Atomoxetine promotes incentive value of modafinil and sensitizes exploratory behavior.

Substance dependence is a disorder that alters the functioning of the nervous system due to frequent abuse of drugs. The role of dopamine in the addictive effect of psychostimulants is well known; however, the involvement of the noradrenergic system is still unclear and poorly understood, though drugs like cocaine and amphetamines are known to exert significant activity on this system. The drug modafinil (MOD) has no proven addictive effect. It promotes wakefulness by acting mainly on the dopaminergic system and, to a lesser degree, the noradrenergic (NOR) system. Atomoxetine (ATX) is a non-stimulant drug that acts only on the NOR system, enhancing its activity. The aims of the present study were to analyze the effect of co-activating the DA and NOR systems (with MOD and ATX, respectively) on motor activity and exploratory behavior, and to examine the possible emergence of rewarding properties of MOD and an MOD+ATX mixture. Male Wistar rats at postnatal day 60 were treated chronically (16 days) with either monotherapy with 2ATX, 4ATX, or 60MOD mg/kg, two combinations of these substances -60MOD + 2ATX and 60MOD + 4ATX- or a vehicle. The rats co-administered with 60MOD + 4ATX reduced the rearing behavior frequency induced by MOD, but this behavior was sensitized by self-administration of the MOD+ATX mixture after chronic treatment. The rats pre-treated with 60MOD + 4ATX showed higher self-administration of MOD and greater activity on an operant task to obtain the MOD+ATX mixture. In addition, the 60MOD, 2ATX, and 60MOD + 2ATX groups showed sensitization of exploratory behavior after ingesting the mixture. Results suggest that the noradrenergic system enhances the incentive value of MOD and a MOD+ATX mixture, while also playing an important role in the sensitization of exploratory behavior.

Modafinil Administration to Preadolescent Rat Impairs Non-Selective Attention, Frontal Cortex D2 Expression and Mesolimbic GABA Levels.

The misuse of psychostimulants is an increasing behavior among young people, highlighting in some countries the abuse of modafinil (MOD) as a neuropotentiator. However, several clinical trials are investigating MOD as an alternative pharmacological treatment for attentional deficit and hyperactivity disorder (ADHD) in children and adolescents. On the other hand, the early use of psychostimulants and the misdiagnosis rates in ADHD make it crucial to investigate the brain effects of this type of drug in young healthy individuals. The aim of this work was to evaluate the effects of chronic MOD treatment on neurochemicals (γ-aminobutyric acid and glutamate), dopamine receptor 2 (D2) expression and behavior (non-selective attention "NSA") in the mesocorticolimbic system of young healthy Sprague-Dawley rats. Preadolescent male rats were injected with MOD (75 mg/kg, i.p.) or a vehicle for 14 days (from postnatal day 22 to 35). At postnatal day 36, we measured the GLU and GABA contents and their extracellular levels in the nucleus accumbens (NAc). In addition, the GLU and GABA contents were measured in the ventral tegmental area (VTA) and D2 protein levels in the prefrontal cortex (PFC). Chronic use of MOD during adolescence induces behavioral and neurochemical changes associated with the mesocorticolimbic system, such as a reduction in PFC D2 expression, VTA GABA levels and NSA. These results contribute to the understanding of the neurological effects of chronic MOD use on a young healthy brain.

Modafinil acquires reinforcing effects when combined with citalopram.

Modafinil (MOD) is a wakefulness promoter used to treat sleep disorders such as narcolepsy and obstructive sleep apnea. Its action mechanism consists in inhibiting dopamine (DAT) and norepinephrine (NET) transporters, but it has no affinity for the serotonin transporter (SERT). Modafinil's addictive potential is not yet clear, but one feature that differentiates it from potentially addictive drugs like cocaine revolves around affinity for SERT. The aims of the present study were to determine whether co-administration of MOD with the selective serotonin reuptake inhibitor citalopram (CIT) can increase MOD's psychostimulant effects on motor activity (MA), verify the effects of subsequent self-administration of MOD mixed with CIT, and document the presence of any symptoms of withdrawal. At 60 postnatal days (PD), male Wistar rats were treated chronically (16 days) with MOD at 30 or 60 mg/kg, with MOD+CIT at four dosage combinations administered to four groups (30MOD + CIT3, 30MOD + CIT5, 60MOD + CIT3, 60MOD + CIT5 mg/kg), or with a vehicle. After 40 min of daily drug administration, MA was measured on the open field test. MA increased only in the 60MOD group. The rats co-administered with 30MOD + 3CIT and 60MOD + 3CIT showed a decrease in the motivation to seek a pleasurable stimulus (lower consumption of sweet solution) after treatment concluded. The 60MOD and 60MOD + 3CIT groups showed MA sensitization after MOD intake. Additionally, higher self-administration of the mixture was observed in the groups pre-treated with 30MOD + 3CIT and 60MOD + 3CIT. Results suggest that serotonergic activity enhances modafinil's psychostimulant effects.

[Adrenal crisis associated with modafinil use]. / Crisis adrenal asociada al uso de modafinilo.

Adrenal crisis is the most extreme presentation form of adrenal insufficiency and represents a life-threatening endocrinological emergency. This situation can be triggered by different causes including the use of CYP3A4-inducing drugs, which accelerate hydrocortisone clearance. We describe the case of an 85-year-old woman with secondary adrenal insufficiency and chronic renal disease, who presented symptoms compatible with adrenal crisis (asthenia, adynamia, severe hyponatremia associated with neurological symptoms and hypotension) nine days after the start of modafinil treatment. The clinical picture improved rapidly with the suspension of modafinil and the administration of intravenous hydrocortisone. After ruling out the possible triggering causes (infectious, ischemic, pulmonary thromboembolism and failure to take hydrocortisone), it was interpreted that modafinil precipitated the symptoms of adrenal insufficiency by increasing the steroid clearance. Modafinil has the ability to induce the activity of CYP3A4 and consequently decrease the bioavailability of hydrocortisone. We emphasize the need to adjust steroid dose replacement in subjects receiving metabolism-inducing drugs.

La crisis adrenal es la forma más extrema de presentación de la insuficiencia adrenal y representa una urgencia endocrinológica que llega a poner en riesgo la vida. Esta situación puede ser desencadenada por diferentes causas, entre las cuales se incluye el uso de fármacos inductores del CYP3A4, que aceleran la depuración de la hidrocortisona. Describimos el caso de una mujer de 85 años, con antecedentes de insuficiencia adrenal secundaria y enfermedad renal crónica, que presentó síntomas compatibles con crisis adrenal (astenia, adinamia, hiponatremia grave con síntomas neurológicos e hipotensión arterial) luego de nueve días del inicio de tratamiento con modafinilo. El cuadro clínico mejoró rápidamente con la suspensión del modafinilo y la administración de hidrocortisona endovenosa. Luego de descartar las posibles causas desencadenantes (infecciosas, isquémicas, tromboembolismo pulmonar y omisión en la toma de hidrocortisona), se interpretó que el modafinilo precipitó los síntomas de insuficiencia adrenal al aumentar la depuración del corticoide. El modafinilo tiene la capacidad de inducir la actividad del CYP3A4 y, en consecuencia, disminuir la biodisponibilidad de la hidrocortisona. Recalcamos la necesidad de ajustar la dosis de reemplazo de corticoides en sujetos que reciben fármacos inductores del metabolismo.

Crisis adrenal asociada al uso de modafinilo / Adrenal crisis associated with modafinil use

Resumen La crisis adrenal es la forma más extrema de presentación de la insuficiencia adrenal y representa una urgencia endocrinológica que llega a poner en riesgo la vida. Esta situación puede ser des encadenada por diferentes causas, entre las cuales se incluye el uso de fármacos inductores del CYP3A4, que aceleran la depuración de la hidrocortisona. Describimos el caso de una mujer de 85 años, con antecedentes de insuficiencia adrenal secundaria y enfermedad renal crónica, que presentó síntomas compatibles con crisis adrenal (astenia, adinamia, hiponatremia grave con síntomas neurológicos e hipotensión arterial) luego de nueve días del inicio de tratamiento con modafinilo. El cuadro clínico mejoró rápidamente con la suspensión del modafinilo y la administración de hidrocortisona endovenosa. Luego de descartar las posibles causas desencadenantes (infecciosas, isquémicas, tromboembolismo pulmonar y omisión en la toma de hidrocortisona), se interpretó que el modafinilo precipitó los síntomas de insuficiencia adrenal al aumentar la depuración del corticoide. El modafinilo tiene la capacidad de inducir la actividad del CYP3A4 y, en consecuencia, disminuir la biodisponibilidad de la hidrocortisona. Recalcamos la necesidad de ajustar la dosis de reemplazo de corticoides en sujetos que reciben fármacos inductores del metabolismo.

Abstract Adrenal crisis is the most extreme presentation form of adrenal insufficiency and represents a life-threatening endocrinological emergency. This situation can be triggered by different causes including the use of CYP3A4-inducing drugs, which accelerate hydrocortisone clearance. We describe the case of an 85-year-old woman with secondary adrenal insufficiency and chronic renal disease, who presented symptoms compatible with adrenal crisis (asthenia, adynamia, severe hyponatremia associated with neurological symptoms and hypotension) nine days after the start of modafinil treat ment. The clinical picture improved rapidly with the suspension of modafinil and the administration of intravenous hydrocortisone. After ruling out the possible triggering causes (infectious, ischemic, pulmonary thromboembo lism and failure to take hydrocortisone), it was interpreted that modafinil precipitated the symptoms of adrenal insufficiency by increasing the steroid clearance. Modafinil has the ability to induce the activity of CYP3A4 and consequently decrease the bioavailability of hydrocortisone. We emphasize the need to adjust steroid dose re placement in subjects receiving metabolism-inducing drugs.

Prescription psychostimulants for the treatment of stimulant use disorder: a systematic review and meta-analysis.

RATIONALE: Agonist-based pharmacologic intervention is an accepted approach in treatment of opioid and tobacco use disorders. OBJECTIVES: We conducted a systematic review and meta-analysis to evaluate usefulness of an agonist approach as treatment of (psycho)stimulant use disorder (PSUD). METHODS: We reviewed PubMed/Medline, LILACS, and ClinicalTrials.gov databases searching for randomized, double-blind, placebo-controlled, parallel-design studies evaluating outcomes of individuals treated for cocaine- or amphetamine-type substance use disorder. We combined results of all trials that included the following prescription psychostimulants (PPs): modafinil, methylphenidate, or amphetamines (mixed amphetamine salts, lisdexamphetamine, and dextroamphetamine). The combined sample consisted of 2889 patients. Outcomes of interest included the following: drug abstinence (defined as 2-3 weeks of sustained abstinence and the average maximum days of consecutive abstinence), percentage of drug-negative urine tests across trial, and retention in treatment. We conducted random-effects meta-analyses and assessed quality of evidence using the GRADE system. RESULTS: Thirty-eight trials were included. Treatment with PPs increases rates of sustained abstinence [risk ratio (RR) = 1.45, 95% confidence interval (CI) = (1.10, 1.92)] and duration of abstinence [mean difference (MD) = 3.34, 95% CI = (1.06, 5.62)] in patients with PSUD, particularly those with cocaine use disorder (very low-quality evidence). Prescription amphetamines were particularly efficacious in promoting sustained abstinence in patients with cocaine use disorder [RR = 2.44, 95% CI = (1.66, 3.58)], and higher doses of PPs were particularly efficacious for treatment of cocaine use disorder [RR = 1.95, 95% CI = (1.38, 2.77)] (moderate-quality evidence). Treatment with prescription amphetamines also yielded more cocaine-negative urines [MD = 8.37%, 95% CI = (3.75, 12.98)]. There was no effect of PPs on the retention in treatment. CONCLUSION: Prescription psychostimulants, particularly prescription amphetamines given in robust doses, have a clinically significant beneficial effect to promote abstinence in the treatment of individuals with PSUD, specifically the population with cocaine use disorder.

[Circulation of information on drugs and other substances to increase cognitive performance: a study of a Brazilian blog (2015-2017)]. / Circulación de información sobre medicamentos y otras sustancias para aumentar el rendimiento cognitivo: un estudio de un blog brasileño (2015-2017).

By observing the processes of (bio)medicalization and pharmacologization of society, this article addresses drugs that have been used by healthy individuals to increase cognitive dimensions such as alertness, memory, and concentration. The use of so-called "smart drugs" or "nootropics" has spread among young people, aided by the internet. The circulation of information about such drugs are analyzed using a Brazilian blog called "Cérebro Turbinado," through publications available for public access between 2015 and 2017. The study adopts theoretical and methodological frameworks of the social sciences, including an anthropological perspective. Documental research was conducted on the internet, specifically with scientific dissemination materials and the material available from the aforementioned blog. The results show that the blog acts as a medium for spreading biomedical knowledge among the lay public and indicates the production of new forms of subjectivity by revealing the meanings attributed to these substances in socialization processes.

Al observar los procesos de (bio)medicalización y farmacologización de la sociedad, este artículo aborda los medicamentos que han sido utilizados por individuos sanos para aumentar sus dimensiones cognitivas, como el estado de alerta, la memoria y la concentración. Las llamadas "drogas inteligentes" o "drogas nootrópicas" se han extendido entre los jóvenes a través de Internet. La circulación de información sobre tales drogas se analiza desde un blog brasileño llamado Cérebro Turbinado, sobre el que se realizó una investigación documental basada en el material publicado en el blog entre 2015 y 2017, de acceso público. La investigación adopta marcos teóricos y metodológicos de las ciencias sociales, junto a una perspectiva antropológica. Los resultados muestran que el blog actúa como un medio para la difusión del conocimiento biomédico entre el público lego y muestra la producción de nuevas formas de subjetividad al revelar los significados que se atribuyen a tales sustancias en los procesos de socialización.

Modafinil reduces choice impulsivity while increasing motor activity in preadolescent rats treated prenatally with alcohol.

Rats exposed prenatally to alcohol show a reduction in the spontaneous activity of dopaminergic neurons of the ventral tegmental area (VTA), as well as greater impulsive behavior and motor activity, behavioral alterations that have been related to dopaminergic dysfunction. Modafinil (MOD) is a dopamine (DA) reuptake blocker prescribed to treat sleep disorders; however, in recent years it has been used for the treatment of ADHD with positive results. Also, studies in humans and rodents show beneficial effects on learning and attention; however, studies evaluating MOD effects on impulsivity are few and show contradictory results. The purpose of this work was to evaluate the effect of a daily dose of MOD (60 mg/kg i.g.) on cognitive (or choice) impulsivity and motor activity in male preadolescent rats exposed prenatally to alcohol or sucrose (isocaloric control). MOD reduced the impulsive responses in a delay discounting task (DDT) at the same time that increased the motor activity, in both healthy and prenatal alcohol treated rats; however, MOD reduced the response latency in DDT only in prenatal alcohol treated rats. This differential effect of DA activation on impulsivity and motor activity show that the MOD dose that improves the impulse control, does not necessarily decrease motor activity, and suggests a possible differential neural mechanism underlying the expression of these behaviors. On the other hand, the changes in the response latency, only in prenatal alcohol treated groups, suggest that decision-making in animals with a dopaminergic dysfunction is more susceptible to be affected by MOD action.

Acute Regulation of the Arousal-Enhancing Drugs Caffeine and Modafinil on Class IIa HDACs In Vivo and In Vitro: Focus on HDAC7.

Psychostimulant drugs, such as modafinil and caffeine, induce transcriptional alterations through the dysregulation of epigenetic mechanisms. We have previously demonstrated that acute modafinil administration is accompanied by multiple changes in the expression of histone deacetylases (HDACs) within the mouse medial prefrontal cortex (mPFC). Herein, we compared alterations in class IIa HDACs in the mouse mPFC and dorsal striatum (DS) after a single exposure to each psychostimulant. We treated male C57BL/6 mice with modafinil (90 mg/kg, i.p.), caffeine (10 mg/kg, i.p.), or vehicle and evaluated locomotor activity. Following, we examined hdac4, hdac5, and hdac7 mRNA expression using qRT-PCR and HDAC7, pHDAC7, and pHDACs4/5/7 using Western blot. Last, we explored generalized effects in N2a cell line using modafinil (100 µM and 1 mM) or caffeine (80 µM and 800 µM). Our results indicate that modafinil had greater effects on locomotor activity compared with caffeine. qRT-PCR experiments revealed that modafinil decreased hdac5 and hdac7 mRNA expression in the DS, while caffeine had no effects. In the mPFC, modafinil increased hdac7 mRNA expression, with no effects observed for caffeine. Western blot revealed that within the DS, modafinil induced increases in HDAC7, pHDAC7, and pHDACs4/5/7 protein expression, while, in the mPFC, caffeine induced decreases in HDAC7, pHDAC7, and pHDACs4/5/7 protein levels. In vitro studies revealed that modafinil increased hdac4, hdac5, and hdac7 mRNA levels in N2a, while caffeine only increased hdac5 at a higher dose. These findings support the notion that modafinil and caffeine exert distinct regulation of class IIa HDAC family members and that these transcriptional and translational consequences are region-specific.

Efectos adversos a nivel cardiovascular y neurológico asociados al consumo de modafinilo / Adverse effects at the cardiovascular and neurological level associated with the consumption of modafinil

Resumen Introducción: el modafinilo es un fármaco neuroestimulante utilizado principalmente para promover estados de vigilia atención y disminuir la fatiga ante ciertos comportamientos que propician la somnolencia diurna excesiva. Objetivo: identificar en la literatura científica los efectos adversos neurológicos y cardiovasculares causados por el consumo del modafinilo. Materiales y Métodos: revisión bibliográfica de los artículos encontrados entre los meses de abril y julio de 2019 en las bases de datos PUBMED, SCOPUS, DIALNET. 51 artículos superaron la evaluación de calidad metodológica y se incluyeron en la revisión. Resultados: se identificaron que los principales efectos adversos a nivel cardiovascular son la cardiomiopatía Tako-Tsubo y la taquicardia ventricular polimórfica, mientras que a nivel neurológico puede generar insomnio y distonías. Conclusiones: El consumo del modafinilo genera repercusiones en las funciones cognitivas y cardiovasculares por lo cual no es aconsejable su uso a largo plazo en personas sanas. MÉD. UIS.2020;33(1):31-8.

Abstract Introduction: modafinil is a neurostimulant drug used mainly to promote wakefulness, attention and decrease fatigue in certain behaviors that cause excessive daytime sleepiness. Objective: identify in the scientific literature the neurological and cardiovascular adverse effects caused by the consumption of modafinil. Materials and Methods: bibliographic review of the articles found between the months of April and July of 2019 in the PUBMED, SCOPUS, DIALNET databases. 51 articles passed the methodological quality assessment and were included in the review. Results: the main adverse effects at the cardiovascular level were identified as Tako-Tsubo cardiomyopathy and polymorphic ventricular tachycardia, while at the neurological level it can generate insomnia and dystonia. Conclusions: the consumption of modafinil generates repercussions on cognitive and cardiovascular functions, so its long-term use in healthy people is not advisable. MÉD.UIS.2020;33(1):31-8.

Psychostimulant Use for Neuroenhancement (Smart Drugs) among College Students in Brazil.

Background: College students are susceptible to using cognitive enhancement drugs, also known as smart drugs. Objectives: estimate the prevalence of smart drug use and investigate the factors related to access and use among undergraduate students. Methods: cross-sectional study performed among all students who entered the university in 2017 using an anonymous, self-administered questionnaire. Smart drug usage was defined as taking methylphenidate, modafinil or piracetam at any point in life and in the preceding 12 months. We characterized the means of obtaining smart drugs, reasons for using and students' residential situation. We asked students who did not use any medication if they were interested in taking it and the reasons for not using. Results: Out of 1865 respondents, 4.2% had used smart drugs in the last 12 months, and the prevalence among law students reached 14.3%. The most commonly used smart drug was methylphenidate. Among the students who did not present ADD diagnosis, the drug was obtained mostly through a friend. More than 300 students reported a desire to use some smart drug, but they did not, mainly due to the fear of side effects. Conclusions: The current study has found a variety of frequency of smart drug use among college students and has also showed that many students are willing to take some kind of cognitive enhancement drug. Therefore, it is important to discuss this issue from a public health perspective.

The mutagenic effect of psychostimulant modafinil in Wistar rats in vivo.

The demands imposed by today's world require a fast and efficient society, then, significant section of the population looks for support from psychotropic medicine. Modafinil is a psychostimulant that promotes wakefulness, it being recommended for treatment of narcolepsy, obstructive sleep apnea, and shift-work sleep disorder, besides being a cognitive function potentiator. However, chemical components of drugs can alter genetic material. Thus, the present study evaluated the cytotoxic and clastogenic/mutagenic potential of 0.25, 0.50, and 0.75 mg of Modafinil/mL of corn oil/100g body weight in acute treatments and subacute treatments, 15 days, to Rattus norvegicus, treated via gavage in a single daily dose. The drug was not cytotoxic at any of the evaluated doses in either of the treatments. However, the medicine showed clastogenic/mutagenic activity in the acute treatment group at the standard dose and at double dose. Data from the present study indicates that there should be greater caution as to the use of this psychostimulant by human beings.

HDAC superfamily promoters acetylation is differentially regulated by modafinil and methamphetamine in the mouse medial prefrontal cortex.

Dysregulation of histone deacetylases (HDAC) has been proposed as a potential contributor to aberrant transcriptional profiles that can lead to changes in cognitive functions. It is known that METH negatively impacts the prefrontal cortex (PFC) leading to cognitive decline and addiction whereas modafinil enhances cognition and has a low abuse liability. We investigated if modafinil (90 mg/kg) and methamphetmine (METH) (1 mg/kg) may differentially influence the acetylation status of histones 3 and 4 (H3ac and H4ac) at proximal promoters of class I, II, III, and IV HDACs. We found that METH produced broader acetylation effects in comparison with modafinil in the medial PFC. For single dose, METH affected H4ac by increasing its acetylation at class I Hdac1 and class IIb Hdac10, decreasing it at class IIa Hdac4 and Hdac5. Modafinil increased H3ac and decreased H4ac of Hdac7. For mRNA, single-dose METH increased Hdac4 and modafinil increased Hdac7 expression. For repeated treatments (4 d after daily injections over 7 d), we found specific effects only for METH. We found that METH increased H4ac in class IIa Hdac4 and Hdac5 and decreased H3/H4ac at class I Hdac1, Hdac2, and Hdac8. At the mRNA level, repeated METH increased Hdac4 and decreased Hdac2. Class III and IV HDACs were only responsive to repeated treatments, where METH affected the H3/H4ac status of Sirt2, Sirt3, Sirt7, and Hdac11. Our results suggest that HDAC targets linked to the effects of modafinil and METH may be related to the cognitive-enhancing vs cognitive-impairing effects of these psychostimulants.

Circulación de información sobre medicamentos y otras sustancias para aumentar el rendimiento cognitivo: un estudio de un blog brasileño (2015-2017) / Circulation of information on drugs and other substances to increase cognitive performance: a study of a Brazilian blog (2015-2017)

RESUMEN Al observar los procesos de (bio)medicalización y farmacologización de la sociedad, este artículo aborda los medicamentos que han sido utilizados por individuos sanos para aumentar sus dimensiones cognitivas, como el estado de alerta, la memoria y la concentración. Las llamadas "drogas inteligentes" o "drogas nootrópicas" se han extendido entre los jóvenes a través de Internet. La circulación de información sobre tales drogas se analiza desde un blog brasileño llamado Cérebro Turbinado, sobre el que se realizó una investigación documental basada en el material publicado en el blog entre 2015 y 2017, de acceso público. La investigación adopta marcos teóricos y metodológicos de las ciencias sociales, junto a una perspectiva antropológica. Los resultados muestran que el blog actúa como un medio para la difusión del conocimiento biomédico entre el público lego y muestra la producción de nuevas formas de subjetividad al revelar los significados que se atribuyen a tales sustancias en los procesos de socialización.

ABSTRACT By observing the processes of (bio)medicalization and pharmaceuticalization of society, this article addresses drugs that have been used by healthy individuals to increase cognitive dimensions such as alertness, memory, and concentration. The use of so-called "smart drugs" or "nootropics" has spread among young people, aided by the internet. The circulation of information about such drugs are analyzed using a Brazilian blog called "Cérebro Turbinado," through publications available for public access between 2015 and 2017. The study adopts theoretical and methodological frameworks of the social sciences, including an anthropological perspective. Documental research was conducted on the internet, specifically with scientific dissemination materials and the material available from the aforementioned blog. The results show that the blog acts as a medium for spreading biomedical knowledge among the lay public and indicates the production of new forms of subjectivity by revealing the meanings attributed to these substances in socialization processes.

Therapeutic treatment with Modafinil decreases the severity of experimental autoimmune encephalomyelitis in mice.

The psychostimulant drug modafinil has been used for many years for the treatment of sleep disorders. Recent studies have indicated that modafinil has immunomodulatory properties in the central nervous system (CNS) and peripheral immune cells. Thus, our aim was to determine the effects of in vivo therapeutic treatment with modafinil on the severity of clinical symptoms and immune response during the acute phase of experimental autoimmune encephalomyelitis (EAE), an experimental model of multiple sclerosis. Modafinil treatment, given after the onset of symptoms, resulted in an improvement of EAE symptoms and motor impairment, which was correlated with reduced cellular infiltrate and a decreased percentage of T helper (Th) 1 cells in the CNS. The spinal cord analysis revealed that modafinil treatment decreased interferon (IFN)-γ and interleukin (IL)-6 protein levels and down regulated genes related to Th1 immunity, such as IFN-γ and TBX21, without affecting Th17-related genes. Our research indicates that therapeutic modafinil treatment has anti-inflammatory properties in an EAE model by inhibiting brain Th1 response, and may be useful as adjuvant treatment for multiple sclerosis.

Differential effect of modafinil on impulsivity, attention and motor activity in preadolescent rats prenatally treated with alcohol.

The purpose of the present research was to study the effect of different doses of modafinil (0, 10, 30 and 60 mg/kg) on reactive impulsivity, attention and hyperactivity in male Wistar rats treated with prenatal alcohol (PA), treatment that produces an alteration in dopaminergic (DA) neurons. The control rats were treated prenatally with sucrose (PS). Animals with PA were less efficient, more impulsive, and inattentive compared to PSs, in a Go-Signal-Task paradigm. The results indicated that a dose of 30 mg/kg of modafinil increased the number of correct responses in the task; decreased impulsivity and did not affect the attention in the PA animals. In contrast, in the PS animals the doses of 30 and 60 mg/kg of modafinil decreased the number of correct responses and increased the impulsivity. Inattention was only increased with 30 mg/kg in PS animals. Hyperactivity increased with a dose-response effect of modafinil in the PS group; meanwhile, this behavior increased only with the dose of 60 mg/kg in the PA group. A moderate dose of modafinil had beneficial effects on behaviors that are altered in animals with a dysfunction of the dopaminergic system; on the other hand, it has a deleterious effect on these behaviors in healthy animals, which suggests that it is due to the predominance of the psychostimulant effect of this drug. The main target of modafinil is the DA system, thus, the data suggest that this system has an important role in impulsive behavior and hyperactivity.

Modafinil reduces amphetamine preference and prevents anxiety-like symptoms during drug withdrawal in young rats: Involvement of dopaminergic targets in VTA and striatum.

Drug abuse and addiction are overwhelming health problems mainly during adolescence. Based on a previous study of our research group, the rats that received modafinil (MD) during the adolescence showed less preference for amphetamine (AMPH) in adulthood. Our current hypothesis is that MD will show beneficial effects against AMPH preference and abstinence symptoms during adolescence, a critical lifetime period when drug hedonic effects are more pronounced. We investigated the influence of MD pretreatment on AMPH preference in conditioned place preference (CPP) paradigm in adolescent rats and anxiety-like symptoms during drug withdrawal (48 h after the last AMPH dose) in elevated plus maze (EPM) task. Besides that, oxidative and molecular status were evaluated in the ventral tegmental area (VTA) and striatum. Our findings showed, as it was expected, that adolescent animals developed AMPH preference together with anxiety-like symptoms during the drug withdrawal while the MD pretreatment prevented those behaviors. Besides promoting benefits on reward parameters, MD was able to preserve VTA and striatum from oxidative damages. This was observed by the increased catalase activity and reduced generation of reactive species and lipid peroxidation, which were inversely modified by AMPH exposure. At molecular level, MD exerted an interesting modulatory activity on the VTA and induced an up-regulation in striatal dopaminergic targets (TH, DAT, D1R and D2R). So far, during the adolescence, MD presented beneficial behavioral outcomes that could be attributed to its modulatory activity on the striatal dopaminergic system in an attempt to maintain the adequate dopamine levels.

The effects of single-dose injections of modafinil and methamphetamine on epigenetic and functional markers in the mouse medial prefrontal cortex: potential role of dopamine receptors.

METH use causes neuroadaptations that negatively impact the prefrontal cortex (PFC) leading to addiction and associated cognitive decline in animals and humans. In contrast, modafinil enhances cognition by increasing PFC function. Accumulated evidence indicates that psychostimulant drugs, including modafinil and METH, regulate gene expression via epigenetic modifications. In this study, we measured the effects of single-dose injections of modafinil and METH on the protein levels of acetylated histone H3 (H3ac) and H4ac, deacetylases HDAC1 and HDAC2, and of the NMDA subunit GluN1 in the medial PFC (mPFC) of mice euthanized 1 h after drug administration. To test if dopamine (DA) receptors (DRs) participate in the biochemical effects of the two drugs, we injected the D1Rs antagonist, SCH23390, or the D2Rs antagonist, raclopride, 30 min before administration of METH and modafinil. We evaluated each drug effect on glutamate synaptic transmission in D1R-expressing layer V pyramidal neurons. We also measured the enrichment of H3ac and H4ac at the promoters of several genes including DA, NE, orexin, histamine, and glutamate receptors, and their mRNA expression, since they are responsive to chronic modafinil and METH treatment. Acute modafinil and METH injections caused similar effects on total histone acetylation, increasing H3ac and decreasing H4ac, and they also increased HDAC1, HDAC2 and GluN1 protein levels in the mouse mPFC. In addition, the effects of the drugs were prevented by pre-treatment with D1Rs and D2Rs antagonists. Specifically, the changes in H4ac, HDAC2, and GluN1 were responsive to SCH23390, whereas those of H3ac and GluN1 were responsive to raclopride. Whole-cell patch clamp in transgenic BAC-Drd1a-tdTomato mice showed that METH, but not modafinil, induced paired-pulse facilitation of EPSCs, suggesting reduced presynaptic probability of glutamate release onto layer V pyramidal neurons. Analysis of histone 3/4 enrichment at specific promoters revealed: i) distinct effects of the drugs on histone 3 acetylation, with modafinil increasing H3ac at Drd1 and Adra1b promoters, but METH increasing H3ac at Adra1a; ii) distinct effects on histone 4 acetylation enrichment, with modafinil increasing H4ac at the Drd2 promoter and decreasing it at Hrh1, but METH increasing H4ac at Drd1; iii) comparable effects of both psychostimulants, increasing H3ac at Drd2, Hcrtr1, and Hrh1 promoters, decreasing H3ac at Hrh3, increasing H4ac at Hcrtr1, and decreasing H4ac at Hcrtr2, Hrh3, and Grin1 promoters. Interestingly, only METH altered mRNA levels of genes with altered histone acetylation status, inducing increased expression of Drd1a, Adra1a, Hcrtr1, and Hrh1, and decreasing Grin1. Our study suggests that although acute METH and modafinil can both increase DA neurotransmission in the mPFC, there are similar and contrasting epigenetic and transcriptional consequences that may account for their divergent clinical effects.

Modafinil for poststroke patients: A systematic review.

INTRODUCTION: Stroke is a major cause of death and disability worldwide. The use of modafinil, a wakefulness-promoting agent, is hypothesised to benefit stroke patients. METHODS: We performed a systematic review in accordance with the Cochrane Handbook for Systematic Reviews of Interventions recommendations to assess the efficacy and safety of modafinil in poststroke patients. We prospectively registered the review protocol in PROSPERO (CRD42017078465) and reported the systematic review following the PRISMA statement. RESULTS: Two published studies (77 participants) and one ongoing randomised controlled trial, with limited methodological quality, assessed the effects of modafinil (200 mg or 400 mg) for adults from 14 days poststroke up to 3 months poststroke and fulfilled our inclusion criteria. The clinical and methodological variability between studies precluded meta-analyses. Overall, these studies showed some benefit of modafinil for fatigue, but no benefit for disability, cognition, and for subscores of stroke-specific quality of life. Data for adverse events were scarce and mortality was not considered by studies. Due to very low quality related to the evidence, we are uncertain about the effects of modafinil for all outcomes assessed by our systematic review. CONCLUSION: Based on two small randomised controlled trial, which provided very low quality evidence, the effects (benefits and harms) of modafinil for stroke patients are unclear and do not support its routinely use in clinical practice for this clinical situation. Number of Protocol registration in PROSPERO database: CRD42017078465 (available from http://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42017078465).