use through distinct modulation of Akt/mTOR and MEK/ERK1/2 pathways in memory-processing nuclei.

An approach for prioritizing candidate genes from RNA-seq using preclinical cocaine self-administration datasets as a test case.

RNA-sequencing (RNA-seq) technology has led to a surge of neuroscience research using animal models to probe the complex molecular mechanisms underlying brain function and behavior, including substance use disorders. However, findings from rodent studies often fail to be translated into clinical treatments. Here, we developed a novel pipeline for narrowing candidate genes from preclinical studies by translational potential and demonstrated its utility in 2 RNA-seq studies of rodent self-administration. This pipeline uses evolutionary conservation and preferential expression of genes across brain tissues to prioritize candidate genes, increasing the translational utility of RNA-seq in model organisms. Initially, we demonstrate the utility of our prioritization pipeline using an uncorrected P-value. However, we found no differentially expressed genes in either dataset after correcting for multiple testing with false discovery rate (FDR < 0.05 or <0.1). This is likely due to low statistical power that is common across rodent behavioral studies, and, therefore, we additionally illustrate the use of our pipeline on a third dataset with differentially expressed genes corrected for multiple testing (FDR < 0.05). We also advocate for improved RNA-seq data collection, statistical testing, and metadata reporting that will bolster the field's ability to identify reliable candidate genes and improve the translational value of bioinformatics in rodent research.

Selective α3ß4 Nicotinic Acetylcholine Receptor Ligand as a Potential Tracer for Drug Addiction.

α3ß4 Nicotinic acetylcholine receptor (nAChR) has been recognized as an emerging biomarker for the early detection of drug addiction. Herein, α3ß4 nAChR ligands were designed and synthesized to improve the binding affinity and selectivity of two lead compounds, (S)-QND8 and (S)-T2, for the development of an α3ß4 nAChR tracer. The structural modification was achieved by retaining the key features and expanding the molecular structure with a benzyloxy group to increase the lipophilicity for blood-brain barrier penetration and to extend the ligand-receptor interaction. The preserved key features are a fluorine atom for radiotracer development and a p-hydroxyl motif for ligand-receptor binding affinity. Four (R)- and (S)-quinuclidine-triazole (AK1-AK4) were synthesized and the binding affinity, together with selectivity to α3ß4 nAChR subtype, were determined by competitive radioligand binding assay using [3H]epibatidine as a radioligand. Among all modified compounds, AK3 showed the highest binding affinity and selectivity to α3ß4 nAChR with a Ki value of 3.18 nM, comparable to (S)-QND8 and (S)-T2 and 3069-fold higher affinity to α3ß4 nAChR in comparison to α7 nAChR. The α3ß4 nAChR selectivity of AK3 was considerably higher than those of (S)-QND8 (11.8-fold) and (S)-T2 (294-fold). AK3 was shown to be a promising α3ß4 nAChR tracer for further development as a radiotracer for drug addiction.

Korean Red Ginseng inhibits methamphetamine addictive behaviors by regulating dopaminergic and NMDAergic system in rodents.

BACKGROUND: Methamphetamine (METH) is the most widely used psychostimulant and has been known to exhibit reinforcing effects even after long abstinence. We showed the inhibitory effect of Korean Red Ginseng extract (RGE) on METH-induced addictive behaviors in animal models mimicking the human drug-use pattern. METHODS: We first investigated the effect of RGE on the acquisition of METH-induced dependence using self-administration and conditioned place preference (CPP) tests. Additionally, further experiments such as METH-induced motivational behavior and seeking behavior were conducted. To study the underlying mechanism, dopamine receptor, dopamine transporter, and N-methyl-D-aspartate receptor were assessed through Western blot analysis. RESULTS: Treatment with RGE significantly reduced METH-induced self-administration on a fixed-ratio 1 schedule of reinforcement. It could be also decreased a progressive ratio schedule, and inhibited METH-primed reinstatement. In CPP, RGE significantly prevented the development of METH-induced CPP. Moreover, RGE not only shortened the withdrawal period clearly, but also prevented the reinstatement of CPP. RGE treatment also reversed METH-induced overexpression of dopamine transporter, dopamine receptor D1, and NMDA receptor in the nucleus accumbens. CONCLUSION: Our findings reflect that RGE has therapeutic potential to suppress METH-induced addictive behaviors by regulating dopaminergic and NMDAergic system.

Investigating the potential of mirtazapine to induce drug-seeking behavior in free-choice drinking mouse model.

Addiction to various drugs and chemicals is a significant public health concern worldwide. Addiction to prescription medications has increased due to the psychoactive effects of these medications, their availability, low price, and the lack of legal consequences for abusers. One of such prescription medication is mirtazapine (MIRT). MIRT is an antidepressant that has recently been reported to be abused and could induce withdrawal symptoms in different case studies. No previous study has investigated its abuse potential in animal models of drug addiction. Here, we conducted a free-choice drinking paradigm to investigate voluntary drinking of MIRT at two different concentrations. Male BALB/c mice were given unlimited access to two water bottles for five days before being divided into three groups: the first group had free access to two water bottles. The second group (MIRT10) and the third group (MIRT20) was allowed unlimited choice to one bottle of water and one bottle of MIRT at concentrations of 0.03 and 0.06 mg/mL, respectively. The average daily MIRT intake in the MIRT20 group was significantly higher on all tested days than that in the MIRT10 group. Moreover, mice in the MIRT20 group preferred to self-administer MIRT over water, indicating that MIRT can induce drug-seeking behavior. To further investigate the addictive potential of MIRT and its possible deterioration of memory and recognition, as reported with several known drugs of abuse, animals underwent a novel object recognition test. Mice in the MIRT20 group demonstrated significant deterioration in memory and recognition, indicating its effects on different brain regions involved in recognition, similar to other known drugs of abuse. The forced swimming test and tail suspension test were used to test MIRT-induced withdrawal symptoms after forced abstinence. After eight days of abstinence, mice in the MIRT20 group demonstrated significant depression-like symptoms in both the TST and FST, manifested by a significant increase in immobility time. MIRT was shown to induce drug-seeking behavior, deteriorate recognition, and cause withdrawal symptoms. This might confirm that MIRT has the potential to induce drug dependence and further studies are warranted to explore the neurobiological basis of MIRT-induced drug-seeking behavior.

Sex- and genotype-dependent nicotine plus cue-primed reinstatement is enhanced in adolescent Sprague Dawley rats containing the human CHRNA6 3'-UTR polymorphism (rs2304297).

Rationale: Large-scale human candidate gene studies have indicated that a genetic variant (rs2304297) in the alpha(α)6 nicotinic acetylcholine receptor (nAChR) subunit, encoded by the CHRNA6 gene, may play a key role in adolescent nicotine addictive behavior. We hypothesized that the polymorphism selectively enhances nicotine + cue-primed reinstatement, but not nicotine- or cue-reinstatement in α6 GG (risk) vs. α6 CC (non-risk) allele carriers, without having baseline effects on natural rewards. Methods: Using CRISPR-Cas9 genomic engineering, we developed a humanized rat line with the human gene variant of the CHRNA6 3'-UTR C 123 G polymorphism in Sprague-Dawley rats. Genetically modified adolescent male and female rats were food trained under a fixed-ratio (FR)1 schedule of reinforcement and progressively increased to FR5. Animals were implanted with catheters and began nicotine self-administration (15 µg/kg/infusion) at FR5. Upon reaching stable responding, reinforced behavior was extinguished by removal of drug and cues. Reinstatement testing began for cue only, nicotine only, and nicotine + cue in a Latin Square Design. Animals were returned to extinction conditions for 2 days minimum between testing. Results: For natural food rewards, nicotine self-administration, progressive ratio, and extinction, adolescent male and female (α6 GG and α6 CC ) rats exhibited equivalent behaviors. Male α6 GG rats show enhanced nicotine + cue-primed reinstatement when compared with male α6 CC rats. This genotype effect on reinstatement was not seen in female rats. Conclusion: Our findings support the in vivo functional role of the human CHRNA6 3'-UTR SNP genetic variant in sex-dependently enhancing nicotine seeking behavior in adolescent rats. Overall, the findings support clinical and preclinical data highlighting a role of α6 nAChRs mediating sex heterogeneity in substance use and related phenotypes.

The use of person-first language in scientific literature focused on drug-seeking behavior: a cross-sectional analysis.

CONTEXT: Person first language (PFL) - a way of referring to individuals with medical conditions or disability that emphasizes the person over their condition or disability - is important in reducing the stigma surrounding individuals who exhibit drug-seeking behavior. Drug-seeking behavior is generally associated with a negative connotation by healthcare professionals, which may create poor provider perceptions of these individuals and potentially impact patient care. Therefore, to reduce stigmatization surrounding drug-seeking behavior and to improve patient care in these individuals, the use of PFL should be promoted. OBJECTIVES: The primary objective of this study is to investigate how frequently research articles focused on drug-seeking behavior adhere to PFL. METHODS: We performed a cross-sectional analysis systematically searching PubMed for articles published between May 1, 2011, and April 30, 2020, focused on drug-seeking behavior. To be included, the article must have met the following criteria: (1) published in a peer-reviewed journal; (2) relevant to drug-seeking behavior; and (3) must include human subjects and be retrievable in English. All articles were screened and data were extracted independently in a masked, duplicate fashion. Each article was reviewed for 19 predefined non-PFL terms with certain terms adopted from the American Medical Association Manual of Style. RESULTS: Our search returned 699 articles related to drug-seeking behavior, of which 390 articles met inclusion criteria and were analyzed for non-PFL. Our analysis found only 13.6% (53/390) of articles adhered to PFL while 86.4% (337/390) of articles contained at least some form of non-PFL. There was no association between PFL adherence and extracted study characteristics. CONCLUSIONS: PFL adherence is uncommon among research literature focused on drug-seeking behavior. The power of language can be profound, and should be understood by researchers, health care providers, and educators alike, specifically when dealing with known and exhibited characteristics of substance use disorders. This is relevant because of the high prevalence of substance use disorders, limited amount of prior research, and the impact stigma has on patients and healthcare providers.

Predictors of Self-medication in Iran: A Notional Survey Study.

While logical use of medicine is a priority in all health systems, people do self-medication- mainly using Nonprescription Drugs or Over the Counter (OTC) drugs- for different reasons. Self-medication is rising in many developing countries that could increase healthcare expenditure. The present study aimed to find the self-medication rate and predisposing, enabling, and need factors affecting it based on the Anderson behavioral model in the Iranian population. The present study uses 22470 households' data acquired from Iranian utilization of healthcare survey at the national level (2016). Due to the study objective, the data of 13005 people who were over 15 years old and had outpatient healthcare needs two weeks before the survey. The survey included a binary question about self-medication, which is considered a dependent variable. Age, gender, marital status, literacy, job status, socio-economic status, location, basic health insurance, complementary health insurance, and need for health services were considered as independent variables. Data were analyzed using logistic regression. The self-medication rate was calculated at 26.3% that was different among different subgroups of the population. According to the model estimates, married (OR = 0.80, CI = 0.71-0.91) and housekeepers (OR = 0.79, CI = 0.67-0.93) had significantly lower self-medication. Moreover, the urban population (OR = 1.29, CI = 1.17-1.43), people without basic (OR = 1.32, CI = 1.10-1.58), and supplementary (OR = 1.18, CI = 1.04-1.35) health insurance and also people who had two or higher number of outpatient healthcare needs had significantly more self-medication (OR = 2.96, CI = 2.67-3.29). It can be concluded that need, enabling, and predisposing factors are respectively the main determinants of self-medication behavior. From a policy point of view, increasing effective health insurance coverage with a focus on people who have more health care needs can be helpful.

Bidirectional role of acupuncture in the treatment of drug addiction.

Drug addiction is a chronically relapsing disorder, affecting people from all walks of life. Studies of acupuncture effects on drug addiction are intriguing in light of the fact that acupuncture can be used as a convenient therapeutic intervention for treating drug addiction by direct activation of brain pathway. The current review aims to discuss the neurobiological mechanisms underlying acupuncture's effectiveness in the treatment of drug addiction, on the basis of two different theories (the incentive sensitization theory and the opponent process theory) that have seemingly opposite view on the role of the mesolimbic reward pathways in mediating compulsive drug-seeking behavior. This review provides evidence that acupuncture may reduce relapse to drug-seeking behavior by regulating neurotransmitters involved in drug craving modulation via somatosensory afferent mechanisms. Also, acupuncture normalizes hyper-reactivity or hypoactivity of the mesolimbic dopamine system in these opposed processes in drug addiction, suggesting bidirectional role of acupuncture in regulation of drug addiction. This proposes that acupuncture may reduce drug craving by correcting both dysfunctions of the mesolimbic dopamine pathway.

N-acetylcysteine reduces cocaine-seeking behavior and anterior cingulate glutamate/glutamine levels among cocaine-dependent individuals.

N-acetylcysteine (NAC) is a cystine prodrug shown to reduce cocaine- and cue-primed reinstatement of cocaine-seeking behavior in preclinical studies. In this inpatient study, the effects of NAC maintenance versus placebo on cocaine-seeking behavior were examined during cocaine-primed and unprimed self-administration sessions among non-treatment-seeking, cocaine-dependent individuals. Twelve participants completed this double-blind, placebo-controlled, within-subject crossover study. Each participant was maintained for 1 week (Sat-Fri) on NAC (1200-mg TID; 3600 mg/day total) and 1 week on placebo (0-mg TID); medication order was randomized. A subset of participants underwent proton magnetic resonance spectroscopy scans (n = 8) on the third day of medication (Mon) to assess neurochemistry in the rostral anterior cingulate (rACC; voxel = 4.5 cm3 ). In four randomized sessions (Tue-Fri) each week, each participant could earn unit amounts of cocaine (10 mg, fixed) versus money ($0.50 vs. $1.50) on a choice, progressive ratio schedule after insufflating active versus placebo cocaine-priming doses (110 mg vs. 4 mg). Relative to the placebo priming dose, the active cocaine priming dose (110 mg) increased cocaine-seeking behavior (p = .003). NAC reduced cocaine-primed cocaine-seeking behavior compared with placebo levels (p = .044) but did not alter placebo-primed cocaine-seeking behavior. The larger money alternative ($1.50) suppressed cocaine-seeking behavior relative to the smaller money alternative ($0.50; p = .011). Compared with placebo levels, NAC significantly decreased rACC glutamate + glutamine levels (p = .035) and numerically decreased rACC glutamate levels (p = .085). These preliminary findings indicate that NAC suppresses cocaine-seeking behavior in some, but not all, experimental scenarios. Further, our findings suggest NAC may exert its therapeutic effects by modulating excitatory tone in the rACC.

A novel method to study reward-context associations and drug-seeking behaviors.

Animal models have significantly contributed to the understanding of reward-related behaviors, such as in Substance Use Disorder research. One of the most heavily utilized paradigms to date is conditioned place preference (CPP). However, CPP is limited by non-contingent exposure. Our new method advances this classic method by utilizing its benefits and simultaneously diminishing its limitations. We used a traditional 3-compartment CPP apparatus, where each chamber differs by both visual and tactile contexts. We restructured the apparatus allowing for insertion of bottles so that mice could orally self-administer sucrose or morphine-containing solutions in a specific context. Our results show that mice who self-administer sucrose or morphine show a place preference for the sucrose- or morphine-paired chamber. This place preference lasts for 21 d in sucrose-treated, but not morphine-treated mice. Additionally, we found that that mice will drink more water in the morphine-paired context during extinction tests. This model combines the distinct contextual cues associated with conditioned place preference and combines them with voluntary self-administration, thus enabling researchers to measure behavior using a model that incorporates spatial memory involved in affective states, while also providing a quantifiable readout of context/environment-specific drug seeking. In conclusion, we combined CPP and voluntary intake to establish a novel technique to assess not only preference for a context associated with rewarding stimuli (natural or drug), but also seeking, retention, and locomotor activity. This model can be further utilized to examine other drugs of abuse, extinction training, other learning models, or to allow for the assessment of neurobiological manipulations.

Suppression of cocaine relapse-like behaviors upon pimavanserin and lorcaserin co-administration.

Cocaine use disorder (CUD) is a major public health challenge for which there are no pharmacotherapeutics approved by the United States Food and Drug Administration (FDA). The propensity to relapse in CUD involves several vulnerability factors including sensitivity to cues associated with cocaine-taking. Serotonin (5-hydroxytryptamine, 5-HT) neurotransmission, particularly through the 5-HT2A receptor (5-HT2AR) and 5-HT2C receptor (5-HT2CR), is mechanistically linked to cocaine-seeking in preclinical models. In the present experiments, we employed self-administration assays in male rats to investigate whether acute and/or repeated administration of the FDA-approved selective 5-HT2AR antagonist/inverse agonist pimavanserin, selective 5-HT2CR agonist lorcaserin or their combination would alter cocaine intake and/or cocaine-seeking behavior. We found that acute administration of lorcaserin, but not pimavanserin, attenuated cocaine intake while pimavanserin plus lorcaserin did not impact cocaine self-administration. In contrast, 10-days of repeated administration of pimavanserin, lorcaserin, or pimavanserin plus lorcaserin during forced abstinence from cocaine self-administration, blunted cocaine-seeking, similar to the acute administration of each ligand. Taken together, these data reveal the efficacy of repeated treatment with pimavanserin plus lorcaserin to attenuate factors important to relapse-like behaviors in rodent models of CUD. This article is part of the special issue entitled 'Serotonin Research: Crossing Scales and Boundaries'.

Illicit drug use among students of a university in Southern Brazil

ABSTRACT OBJECTIVE To describe drug consumption and the co-occurrence use of more than one illegal drug as well as associated factors in freshmen at a public university in Southern Brazil. METHODS Cross-sectional study with census of students entering undergraduate courses in 2017. A total of 1,788 university students answered questions about illicit drug use. For analysis, ordinal logistic regression was used. RESULTS Marijuana was the most consumed drug (lifetime: 42.1%; 30-day use: 22.7%), followed by hallucinogens (lifetime: 13.1%, 30-day use: 2.8%). Rates for lifetime use of 0, 1 and 2 or more drugs were 56.2%, 23.3% and 20.4%, respectively, and were associated with men (OR = 2.2; 95%CI:1.4-3.5), being at least 23 years old (OR = 2.7; 95%CI: 1.4-5.1), under 18 years old first experimentation with drugs (OR = 2.3; 95%CI: 1.3-3.9) and living with friends (OR = 2.0; 95%CI: 1.2-3.4). Rates for 30-day use of 0, 1 and 2 or more drugs were 76.8%; 18.1% and 5.1%, respectively, and were associated with being single, separated or widowed (OR = 3.2; 95%CI: 1.4-7.0), lower socioeconomic classes (OR = 0.3; 95%CI: 0.1-1.1; p = 0.001), under 18 years old first experimentation with drugs (OR = 1.8; 95%CI: 1.1-2.9) and living with friends (OR = 1.8 95%CI: 1.2-2.8). CONCLUSION Results indicate that students are at greater risk of illicit drug-related health problems. Thus, a better understanding of this consumption should be pursued, as well as the development of a prevention plan.

Understanding Addiction Using Animal Models.

Drug addiction is a neuropsychiatric disorder with grave personal consequences that has an extraordinary global economic impact. Despite decades of research, the options available to treat addiction are often ineffective because our rudimentary understanding of drug-induced pathology in brain circuits and synaptic physiology inhibits the rational design of successful therapies. This understanding will arise first from animal models of addiction where experimentation at the level of circuits and molecular biology is possible. We will review the most common preclinical models of addictive behavior and discuss the advantages and disadvantages of each. This includes non-contingent models in which animals are passively exposed to rewarding substances, as well as widely used contingent models such as drug self-administration and relapse. For the latter, we elaborate on the different ways of mimicking craving and relapse, which include using acute stress, drug administration or exposure to cues and contexts previously paired with drug self-administration. We further describe paradigms where drug-taking is challenged by alternative rewards, such as appetitive foods or social interaction. In an attempt to better model the individual vulnerability to drug abuse that characterizes human addiction, the field has also established preclinical paradigms in which drug-induced behaviors are ranked by various criteria of drug use in the presence of negative consequences. Separation of more vulnerable animals according to these criteria, along with other innate predispositions including goal- or sign-tracking, sensation-seeking behavior or impulsivity, has established individual genetic susceptibilities to developing drug addiction and relapse vulnerability. We further examine current models of behavioral addictions such as gambling, a disorder included in the DSM-5, and exercise, mentioned in the DSM-5 but not included yet due to insufficient peer-reviewed evidence. Finally, after reviewing the face validity of the aforementioned models, we consider the most common standardized tests used by pharmaceutical companies to assess the addictive potential of a drug during clinical trials.

Envolvimento com álcool, tabaco e outras substâncias por estudantes universitários / Undergraduate students and their entry into alcohol, tobacco and other drugs / Estudiantes universitarios y su incursión en el alcohol, tabaco y otras sustancias

Resumo Introdução O presente estudo teve por objetivo identificar o quantitativo de estudantes em uma instituição de ensino superior no interior paulista que vivenciam o envolvimento com o álcool, o tabaco e ou outras substâncias, e avaliar a ocorrência e nível de dependência nos mesmos. Materiais e Métodos Trata-se de extrato de uma pesquisa de levantamento, exploratória, descritiva, de abordagem quantitativa, realizada com 416 estudantes universitários. A coleta de dados se deu no decorrer do 3º trimestre de 2017, com aplicação de questionário semiestruturado, elaborado pelos autores e Questionário para Triagem do Uso de Álcool, Tabaco e Outras Substâncias. Os dados foram analisados com uso de análise estatística descritiva, teste de Qui-Quadrado de Pearson e de acordo com as instruções para aplicação do instrumento selecionado. A pesquisa foi submetida e aprovada pelo Comitê de Ética em Pesquisa. Resultados Os índices gerais de envolvimento e o tipo de drogas são: 140 (30%) para derivados do tabaco, 303 (66%) para bebidas alcoólicas, 89 (19%) para maconha, 32 (7%) para cocaína/crack, 24 (5%) para anfetaminas ou êxtase, 30 (7%) para inalantes, 45 (10%) para hipnóticos/sedativos, 36 (8%) para alucinógenos, e nove (2%) para opióides. Discussão Houve envolvimento com todos os tipos de substâncias, associado a romantização quanto ao uso das mesmas no ambiente universitário e facilidade de acesso. Conclusões O envolvimento de universitários com álcool, tabaco e outras substâncias é real e intenso. Além do envolvimento, o risco para dependência dessas substâncias se caracteriza como grande problema social e de saúde.

Abstract Introduction This study aimed to identify the number of students from a higher education institution into the interior of São Paulo state who experienced their entry into alcohol, tobacco and other substances in order to evaluate the occurrence and dependency level on them. Materials and Methods An extract of a compiling, exploratory, descriptive study under a quantitative approach was conducted in 416 undergraduate students. The data were collected over the third quarter of 2017 by applying a semi-structured questionnaire prepared by the authors in addition to the Triage Questionnaire for Alcohol, Tobacco and other Drugs Use. A descriptive statistical analysis was conducted for data analysis as well as a Pearson' chi-squared test, according to the instructions for the application of the selected instrument. This study was received and approved by the Research Ethics Committee. Results The general rates for entry and drug type are 140 (30%) for tobacco derivatives, 303 (66%) for alcohol beverages, 89 (19%) for marijuana, 32 (7%) for cocaine/crack, 24 (5%) for amphetamines or ecstasy, 30 (7%) for inhalant drugs, 45 (10%) for hypnotics/sedatives, 36 (8%) for hallucinogens and 9 (2%) for opioids. Discussion Students showed to be involved in all types of substances which is linked to flexibility in relation to their use in the university environment and their easy access. Conclusions Undergraduate students have a real and intense relationship with alcohol, tobacco and other drugs. In addition to this relationship, the risk of addiction to these substances is presented as a major social and healthcare problem.

Resumen Introducción El presente estudio tuvo como objetivo identificar la cantidad de estudiantes en una institución de educación superior en el interior paulista que experimentan su incursión en el alcohol, el tabaco y otras sustancias, y evaluar así la ocurrencia y el nivel de dependencia de los mismos. Materiales y Métodos Se trata de un extracto de un estudio de levantamiento, exploratorio, descriptivo, de enfoque cuantitativo, realizado con 416 estudiantes universitarios. Los datos fueron recolectados en el transcurso del 3º trimestre de 2017, mediante la aplicación de un cuestionario semi-estructurado, elaborado por los autores y del Cuestionario para Triaje de Uso de Alcohol, Tabaco y otras Sustancias. Los datos fueron analizados a través de un análisis estadístico descriptivo, la prueba de Qui-Cuadrado de Pearson y de acuerdo con las instrucciones para la aplicación del instrumento seleccionado. El estudio fue recibido y aprobado por el Comité de Ética en Investigación. Resultados Los índices generales de incursión y el tipo de drogas son: 140 (30%) para derivados del cigarrillo, 303 (66%) para bebidas alcohólicas, 89 (19%) para marihuana, 32 (7%) para cocaína/crack, 24 (5%) para anfetaminas o éxtasis, 30 (7%) para drogas inhaladas, 45 (10%) para hipnóticos/sedantes, 36 (8%) para alucinógenos, y nueve (2%) para opioides. Discusión Los estudiantes demostraron haber estado involucrados con todos los tipos de sustancias, lo que se asocia a la flexibilización con respecto al uso de las mismas en el ambiente universitario y a la facilidad de acceso. Conclusiones La relación de los universitarios con el alcohol, el cigarrillo y otras sustancias es real e intensa. Además de esa relación, el riesgo de adicción a estas sustancias se configura como un gran problema social y de salud.

Perceptions of coach doping confrontation efficacy and athlete susceptibility to intentional and inadvertent doping.

OBJECTIVES: We tested a conceptually grounded model linking athlete perceptions of strength and conditioning and technical coach doping confrontation efficacy (DCE) with athletes' doping self-regulatory efficacy (SRE), doping moral disengagement (MD), and susceptibility to intentional and inadvertent doping. DESIGN: Cross-sectional, correlational. METHODS: Participants were high-level athletes (nmale  = 532; nfemale  = 290) recruited in Australia (n = 261), the UK (n = 300), and the USA (n = 261). All participants completed questionnaires assessing the variables alongside a variant of the randomized response technique to estimate the prevalence of doping. RESULTS: The estimated prevalence of intentional doping in the sample was 13.9%. Structural equation modeling established: (a) perceptions of technical and strength and conditioning coaches' DCE positively predicted doping SRE; (b) doping SRE negatively predicted doping MD; (c) doping MD positively predicted susceptibility to intentional and inadvertent doping; and (d) the predictive effects of coach perceptions on susceptibility to doping were mediated by doping SRE and doping MD. Multisample analyses demonstrated these predictive effects were invariant between males and females and across the three countries represented. CONCLUSIONS: The findings show the conceptually grounded model to offer extended understanding of how multiple individuals within the athlete support personnel network may influence athlete doping.

Neural Circuits Associated with 5-HT1B Receptor Agonist Inhibition of Methamphetamine Seeking in the Conditioned Place Preference Model.

5-HT1B receptors (5-HT1BRs) modulate psychostimulant reward and incentive motivation in rodents. Here we investigated the effects of the 5-HT1BR agonist CP94253 (10 mg/kg, IP) on the acquisition and expression of methamphetamine (Meth) conditioned place preference (CPP) in C57BL/6 male mice. We subsequently examined the potential brain regions involved in CP94253 effects using FOS as a marker of neural activity. In the acquisition experiment, mice received the agonist 30 min before each of the Meth injections given during conditioning. In the expression experiment, mice that had acquired Meth-CPP were given either saline or CP94253 and were tested for CPP 30 min later. We found that CP94253 attenuated the expression of Meth-CPP, but had no effect on acquisition. Mice expressing Meth-CPP had elevated numbers of FOS+ cells in the ventral tegmental area (VTA) and basolateral amygdala (BlA) and reduced FOS+ cells in the central amygdala (CeA) compared to saline controls. CP94253 given before the expression test, but not acutely in drug-naive mice, enhanced FOS+ cells in the VTA, the nucleus accumbens (NAc) shell and core, and the dorsomedial striatum and reversed the Meth-conditioned changes in FOS in the BlA and CeA. Approximately 50-70% of FOS+ cells in the NAc and VTA were GABAergic regardless of group. By contrast, we did not observe FOS-labeling in dopamine neurons in the VTA. The findings suggest that CP94253 attenuates the motivational effects of the Meth-associated environment and highlight the amygdala, VTA, NAc, and dorsomedial striatum as potential regions involved in this effect.

ATTITUDES TOWARD PERSONS WHO ABUSE DRUGS IN ONE URBAN COMMUNITY OF WOODBROOK IN PORT OF SPAIN -TRINIDAD & TOBAGO / Atitudes em relação a pessoas que abusam de drogas em uma comunidade urbana de Woodbrook em Port of Spain - Trinidad e Tobago / Actitudes en relación a personas que hacen uso excesivo de drogas en una comunidad urbana de Woodbrook en Puerto de España - Trinidad y Tobago

ABSTRACT Objective: this study will present insights on the situation in the surveyed sample as it relates to attitudes towards persons who abuse alcohol by age and gender and would constitute a platform upon which further research can be conducted by researchers in the drug field. Method: this cross-sectional study examines the profile of a sample of residents in the Electoral District of Woodbrook, Port-of-Spain, Trinidad and Tobago. The sample consisted of 121 respondents. Results: alcohol was the most abused drug (85.2%), followed by marijuana (86%), cocaine (69%) and cocaine derivative (41.8%). The prevailing attitude towards persons who abused alcohol was ambivalence (64.8%); this was followed to a lesser extent by an attitude of negativity (34.4%), and the least significant attitude among respondents was premised on positivity (.8%). Respondents also held a negative attitude towards those who abused cocaine and marijuana. Conclusion: the high level of ambivalence towards alcohol use may be intertwined with the social acceptability and high usage of this drug reported from among those surveyed in the Electoral District of Woodbrook.

RESUMO Objetivo: este estudo apresentará insights sobre a situação na amostra pesquisada no que se refere a atitudes em relação às pessoas que abusam de álcool por idade e sexo e que constituiria uma plataforma sobre a qual mais pesquisas podem ser conduzidas por pesquisadores no campo das drogas. Método: transversal que examina o perfil de uma amostra de residentes no Distrito Eleitoral de Woodbrook, Port of Spain, Trinidad e Tobago. A amostra foi composta por 121 respondentes. Resultados: o álcool foi a droga mais utilizada (85,2%), seguido pela maconha (86%), cocaína (69%) e derivado de cocaína (41,8%). A atitude predominante em relação às pessoas que abusaram do álcool foi a ambivalência (64,8%); isso foi seguido em menor medida por uma atitude de negatividade (34,4%), e a atitude menos significativa entre os entrevistados foi baseada na positividade (0,8%). Os entrevistados também mantiveram uma atitude negativa em relação àqueles que abusaram de cocaína e maconha. Conclusão: o alto nível de ambivalência em relação ao uso de álcool pode estar interligado com a aceitabilidade social e alto uso dessa droga relatada entre os entrevistados no Distrito Eleitoral de Woodbrook.

RESUMEN Objetivo: este estudio presentará un informe sobre la situación en la muestra investigada en lo que se refiere a actitudes hacia las personas que hacen uso excesivo de alcohol por edad y sexo, y que constituiría una plataforma sobre la cual los investigadores pueden conducir más investigaciones en el campo de las drogas. Método: transversal que examina el perfil de una muestra de residentes en el Distrito Electoral de Woodbrook, Puerto de España, Trinidad y Tobago. La muestra estuvo compuesta por 121 participantes. Resultados: el alcohol fue la droga más utilizada (85,2%), seguida por la marihuana (86%), cocaína (69%) y derivado de la cocaína (41,8%). La actitud predominante en relación a las personas que hicieron uso excesivo de alcohol fue la ambivalencia (64,8%), seguido en menor medida por una actitud negativa (34,4%), y la actitud menos significativa entre los entrevistados se basó en la positividad (0,8%). Los entrevistados también mantuvieron una actitud negativa hacia los que hacen uso excesivo de la cocaína y marihuana. Conclusión: el alto nivel de ambivalencia en relación al uso de alcohol puede estar interconectado con la aceptabilidad social y el uso excesivo de esta droga mencionada entre los entrevistados en el Distrito Electoral de Woodbrook.

Drug Seeking and Relapse: New Evidence of a Role for Orexin and Dynorphin Co-transmission in the Paraventricular Nucleus of the Thalamus.

The long-lasting vulnerability to relapse remains the main challenge for the successful treatment of drug addiction. Neural systems that are involved in processing natural rewards and drugs of abuse overlap. However, neuroplasticity that is caused by drug exposure may be responsible for maladaptive, compulsive, and addictive behavior. The orexin (Orx) system participates in regulating numerous physiological processes, including energy metabolism, arousal, and feeding, and is recruited by drugs of abuse. The Orx system is differentially recruited by drugs and natural rewards. Specifically, we found that the Orx system is more engaged by drugs than by non-drugs, such as sweetened condensed milk (SCM) or a glucose saccharin solution (GSS), in an operant model of reward seeking. Although stimuli (S+) that are conditioned to cocaine (COC), ethanol, and SCM/GSS equally elicited reinstatement, Orx receptor blockade reversed conditioned reinstatement for drugs vs. non-drugs. Moreover, the hypothalamic recruitment of Orx cells was greater in rats that were tested with the COC S+ vs. SCM S+, indicating of a preferential role for the Orx system in perseverative, compulsive-like COC seeking and not behavior that is motivated by palatable food. Accumulating evidence indicates that the paraventricular nucleus of the thalamus (PVT), which receives major Orx projections, mediates drug-seeking behavior. All Orx neurons contain dynorphin (Dyn), and Orx and Dyn are co-released. In the VTA, they play opposing roles in reward and motivation. To fully understand the physiological and behavioral roles of Orx transmission in the PVT, one important consideration is that Orx neurons that project to the PVT may co-release Orx with another peptide, such as Dyn. The PVT expresses both Orx receptors and κ opioid receptors, suggesting that Orx and Dyn act in tandem when released in the PVT, in addition to the VTA. The present review discusses recent findings that suggest the maladaptive recruitment of Orx/Dyn-PVT neurotransmission by drugs of abuse vs. a highly palatable food reward.

Purchase of medications without prescription in Peru: a cross-sectional population-based study.

Background: Low availability of medicines in health services, self-medication, inadequate use of medicines, and inadequate dispensing practices in pharmacies are frequent problems in Peru. We aimed to evaluate how frequent the purchase of medications without medical prescription is in Peru, and which factors are associated with this practice. Methods: We conducted a secondary analysis of the 2016 ENSUSALUD national survey data. Purchase of one or more medicines that require a prescription was measured as a dichotomous variable. Crude and adjusted prevalence ratios (PR) and their 95% confidence intervals (95% CI) were calculated using Poisson regressions model with robust variance to assess the association of purchasing of medicines that require prescriptions with sociodemographic factors. Results: There were 3858 participants in the dataset. The prevalence of purchasing medications without prescriptions was 47.2%. History of having previously consumed the same medication (31.6%), and the delay in receiving an appointment at health facilities (26.9%) were the main reasons to buy medications without a prescription. Regarding the recommendation of the medication purchased, the advice of the pharmacy, and remembering a previous old prescription, were the most frequent reasons (38.3%, and 25.9%, respectively). On the multivariable analysis, users that buy medications without prescription were more likely to be of aged 25-44; reside in the Jungle  and Highlands regions; and self-consumption of the purchase. Individuals with Seguro Integral de Salud (Comprehensive Health Insurance) were less likely to buy medications without prescription. Conclusions: There is a high prevalence of prescription requiring medication being bought without one from pharmacies in Peru. It is necessary to include the evaluation of consumer patterns to develop strategies with the aim to regulate the consumption of prescription drugs in the Peruvian population.