New Drugs, Old Targets: Tweaking the Dopamine System to Treat Psychostimulant Use Disorders.

The abuse of illicit psychostimulants such as cocaine and methamphetamine continues to pose significant health and societal challenges. Despite considerable efforts to develop medications to treat psychostimulant use disorders, none have proven effective, leaving an underserved patient population and unanswered questions about what mechanism(s) of action should be targeted for developing pharmacotherapies. As both cocaine and methamphetamine rapidly increase dopamine (DA) levels in mesolimbic brain regions, leading to euphoria that in some can lead to addiction, targets in which this increased dopaminergic tone may be mitigated have been explored. Further, understanding and targeting mechanisms underlying relapse are fundamental to the success of discovering medications that reduce the reinforcing effects of the drug of abuse, decrease the negative reinforcement or withdrawal/negative affect that occurs during abstinence, or both. Atypical inhibitors of the DA transporter and partial agonists/antagonists at DA D3 receptors are described as two promising targets for future drug development.

Efficacy and Safety of Modafinil for Treatment of Amphetamine-Type Stimulant Use Disorder: A Systematic Review and Meta-Analysis of Randomized Placebo-Controlled Trials: Efficacité et innocuité du modafinil pour le traitement des troubles liés à l'usage de stimulants de type amphétamine : revue systématique et méta-analyse d'essais randomisés contrôlés par placebo.

INTRODUCTION: Amphetamine-type stimulants (ATSs) are related to significant harm worldwide, with limited effective pharmacological treatments for ATS use disorder (ATSUD). Modafinil has been explored as a potential treatment for ATSUD. This systematic review and meta-analysis (PROSPERO ID: CRD42023388487) aimed to evaluate the efficacy and safety of modafinil for the treatment of ATSUD. METHODS: A comprehensive search of major indexing sources and trial registries, from inception to search date, was conducted on February 15, 2023, and updated on October 31, 2023. Eligible studies were randomized placebo-controlled trials (RCTs) of modafinil in individuals meeting the criteria for the Diagnostic and Statistical Manual of Mental Disorders, fourth and fifth editions, diagnoses of ATSUD. Eligible studies were assessed for risk of bias, using the Cochrane Risk of Bias tool. The primary outcome included the effect of modafinil on ATS use. Secondary outcomes included retention in treatment, ATS craving, treatment discontinuation due to adverse events (AEs), and serious AEs. Subgroup analysis by modafinil dose was conducted where appropriate. Risk ratio (RR) or Peto's odds ratio (OR) was calculated for the meta-analysis of dichotomous variables and standardized mean difference (SMD) was calculated for the random-effect meta-analysis of continuous variables. RESULTS: Five RCTs (N = 451 participants) were included. Modafinil did not significantly impact ATS use (RR = 0.99; 95% CI, 0.97 to 1.02; p = 0.655), retention in treatment (RR = 1.02; 95% CI, 0.91 to 1.14; p = 0.799), ATS craving (SMD = -0.36; 95% CI, -1.19 to 0.47; p = 0.398), or treatment discontinuation due to AEs (Peto's OR = 0.48; 95% CI, 0.20 to 1.14; p = 0.100). These results were consistent across subgroup analyses. More episodes of serious AEs were reported in the modafinil group than in the placebo group, at higher doses (Peto's OR = 4.80; 95% CI, 1.18 to 19.56, p = 0.029). CONCLUSION: There is currently no evidence suggesting that modafinil has a statistically significant effect on efficacy outcomes in populations with ATSUD. Continued research into effective treatments and harm reduction strategies for ATSUD is essential.

Modafinil lightens apoptosis and inflammatory response in hepatic ischemia-reperfusion injury through inactivation of TLR9/Myd88/p38 signaling.

Hepatic ischemia/reperfusion injury (IRI) remains a severe threat during liver surgery and transplantation, accounting for unfavorable clinical outcomes. Modafinil (MOD), a wakefulness-inducing compound, is increasingly disclosed to protect against IRI. However, the specific literatures covering the association between MOD and hepatic IRI are few. Here, this paper is committed to unraveling the role and response mechanism of MOD in hepatic IRI. After the establishment of hepatic IRI mice model and cell model, relevant assay kits measured the concentrations of biochemical indicators of hepatotoxicity and hematoxylin and eosin staining estimated liver morphology. Enzyme-linked immunosorbent assay, reverse-transcription quantitative polymerase chain reaction, and western blot evaluated inflammatory levels. Terminal-deoxynucleoitidyl transferase-mediated nick end labeling assay and western blot appraised apoptosis. Western blot also analyzed the expression of Toll-like receptor 9 (TLR9)/myeloid differentiation primary response gene 88 (MyD88)/p38 signaling-associated proteins. Cell counting kit-8 method judged cell viability. MOD was discovered to mitigate liver dysfunction and morphological damage, inflammatory response, apoptosis in vivo and improve cell viability, suppress inflammatory response and apoptosis in vitro. In addition, MOD inactivated TLR9/Myd88/p38 signaling both in vitro and in vivo. Further, TLR9 elevation reversed the inhibitory role of MOD in inflammatory response and cell apoptosis in vitro. Anyway, MOD blocked TLR9/Myd88/p38 signaling to exhibit anti-inflammatory and anti-apoptotic properties in hepatic IRI.

Armodafinil to reduce the sleepiness related side-effects of sleep restriction therapy being used to treat insomnia disorder: An open label clinical trial pilot study compared with historical controls.

Sleep restriction therapy (SRT) is an effective stand-alone behavioural intervention for insomnia disorder. However, its daytime side effects, particularly sleepiness, may be troubling for patients and/or may be a necessary part of the patient's treatment journey. This pilot trial aims to explore the potential benefit of armodafinil, a wakefulness promoter. Patients were treated with SRT with open label adjunctive armodafinil (150 mg/day). Thirty-three patients from previous studies that have undergone exactly the same SRT intervention acted as controls. The primary outcome measure was the insomnia severity index (ISI), and secondary outcomes were the Epworth sleepiness scale, sleep restriction adherence scale (SRAS), and safety from baseline through to 12 weeks. We recruited 25 patients into the trial. Data for the primary end point (ISI at 12 weeks) was available for 20 of the participants. The baseline insomnia severity index was 20.2 (SD 3.3) and decreased to 9.1 (SE 1.1), with no change, to 10.2 and 11.2 at weeks 6 and 12 respectively (all p > 0.05 compared with baseline). The insomnia severity index values for armodafinil patients were statistically inferior to historical controls at the primary time point of 12 weeks (11.2 vs. 6.7, p < 0.01). Sleep restriction therapy plus armodafinil treatment was associated with frequent minor side effects but was generally safe and acceptable to patients. Sleep restriction therapy was associated with a robust clinical response in the insomnia severity index values for insomnia patients. Based upon historical control data, armodafinil does not appear to have beneficial adjunctive effects in addition to sleep restriction therapy alone.

Effects of maternal modafinil treatment on fetal development and neonatal growth parameters - a multicenter case series of the European Network of Teratology Information Services (ENTIS).

OBJECTIVE: In recent years, safety concerns about modafinil exposure during pregnancy have emerged. In particular, increased risks for major congenital anomalies (MCA) and impaired fetal growth were reported, although study results were conflicting. Our investigation aims to examine previously reported safety signals. METHOD: Multicenter case series based on data from 18 Teratology Information Services from 12 countries. Modafinil exposed pregnancies with an estimated date of birth before August 2019 were included in this study. For prospectively ascertained pregnancies, cumulative incidences of pregnancy outcomes, rate of nonchromosomal MCA in first trimester exposed pregnancies and percentiles of neonatal/infant weight and head circumference (HC) were calculated. Potential dose-dependent effects on fetal growth were explored by linear regression models. Retrospectively ascertained cases were screened for pattern of MCA and other adverse events. RESULTS: One hundred and seventy-five prospectively ascertained cases were included, of which 173 were exposed at least during the first trimester. Cumulative incidences for live birth, spontaneous abortion and elective termination of pregnancy were 76.9% (95% CI, 68.0%-84.8%), 9.3% (95% CI, 5.0%-16.9%), and 13.9% (95% CI, 8.1%-23.1%), respectively. Nonchromosomal MCA was present in 3/150 live births, corresponding to an MCA rate of 2.0% (95%CI, 0.6%-6.1%), none were reported in pregnancy losses. Compared to reference standards, birth weight (BW) tended to be lower and neonatal HC to be smaller in exposed newborns (data available for 144 and 73 of 153 live births, respectively). In nonadjusted linear regression models, each 100 mg increase of average dosage per pregnancy day was associated with a decrease in standard deviation score (SDS) of -0.28 SDS (95% CI, -0.45 to -0.10) for BW and of -0.28 SDS (95% CI, -0.56 to 0.01) for HC. Screening of 22 retrospectively reported cases did not reveal any specific pattern of MCA or other adverse outcomes. CONCLUSION: The results do not indicate an increased risk of MCA after in utero exposure to modafinil, but a tendency toward lower BW and reduced neonatal HC. However, these findings should be regarded as preliminary. Until further studies allow for a definite conclusion, modafinil should not be used during pregnancy.

Rapid One-Pot Microwave Assisted Green Synthesis Nitrogen Doped Carbon Quantum Dots as Fluorescent Precursor for Estimation of Modafinil as Post-Covid Neurological Drug in Human Plasma with Greenness Assessments.

The neuro-stimulant anti-narcoleptic drug as modafinil (MOD) is used to treatment neurological conditions caused by COVID-19. MOD was used to treatment narcolepsy, shift-work sleep disorder, and obstructive sleep apnea-related sleepiness. So, an innovative, quick, economical, selective, and ecologically friendly procedure was carried out. A highly sensitive N@CQDs technique was created from green Eruca sativa leaves in about 4 min using microwave synthesis at 700 w. The quantum yield of the synthesized N@CQDs was found to be 41.39%. By increasing the concentration of MOD, the quantum dots' fluorescence intensity was gradually quenched. After being excited at 445 nm, the fluorescence reading was recorded at 515 nm. The linear range was found to be in the range 50 - 700 ng mL-1 with lower limit of quantitation (LOQ) equal to 45.00 ng mL-1. The current method was fully validated and bio analytically according to (US-FDA and ICH) guidelines. Full characterization of the N@CQDs has been conducted by high resolution transmission electron microscope (HRTEM), Zeta potential measurement, fluorescence, UV-VIS, and FTIR spectroscopy. Various experimental variables including pH, QDs concentration and the reaction time were optimized. The proposed study is simply implemented for the therapeutic drug monitoring system (TDMS) and various clinical laboratories for further pharmacokinetic research.

A multi-pronged investigation of option generation using depression, PET and modafinil.

Option generation is a critical process in decision making, but previous studies have largely focused on choices between options given by a researcher. Consequently, how we self-generate options for behaviour remain poorly understood. Here, we investigated option generation in major depressive disorder and how dopamine might modulate this process, as well as the effects of modafinil (a putative cognitive enhancer) on option generation in healthy individuals. We first compared differences in self-generated options between healthy non-depressed adults [n = 44, age = 26.3 years (SD 5.9)] and patients with major depressive disorder [n = 54, age = 24.8 years (SD 7.4)]. In the second study, a subset of depressed individuals [n = 22, age = 25.6 years (SD 7.8)] underwent PET scans with 11C-raclopride to examine the relationships between dopamine D2/D3 receptor availability and individual differences in option generation. Finally, a randomized, double-blind, placebo-controlled, three-way crossover study of modafinil (100 mg and 200 mg), was conducted in an independent sample of healthy people [n = 19, age = 23.2 years (SD 4.8)] to compare option generation under different doses of this drug. The first study revealed that patients with major depressive disorder produced significantly fewer options [t(96) = 2.68, P = 0.009, Cohen's d = 0.54], albeit with greater uniqueness [t(96) = -2.54, P = 0.01, Cohen's d = 0.52], on the option generation task compared to healthy controls. In the second study, we found that 11C-raclopride binding potential in the putamen was negatively correlated with fluency (r = -0.69, P = 0.001) but positively associated with uniqueness (r = 0.59, P = 0.007). Hence, depressed individuals with higher densities of unoccupied putamen D2/D3 receptors in the putamen generated fewer but more unique options, whereas patients with lower D2/D3 receptor availability were likely to produce a larger number of similar options. Finally, healthy participants were less unique [F(2,36) = 3.32, P = 0.048, partial η2 = 0.16] and diverse [F(2,36) = 4.31, P = 0.021, partial η2 = 0.19] after taking 200 mg versus 100 mg and 0 mg of modafinil, while fluency increased linearly with dosage at a trend level [F(1,18) = 4.11, P = 0.058, partial η2 = 0.19]. Our results show, for the first time, that option generation is affected in clinical depression and that dopaminergic activity in the putamen of patients with major depressive disorder may play a key role in the self-generation of options. Modafinil was also found to influence option generation in healthy people by reducing the creativity of options produced.

Systemic exertion intolerance disease associated to neuroendocrine dysfunction and cortical atrophy: a case report.

BACKGROUND: Scarce evidence about the organic and functional abnormalities of systemic exertion intolerance disease (SEID) is found in literature and the pathophysiology is still unclear. METHODS: Following the CARE Guidelines, this case report describes a patient with a 5-year history of nonspecific symptoms, lately recognized as SEID. RESULTS: Low serum thyroid- and adrenocorticotropic stimulating hormone levels, and 24-h urinary cortisol excretion almost twice the upper limit were detected. Computed tomography scan found significant cortical atrophy. Low-dose modafinil improved the clinical outcome, added to nonpharmacologic approach. CONCLUSION: To ascertain an accurate SEID diagnosis and treatment are a challenge in daily clinical practice, that must be engaged based in clear methods and good practice recommendations. Thus, family practitioners should be aware of this diagnosis.

Pharmacokinetics of Novel Dopamine Transporter Inhibitor CE-123 and Modafinil with a Focus on Central Nervous System Distribution.

S-CE-123, a novel dopamine transporter inhibitor, has emerged as a potential candidate for cognitive enhancement. The objective of this study was to compare the tissue distribution profiles, with a specific focus on central nervous system distribution and metabolism, of S-CE-123 and R-modafinil. To address this objective, a precise liquid chromatography-high resolution mass spectrometry method was developed and partially validated. Neuropharmacokinetic parameters were assessed using the Combinatory Mapping Approach. Our findings reveal distinct differences between the two compounds. Notably, S-CE-123 demonstrates a significantly superior extent of transport across the blood-brain barrier (BBB), with an unbound brain-to-plasma concentration ratio (Kp,uu,brain) of 0.5, compared to R-modafinil's Kp,uu,brain of 0.1. A similar pattern was observed for the transport across the blood-spinal cord barrier. Concerning the drug transport across cellular membranes, we observed that S-CE-123 primarily localizes in the brain interstitial space, whereas R-modafinil distributes more evenly across both sides of the plasma membrane of the brain's parenchymal cells (Kp,uu,cell). Furthermore, our study highlights the substantial differences in hepatic metabolic stability, with S-CE-123 having a 9.3-fold faster metabolism compared to R-modafinil. In summary, the combination of improved BBB transport and higher affinity of S-CE-123 to dopamine transporters in comparison to R-modafinil makes S-CE-123 a promising candidate for further testing for the treatment of cognitive decline.

Are There Prevalent Sex Differences in Psychostimulant Use Disorder? A Focus on the Potential Therapeutic Efficacy of Atypical Dopamine Uptake Inhibitors.

Psychostimulant use disorders (PSUD) affect a growing number of men and women and exert sizable public health and economic burdens on our global society. Notably, there are some sex differences in the onset of dependence, relapse rates, and treatment success with PSUD observed in preclinical and clinical studies. The subtle sex differences observed in the behavioral aspects of PSUD may be associated with differences in the neurochemistry of the dopaminergic system between sexes. Preclinically, psychostimulants have been shown to increase synaptic dopamine (DA) levels and may downregulate the dopamine transporter (DAT). This effect is greatest in females during the high estradiol phase of the estrous cycle. Interestingly, women have been shown to be more likely to begin drug use at younger ages and report higher levels of desire to use cocaine than males. Even though there is currently no FDA-approved medication, modafinil, a DAT inhibitor approved for use in the treatment of narcolepsy and sleep disorders, has shown promise in the treatment of PSUD among specific populations of affected individuals. In this review, we highlight the therapeutic potential of modafinil and other atypical DAT inhibitors focusing on the lack of sex differences in the actions of these agents.

Cognitive enhancement: Effects of methylphenidate, modafinil, and caffeine on latent memory and resting state functional connectivity in healthy adults.

Stimulants like methylphenidate, modafinil, and caffeine have repeatedly shown to enhance cognitive processes such as attention and memory. However, brain-functional mechanisms underlying such cognitive enhancing effects of stimulants are still poorly characterized. Here, we utilized behavioral and resting-state fMRI data from a double-blind randomized placebocontrolled study of methylphenidate, modafinil, and caffeine in 48 healthy male adults. The results show that performance in different memory tasks is enhanced, and functional connectivity (FC) specifically between the frontoparietal network (FPN) and default mode network (DMN) is modulated by the stimulants in comparison to placebo. Decreased negative connectivity between right prefrontal and medial parietal but also between medial temporal lobe and visual brain regions predicted stimulant-induced latent memory enhancement. We discuss dopamine's role in attention and memory as well as its ability to modulate FC between large-scale neural networks (e.g., FPN and DMN) as a potential cognitive enhancement mechanism.

Modafinil ameliorates the decline in pronunciation-related working memory caused by 36-h acute total sleep deprivation: An ERP study.

We aimed to explore whether modafinil mitigates the working memory decline induced by 36 h of acute total sleep deprivation (36-h TSD). Sixteen healthy male participants were enrolled in a randomized double-blind crossover control study involving three sleep-deprivation sessions. Participants were administered 400 mg of placebo, caffeine, or modafinil during these sessions. Behavior and EEG data were recorded while participants performed pronunciation-related working memory tasks. Behavioral indicators showed that, compared with placebo, modafinil improved the accuracy of pronunciation-related working memory tasks and reduced the response time. Compared with before sleep deprivation, the amplitudes of the event-related potentials (ERPs) increased in the N2 component and decreased in the P3 component after sleep deprivation in the placebo condition. In the caffeine condition, the amplitude of the P3 component decreased, the latency of the N2 component was prolonged, and the N2 amplitude remained unchanged. In the modafinil condition, the P3 latency was shortened, and no significant difference was found in the amplitude of the N2 or P3 ERPs; no significant difference was recorded in the N2 latency. Modafinil (400 mg) effectively ameliorated the decline in pronunciation-related working memory after 36-h TSD, suggesting that it may effectively counteract cognitive decline caused by acute sleep deprivation.

THN 102 for Excessive Daytime Sleepiness Associated with Parkinson's Disease: A Phase 2a Trial.

BACKGROUND: Excessive daytime sleepiness (EDS) is a frequent and disabling symptom of Parkinson's disease (PD) without approved treatment. THN102 is a novel combination drug of modafinil and low-dose flecainide. OBJECTIVE: The aim of this study is to evaluate the safety and efficacy of THN102 in PD patients with EDS. METHODS: The method involved a randomized, double-blind, placebo-controlled, crossover trial testing two doses of THN102 (200 mg/d modafinil with 2 mg/d [200/2] or 18 mg/d flecainide [200/18]) versus placebo; 75 patients were exposed to treatment. The primary endpoint was safety. The primary efficacy outcome was the change in Epworth Sleepiness Scale (ESS) score. RESULTS: Both doses of THN102 were well tolerated. ESS significantly improved with THN102 200/2 (least square means vs. placebo [95% confidence interval, CI]: -1.4 [-2.49; -0.31], P = 0.012) but did not change significantly with the 200/18 dosage. CONCLUSIONS: THN102 was well tolerated and showed a signal of efficacy at the 200/2 dose, supporting further development for the treatment of EDS in PD. © 2021 International Parkinson and Movement Disorder Society.

Modafinil exerts anticonvulsive effects against lithium-pilocarpine-induced status epilepticus in rats: A role for tumor necrosis factor-α and nitric oxide signaling.

BACKGROUND: Status epilepticus (SE) is a continuous episode of seizures which leads to hippocampal neurodegeneration, severe systemic inflammation, and extreme damage to the brain. Modafinil, a psychostimulant and wake-promoting agent, has exerted neuroprotective and anti-inflammatory effects in previous preclinical studies. The aim of this study was to assess effects of modafinil on the lithium-pilocarpine-induced SE rat model and to explore possible involvement of tumor necrosis factor-α (TNF-α) and nitric oxide (NO) pathways in this regard. METHODS: Status epilepticus was provoked by injection of lithium chloride (127 mg/kg, intraperitoneally [i.p]) and pilocarpine (60 mg/kg, i.p.) in rats. Animals received different modafinil doses (50, 75, 100, and 150 mg/kg, i.p.) and SE scores were documented over 3 hours of duration. Moreover, the role of the nitrergic pathway in the effects of modafinil was evaluated by injection of the non-selective NO synthase (NOS) inhibitor L-NG-Nitro arginine methyl ester (L-NAME, 10 mg/kg, i.p.), the selective neuronal NOS inhibitor 7-nitroindazole (30 mg/kg, i.p.), and the selective inducible NOS inhibitor aminoguanidine (100 mg/kg, i.p.) 15 min before saline/vehicle or modafinil. The ELISA method was used to quantify TNF-α and NO metabolite levels in the isolated hippocampus. RESULTS: Modafinil at 100 mg/kg significantly decreased SE scores (P < 0.01). Pre-treatment with L-NAME, 7-nitroindazole, and aminoguanidine significantly reversed the anticonvulsive effects of modafinil. Status epilepticus-induced animals showed significantly higher NO metabolite and TNF-α levels in their hippocampal tissues, an effect that was reversed by modafinil (100 mg/kg, i.p.) treatment. Administration of NOS inhibitors resulted in excessive NO level reduction but an escalation of TNF-α level in modafinil-treated SE-animals. CONCLUSION: Our study revealed anticonvulsive effects of modafinil in the lithium-pilocarpine-induced SE rat model via possible involvement of TNF-α and nitrergic pathways.

Modafinil rescues repeated morphine-induced synaptic and behavioural impairments via activation of D1R-ERK-CREB pathway in medial prefrontal cortex.

Long-term opioid abuse causes a variety of long-lasting cognitive impairments such as attention, impulsivity and working memory. These cognitive impairments undermine behavioural treatment for drug abuse and lead to poor treatment retention and outcomes. Modafinil is a wake-promoting drug that shows potential in improving attention and memory in humans and animals. However, modafinil's effect on opioid-induced cognitive impairments remains unclear, and the underlying mechanism is poorly understood. This study showed that repeated morphine administration significantly impairs attention, increases impulsivity and reduces motivation to natural rewards in mice. Systemic modafinil treatment at low dose efficiently ameliorates morphine-induced attention dysfunction and improves motivation and working memory in mice. High dose of modafinil has adverse effects on impulsive action and attention. Local infusion of D1R antagonist SCH-23390 reverses the morphine-induced synaptic abnormalities and activation of the D1R-ERK-CREB pathway in medial prefrontal cortex (mPFC). This study demonstrated a protective effect of modafinil in mPFC neurons and offered a therapeutic potential for cognitive deficits in opioid abuse.

Dose-dependent subacute cardiovascular effects of modafinil in rats.

Modafinil is used for the treatment of various sleep disorders; however, its usage among healthy individuals is also increasing. There are a limited number of cardiovascular side effects, including ischemic T-wave changes, dyspnea, hypertension, and tachycardia in the literature. Our research aimed to investigate the dose-dependent subacute cardiovascular effects of modafinil in rats. Thirty-two rats were randomly and equally assigned to a control group (vehicle-treated for 14 days), a subacute low-dose group (SALD, 10 mg/kg for 14 days), a subacute moderate-dose group (SAMD, 100 mg/kg for 14 days), and a subacute high-dose group (SHD, 600 mg/kg for 14 days). The cardiovascular effects of modafinil were evaluated using hemodynamic, biochemical, electrocardiographic, electrophysiologic, and histopathologic parameters. In terms of hemodynamic parameters, heart rate, and systolic/diastolic/mean blood pressure levels, electrophysiological parameters did not reach statistical significance among the groups (p > 0.05). The incidence of T-wave negativity in SAMD and SAHD groups was 25 and 37.5%, respectively. Moreover, one rat per group was affected by an atrioventricular blockage. Malondialdehyde, superoxide dismutase, catalase, and reduced glutathione levels in the heart and vascular tissues, serum troponin-I, and creatine kinase levels were similar between the modafinil-administered groups and the control group (p > 0.05); this indicates that modafinil activated neither oxidative stress nor antioxidant pathway. Also, there was no difference in histopathological parameters between groups (p > 0.05). Supratherapeutic doses of modafinil may have the potential to cause ischemic cardiac damage and atrioventricular blockage, despite inconsistency with literature findings; however, this does not pertain to hemodynamic changes.

The effect of modafinil on passive avoidance memory, brain level of BDNF and oxidative stress markers in sepsis survivor rats.

Propose/aim of study: Modafinil (MD) is a psychostimulant drug used off-label and cognitive dysfunction may be a significant emerging treatment target for this drug. The objective of this study was to evaluate the effect of MD on the neurochemical parameters and memory impairment of rats submitted to sepsis by cecal ligation and perforation (CLP).Material and method: Male Wistar rats (250-350g) were submitted to CLP, or sham as control, and divided into the sham + water, sham + MD (300 mg/kg), CLP + water, and CLP + MD (300 mg/kg) groups. Ten days after the administration of MD and CLP, the rats were submitted to a memory test by passive avoidance apparatus being sacrificed. The nitrite and nitrate (N/N) concentration, myeloperoxidase (MPO) and catalase (CAT) activity, lipid and protein oxidative damage, and brain-derived neurotrophic factor (BDNF) levels were measured in the prefrontal cortex and hippocampus.Results: The passive avoidance test verified an increase in the latency time compared training and test section in the groups sham + water and CLP + MD. Decreased N/N concentration and MPO activity were verified in the prefrontal cortex of rats submitted to CLP and MD treatment, as well as reduced protein and lipid oxidative damage in the hippocampus, which was accompanied by increased CAT activity and BDNF levels.Conclusion: Our data indicate the role of MD in attenuating oxidative stress parameters, the alteration of BDNF, and an improvement in memory impairment in rats ten days after induction of sepsis.

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.

Toward Informed User Decisions About Pharmacological Cognitive Enhancement.

Pharmacological cognitive enhancement (PCE) refers to the use of pharmaceuticals to improve cognitive function when that use is not intended to prevent or treat disease. Those who favour a liberal approach to PCE trust users to make informed decisions about whether enhancing is in their best interest. The author argues that making informed decisions about PCE requires a nuanced risk-benefit analysis that is not accessible to many users. Presently, the PCE use of prescription medications such as methylphenidate and modafinil is widespread but most commonly happens without medical supervision. Direct and indirect barriers generate a situation where the risks and benefits of PCE are inequitably distributed; as a result, PCE is sometimes not in the user's best interest. This is likely to also be the case for future pharmaceuticals. As a result, even if PCE pharmaceuticals were equitably distributed, its associated risks and benefits would not be. The article concludes with a discussion of the prospects of the clinical consultation on one hand, and e-health solutions on the other, in ameliorating the situation, arguing for cautious optimism.

An anti-narcolepsy drug reveals behavioral and fitness costs of extreme activity cycles in arctic-breeding songbirds.

Sleep loss impairs cognitive function, immunological responses and general well-being in humans. However, sleep requirements in mammals and birds vary dramatically. In circumpolar regions with continuous summer light, daily sleep duration is reduced, particularly in breeding birds. The effect of an anti-narcolepsy drug (modafinil) to putatively extend wakefulness was examined in two species of closely related arctic-breeding passerine birds: Lapland longspurs (Calcarius lapponicus) and snow buntings (Plectrophenax nivalis). Free-living adult males were implanted during the nestling phase on day 4 (D4; 4 days post-hatching) with osmotic pumps containing either vehicle or modafinil to extend the active period for 72 h. Nestlings were weighed on D2 and D7 to measure growth rates. Additionally, focal observations were conducted on D6. Male longspurs receiving modafinil made fewer feeding visits and spent less time at the nest but tended to spend more time near the nest than controls. We observed no change in longspur nestling growth rates, but fledging occurred significantly later when males received modafinil, suggesting a fitness cost. In contrast, modafinil had no measurable impact on male or female snow bunting behavior, nestling growth rates or time to fledging. We suggest male longspurs compromise and maintain vigilance at their nests in lieu of sleeping because of the increased predation risk that is characteristic of their tundra nesting habitat. Snow buntings are cavity nesters, and their nests do not require the same vigilance, allowing males to presumably rest following provisioning. These life-history differences between species highlight the role of predation risk in mediating behavioral modifications to prolonged wakefulness in arctic-breeding songbirds.