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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.

RationaleLarge-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 α6GG (risk) vs. α6CC (non-risk) allele carriers, without having baseline effects on natural rewards.MethodsUsing CRISPR-Cas9 genomic engineering, we developed a humanized rat line with the human gene variant of the CHRNA6 3′-UTRC123G 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.ResultsFor natural food rewards, nicotine self-administration, progressive ratio, and extinction, adolescent male and female (α6GG and α6CC) rats exhibited equivalent behaviors. Male α6GG rats show enhanced nicotine + cue-primed reinstatement when compared with male α6CC rats. This genotype effect on reinstatement was not seen in female rats.ConclusionOur 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.

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.

Background: The tendency to the use of drugs is a daily increase, especially among adolescents. We conducted the present study to investigate the role of self-efficacy in predicting drug-seeking behaviors among high school students in Jahrom, Fars province, Iran. Methods: This cross-sectional study was performed on high school students in Jahrom, Fars province, Iran in 2020. The sample size was estimated to be 405 people who were chosen using multi-stage cluster sampling. The data collection tools here included demographic information questionnaire, Iranian Addiction Potential Scale, and self-efficacy questionnaire Children Scale. Data analysis was performed with SPSS version 21 using descriptive statistics and Pearson’s correlation coefficient, Independent t-test, One-way ANOVA, and Linear regression. Results: There was a significant inverse correlation between self-efficacy and drug-seeking behaviors (r=-598, p

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.

CONTEXTO: Os ambientes recreativos noturnos têm conquistado, na atualidade, um protagonismo crescente na vida juvenil, determinando estilos de vida, normalizando o consumo recreativo de álcool/drogas e a adoção de outros comportamentos de risco. OBJETIVO: Delinear o perfil dos jovens portugueses que frequentam ambientes recreativos noturnos e determinar a prevalência de comportamentos violentos relacionados com variáveis sociodemográficas, consumo de álcool e drogas e envolvimento nas atividades recreativas noturnas. METODOLOGIA: Entrevista de 1346 jovens (idade média = 22,49 anos) frequentadores de ambientes recreativos noturnos, de ambos os sexos, em 10 cidades portuguesas, utilizando uma variação da Respondent-driven sampling, entre 2007 e 2010. RESULTADOS: Verificou-se que existe uma relação positiva entre comportamentos violentos, consumo de álcool e drogas e a participação dos jovens na vida recreativa noturna. Conclusões: Sugere-se que a implementação de medidas preventivas neste contexto atenda às características dos jovens apresentadas neste estudo como preditoras de comportamentos violentos.ANTECEDENTES: Los entornos recreativos nocturnos han conquistado, en la actualidad, una importancia creciente en la vida juvenil, determinando los estilos de vida, normalizando el consumo recreativo de alcohol/drogas y la practica de otros comportamientos de riesgo. OBJETIVO: Delinear el perfil de los jóvenes portugueses que frequentan ambientes recreativos nocturnos y determinar la prevalencia de conductas violentas en relación con variables sociodemográficas, consumo de alcohol y drogas y envolvimiento en las actividades recreacionales nocturnas. METODOLOGÍA: Entrevista con 1346 jóvenes (edad media = 22,49 años) frecuentadores de ambientes recreativos nocturnos, de ambos sexos, en 10 ciudades portuguesas, mediante el uso de una variación de la Respondent-Driven Sampling entre 2007 y 2010.Resultados: Se constató una relación positiva entre comportamiento violento, consumo de alcohol y drogas y la participación de los jóvenes en la vida recreativa nocturna. CONCLUSIÓN: Se sugiere que la implementación de medidas preventivas en este contexto atienda a las características de los jóvenes presentados en este estudio, como predictoras de la conducta violenta.BACKGROUND: The night time recreational environments have currently gained an important role in the juvenile life, determining life styles, standardizing the recreational consumption of alcohol and drugs, as well as the adoption of associated risk behaviours. OBJECTIVES: To characterize the profile of Portuguese young people attending nightlife recreational environments and determine the prevalence of violent behaviors based on sociodemographic variables, alcohol consumption and drug use, and engagement in recreational nightlife activities. METHODOLOGY: Interview applied to 1346 young people who used to go to nighttime recreational environments, both sexes, into 10 Portuguese cities, between 2007 and 2010, using the respondent-driven sampling. RESULTS: It was notified the existence of a positive relation among violent behaviours, alcohol consumption and drug use, and young people's engagement in recreational nightlife.Conclusions: It is suggested that preventive actions should be implemented in recreational environments, to meet the characteristics of young people presented in this study as predictors of violent behaviors.

A major challenge for the successful treatment of drug addiction is the long-lasting susceptibility to relapse and multiple processes that have been implicated in the compulsion to resume drug intake during abstinence. Recently, the orexin/hypocretin (Orx/Hcrt) system has been shown to play a role in drug-seeking behavior. The Orx/Hcrt system regulates a wide range of physiological processes, including feeding, energy metabolism, and arousal. It has also been shown to be recruited by drugs of abuse. Orx/Hcrt neurons are predominantly located in the lateral hypothalamus that projects to the paraventricular nucleus of the thalamus (PVT), a region that has been identified as a way-station that processes information and then modulates the mesolimbic reward and extrahypothalamic stress systems. Although not thought to be part of the drug addiction circuitry, recent evidence indicates that the PVT is involved in the modulation of reward function in general and drug-directed behavior in particular. Evidence indicates a role for Orx/Hcrt transmission in the PVT in the modulation of reward function in general and drug-directed behavior in particular. One hypothesis is that following repeated drug exposure, the Orx/Hcrt system acquires a preferential role in mediating the effects of drugs vs. natural rewards. The present review discusses recent findings that suggest maladaptive recruitment of the PVT by drugs of abuse, specifically Orx/Hcrt-PVT neurotransmission.

The orexin/hypocretin (Orx/Hcrt) system has long been considered to regulate a wide range of physiological processes, including feeding, energy metabolism, and arousal. More recently, concordant observations have demonstrated an important role for these peptides in the reinforcing properties of most drugs of abuse. Orx/Hcrt neurons arise in the lateral hypothalamus (LH) and project to all brain structures implicated in the regulation of arousal, stress, and reward. Although Orx/Hcrt neurons have been shown to massively project to the paraventricular nucleus of the thalamus (PVT), only recent evidence suggested that the PVT may be a key relay of Orx/Hcrt-coded reward-related communication between the LH and both the ventral and dorsal striatum. While this thalamic region was not thought to be part of the drug addiction circuitry, an increasing amount of evidence demonstrated that the PVT—particularly PVT Orx/Hcrt transmission—was implicated in the modulation of reward function in general and several aspects of drug-directed behaviors in particular. The present review discusses recent findings that suggest that maladaptive recruitment of PVT Orx/Hcrt signaling by drugs of abuse may promote persistent compulsive drug-seeking behavior following a period of protracted abstinence and as such may represent a relevant target for understanding the long-term vulnerability to drug relapse after withdrawal.

Epidemiological studies reveal that individuals who engage in regular aerobic exercise are less likely to use and abuse illicit drugs. Until recently, very few studies had examined the causal influences that mediate this relationship, and it was not clear whether exercise was effective at reducing substance use and abuse. In the past few years, several preclinical studies have revealed that exercise reduces drug self-administration in laboratory animals. These studies have revealed that exercise produces protective effects in procedures designed to model different transitional phases that occur during the development of, and recover from, a substance use disorder (e.g., acquisition, maintenance, escalation, and relapse/reinstatement of drug use). Moreover, recent studies have revealed several behavioral and neurobiological consequences of exercise that may be responsible for its protective effects in these assays. Collectively, these studies have provided convincing evidence to support the development of exercise-based interventions to reduce compulsive patterns of drug intake in clinical and at-risk populations.

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.