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PloS One 2012Methamphetamine is a drug of abuse that can cause neurotoxic damage in humans and animals. Modafinil, a wake-promoting compound approved for the treatment of sleeping...
Methamphetamine is a drug of abuse that can cause neurotoxic damage in humans and animals. Modafinil, a wake-promoting compound approved for the treatment of sleeping disorders, is being prescribed off label for the treatment of methamphetamine dependence. The aim of the present study was to investigate if modafinil could counteract methamphetamine-induced neuroinflammatory processes, which occur in conjunction with degeneration of dopaminergic terminals in the mouse striatum. We evaluated the effect of a toxic methamphetamine binge in female C57BL/6 mice (4 × 5 mg/kg, i.p., 2 h apart) and modafinil co-administration (2 × 90 mg/kg, i.p., 1 h before the first and fourth methamphetamine injections) on glial cells (microglia and astroglia). We also evaluated the striatal expression of the pro-apoptotic BAX and anti-apoptotic Bcl-2 proteins, which are known to mediate methamphetamine-induced apoptotic effects. Modafinil by itself did not cause reactive gliosis and counteracted methamphetamine-induced microglial and astroglial activation. Modafinil also counteracted the decrease in tyrosine hydroxylase and dopamine transporter levels and prevented methamphetamine-induced increases in the pro-apoptotic BAX and decreases in the anti-apoptotic Bcl-2 protein expression. Our results indicate that modafinil can interfere with methamphetamine actions and provide protection against dopamine toxicity, cell death, and neuroinflammation in the mouse striatum.
Topics: Animals; Apoptosis; Benzhydryl Compounds; Corpus Striatum; Dopamine Plasma Membrane Transport Proteins; Female; Fever; Glial Fibrillary Acidic Protein; Immunohistochemistry; Inflammation; Methamphetamine; Mice; Mice, Inbred C57BL; Modafinil; Tyrosine 3-Monooxygenase
PubMed: 23056363
DOI: 10.1371/journal.pone.0046599 -
PloS One 2020Cognitive enhancing drugs are claimed to improve cognitive functions such as learning and attention. However, little is known presently about the characteristics of...
Cognitive enhancing drugs are claimed to improve cognitive functions such as learning and attention. However, little is known presently about the characteristics of off-prescription cognitive enhancing drug users or their perceived everyday experience with these drugs. As modafinil is the most commonly used off-prescription cognitive enhancing drug, the current study aimed to provide a detailed profile of modafinil users and their experiences and perceptions of this drug. To this end, an online survey, targeting cognitive enhancing drug users and students, was advertised on forum sites. Information was obtained regarding demographic data, illicit drug use, psychiatric diagnosis and experience of modafinil. Of the 404 respondents, 219 reported taking modafinil. Of these the majority were male, American or British, university-educated and currently employed, with a mean age of 27. Overall, modafinil was perceived by users as being safe. Modafinil users reported higher levels of illicit drug use and psychiatric diagnosis than would be expected from population-based data. More frequent reported modafinil use was associated with higher numbers of perceived benefits whilst reported frequency of use was not associated with the number of perceived risks. There was also a tentative link between the reported use of modafinil and the reported presence of psychiatric disorders, largely depression and anxiety. Respondents who had reported a psychiatric diagnosis declared higher subjective benefits of modafinil. This may suggest further beneficial effects of modafinil or it may reflect insufficient medical treatment for psychiatric disorders in some people. Overall, the findings of the current study should be beneficial in informing clinicians and legislative bodies about the modafinil user profile and how modafinil is perceived.
Topics: Adolescent; Adult; Aged; Dose-Response Relationship, Drug; Female; Humans; Internet; Male; Mental Disorders; Mental Health; Middle Aged; Modafinil; Motivation; Prescription Drug Misuse; Risk Factors; Substance-Related Disorders; Surveys and Questionnaires; Young Adult
PubMed: 32023288
DOI: 10.1371/journal.pone.0227818 -
Tijdschrift Voor Psychiatrie 2010For more than two decades psychiatrists have known about and have promoted modafinil, a very promising stimulant that boosts wakefulness in cases of narcolepsy and also... (Review)
Review
BACKGROUND
For more than two decades psychiatrists have known about and have promoted modafinil, a very promising stimulant that boosts wakefulness in cases of narcolepsy and also enhances cognitive functions. At present, however, we must conclude that modafinil is hardly ever used to treat illness other than narcolepsy.
AIM
To review current attitudes and practice with regard to the use and efficacy of modafinil in the treatment of psychiatric disorders.
METHOD
Relevant placebo-controlled studies were retrieved via PubMed (Medline) and Web of Science.
RESULTS
Modafinil is used experimentally to treat ADHD, mood disorders, schizophrenia and substance-dependence. Compared to placebo, modafinil achieves positive but mainly variable results on different clinical and cognitive measures. It achieves results very rapidly, within a week, but over a period of time the results stabilise.
CONCLUSION
Modafinil is particularly successful in the treatment of ADHD, depression and cocaine-dependency on measures of attention and hyperactivity, fatigue and cocaine-use respectively. There is a need for further placebo-controlled trials with longer follow-up periods and larger sample size in order to ensure the safety of the product and to refine its area of efficacy.
Topics: Attention Deficit Disorder with Hyperactivity; Benzhydryl Compounds; Central Nervous System Stimulants; Cocaine-Related Disorders; Humans; Mental Disorders; Modafinil; Narcolepsy; Randomized Controlled Trials as Topic; Schizophrenia; Treatment Outcome; Wakefulness
PubMed: 21064019
DOI: No ID Found -
Brain : a Journal of Neurology Jun 2022Option generation is a critical process in decision making, but previous studies have largely focused on choices between options given by a researcher. Consequently, how... (Randomized Controlled Trial)
Randomized Controlled Trial
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.
Topics: Adult; Cross-Over Studies; Depression; Depressive Disorder, Major; Dopamine; Humans; Modafinil; Positron-Emission Tomography; Raclopride; Receptors, Dopamine D3; Young Adult
PubMed: 35150243
DOI: 10.1093/brain/awab429 -
Sleep Medicine Reviews Jun 2013This review considers recent evidence showing that cells in the reticular activating system (RAS) exhibit (1) electrical coupling mainly in GABAergic cells, and (2)... (Review)
Review
This review considers recent evidence showing that cells in the reticular activating system (RAS) exhibit (1) electrical coupling mainly in GABAergic cells, and (2) gamma band activity in virtually all of the cells. Specifically, cells in the mesopontine pedunculopontine nucleus (PPN), intralaminar parafascicular nucleus (Pf), and pontine dorsal subcoeruleus nucleus dorsalis (SubCD) (1) show electrical coupling, and (2) all fire in the beta/gamma band range when maximally activated, but no higher. The mechanism behind electrical coupling is important because the stimulant modafinil was shown to increase electrical coupling. We also provide recent findings demonstrating that all cells in the PPN and Pf have high threshold, voltage-dependent P/Q-type calcium channels that are essential to gamma band activity. On the other hand, all SubCD, and some PPN, cells manifested sodium-dependent subthreshold oscillations. A novel mechanism for sleep-wake control based on transmitter interactions, electrical coupling, and gamma band activity is described. We speculate that continuous sensory input will modulate coupling and induce gamma band activity in the RAS that could participate in the processes of preconscious awareness, and provide the essential stream of information for the formulation of many of our actions.
Topics: Animals; Awareness; Benzhydryl Compounds; Beta Rhythm; Calcium Channels; Central Nervous System Stimulants; Cerebral Cortex; Electroencephalography; Humans; Intralaminar Thalamic Nuclei; Locus Coeruleus; Modafinil; Neural Pathways; Neurons; Pedunculopontine Tegmental Nucleus; Pons; Reticular Formation; Signal Processing, Computer-Assisted; Sleep; Sodium Channels; Synaptic Transmission; Wakefulness; gamma-Aminobutyric Acid
PubMed: 23044219
DOI: 10.1016/j.smrv.2012.06.002 -
Progress in Neuro-psychopharmacology &... Jan 2019METH use causes neuroadaptations that negatively impact the prefrontal cortex (PFC) leading to addiction and associated cognitive decline in animals and humans. In...
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.
Topics: Animals; Benzazepines; Central Nervous System Stimulants; Chromatin Immunoprecipitation; Dopamine Agents; Epigenesis, Genetic; Excitatory Postsynaptic Potentials; Histone Deacetylase 1; Histones; Male; Methamphetamine; Mice; Mice, Inbred C57BL; Mice, Transgenic; Modafinil; Neurons; Patch-Clamp Techniques; Prefrontal Cortex; Raclopride; Receptors, Biogenic Amine; Receptors, Dopamine
PubMed: 30056065
DOI: 10.1016/j.pnpbp.2018.07.019 -
The Psychiatric Clinics of North America Jun 2012The use of stimulant medications for the treatment of cocaine dependence is an evolving scientific line of research. To date, the most promising results are with the... (Review)
Review
The use of stimulant medications for the treatment of cocaine dependence is an evolving scientific line of research. To date, the most promising results are with the higher-potency medications, the amphetamine analogues, or a combination of a dopaminergic medication with a contingency management behavioral intervention. The development of effective pharmacotherapies for opioid and nicotine dependence using an agonist replacement approach suggests that these promising findings needs to continue to be vigorously investigated. In clinical trial reports, there are very few instances of cardiovascular adverse events, which suggests that for well-selected patients with cocaine dependence, stimulant replacement therapy can be safe. However, clinical trial eligibility criteria excludes most high-risk patients from participating, and introducing stimulant substitution to the wider treatment community would likely expose more vulnerable patients to the medical risks associated with stimulant treatment while using cocaine. As treatment development research moves forward, attention must be paid to helping clinicians select patients who are most likely to benefit from stimulant substitution treatment and how to identify those at risk. An additional concern with the use of stimulant medication treatment of cocaine dependence is prescribing controlled substances for patients with active substance use disorders. Again, within a clinical trial, medication supplies are monitored and distributed carefully in small quantities. In a community setting, misuse or diversion will be risks associated with prescribing controlled substances to patients with addictive disorders, but therapeutic strategies for monitoring and limiting that risk can be implemented. Psychostimulant pharmacotherapy is a promising line of research for the treatment of cocaine dependence, a condition for which no effective pharmacotherapy has been identified. Further research is required to confirm positive results from single-site trials, in particular the study of amphetamines as a treatment for cocaine dependence. As this literature evolves, strategies to manage the risk of prescribing controlled substances to patients with addictive disorders need to be tested and refined. Biases against using controlled substances as a treatment for cocaine dependence should be challenged, much in the way the use of agonist treatment transformed the treatment of opioid dependence despite initial resistance from the field.
Topics: Amphetamines; Animals; Benzhydryl Compounds; Bupropion; Central Nervous System Stimulants; Clinical Trials as Topic; Cocaine; Cocaine-Related Disorders; Combined Modality Therapy; Dopamine Agents; Humans; Methylphenidate; Modafinil; Placebos; Rats; Reinforcement, Psychology; United States
PubMed: 22640764
DOI: 10.1016/j.psc.2012.03.012 -
Psychopharmacology Oct 2013Modafinil (MOD) and its R-enantiomer (R-MOD) are approved medications for narcolepsy and other sleep disorders. They have also been used, off-label, as cognitive... (Review)
Review
RATIONALE AND OBJECTIVES
Modafinil (MOD) and its R-enantiomer (R-MOD) are approved medications for narcolepsy and other sleep disorders. They have also been used, off-label, as cognitive enhancers in populations of patients with mental disorders, including substance abusers that demonstrate impaired cognitive function. A debated nonmedical use of MOD in healthy individuals to improve intellectual performance is raising questions about its potential abuse liability in this population.
RESULTS AND CONCLUSIONS
MOD has low micromolar affinity for the dopamine transporter (DAT). Inhibition of dopamine (DA) reuptake via the DAT explains the enhancement of DA levels in several brain areas, an effect shared with psychostimulants like cocaine, methylphenidate, and the amphetamines. However, its neurochemical effects and anatomical pattern of brain area activation differ from typical psychostimulants and are consistent with its beneficial effects on cognitive performance processes such as attention, learning, and memory. At variance with typical psychostimulants, MOD shows very low, if any, abuse liability, in spite of its use as a cognitive enhancer by otherwise healthy individuals. Finally, recent clinical studies have focused on the potential use of MOD as a medication for treatment of drug abuse, but have not shown consistent outcomes. However, positive trends in several result measures suggest that medications that improve cognitive function, like MOD or R-MOD, may be beneficial for the treatment of substance use disorders in certain patient populations.
Topics: Benzhydryl Compounds; Brain; Cognition; Dopamine; Dopamine Plasma Membrane Transport Proteins; Humans; Modafinil; Molecular Structure; Neurobiology; Nootropic Agents; Off-Label Use; Substance-Related Disorders; Synaptic Transmission
PubMed: 23934211
DOI: 10.1007/s00213-013-3232-4 -
Psychopharmacology Jun 2020Problematic patterns of gambling are characterised by loss of control and persistent gambling often to recover losses. However, little is known about the mechanisms that...
RATIONALE
Problematic patterns of gambling are characterised by loss of control and persistent gambling often to recover losses. However, little is known about the mechanisms that mediate initial choices to begin gambling and then continue to gamble in the face of losing outcomes.
OBJECTIVES
These experiments first assessed gambling and loss-chasing performance under different win/lose probabilities in C57Bl/6 mice, and then investigated the effects of antagonism of 5-HTR with SB242084, 5-HTR agonism with 8-OH-DPAT and modafinil, a putative cognitive enhancer.
RESULTS
As seen in humans and other species, mice demonstrated the expected patterns of behaviour as the odds for winning were altered increasing gambling and loss-chasing when winning was more likely. SB242084 decreased the likelihood to initially gamble, but had no effects on subsequent gambling choices in the face of repeated losses. In contrast, 8-OH-DPAT had no effects on choosing to gamble in the first place, but once started 8-OH-DPAT increased gambling choices in a dose-sensitive manner. Modafinil effects were different to the serotonergic drugs in both decreasing the propensity to initiate gambling and chase losses.
CONCLUSIONS
We present evidence for dissociable effects of systemic drug administration on different aspects of gambling behaviour. These data extend and reinforce the importance of serotonergic mechanisms in mediating discrete components of gambling behaviour. They further demonstrate the ability of modafinil to reduce gambling behaviour. Our work using a novel mouse paradigm may be of utility in modelling the complex psychological and neurobiological underpinnings of gambling problems, including the analysis of genetic and environmental factors.
Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Central Nervous System Stimulants; Cognition; Gambling; Humans; Male; Mice; Modafinil; Receptor, Serotonin, 5-HT1A; Receptor, Serotonin, 5-HT2C; Reinforcement, Psychology; Serotonin; Serotonin 5-HT1 Receptor Agonists
PubMed: 32123974
DOI: 10.1007/s00213-020-05496-x -
Anatomical Record (Hoboken, N.J. : 2007) Sep 2021The present study investigates the neuroprotective effects of modafinil-coated nanoparticle in rats' hippocampal CA1 region. Male Wistar rats (n = 48) were randomly...
Modafinil-coated nanoparticle increases expressions of brain-derived neurotrophic factor, glial cell line-derived neurotrophic factor and neuronal nuclear protein, and protects against middle cerebral artery occlusion-induced neuron apoptosis in the rat hippocampus.
The present study investigates the neuroprotective effects of modafinil-coated nanoparticle in rats' hippocampal CA1 region. Male Wistar rats (n = 48) were randomly divided into four groups. Then middle cerebral artery occlusion (MCAO) was performed by inserting a silicone coat filament in the right internal carotid artery via the external carotid artery until it reached the anterior cerebral artery. Modafinil (100 mg/kg) or modafinil-coated nanoparticle (100 mg/kg) was given to the rats as an oral gavage once a day. Infarct volume, brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), neuronal nuclear protein (NeuN) and Caspase-3 and, Caspase-8 as apoptotic genes were measured in the hippocampal CA1 region. Cresyl violet staining revealed that modafinil nanoparticle significantly decreased the neurodegeneration. Reverse transcription polymerase chain reaction results showed that modafinil nanoparticle use significantly increased the expression of neurotrophic factors (even more than modafinil alone group; p = .01). Moreover, the apoptotic markers were significantly decreased in nanoparticle modafinil (MN group); p < .05). The western blot analysis and Immunohistochemistry results confirmed the neuroprotective and anti-apoptotic effects of modafinil nanoparticle. This study's results showed that the use of modafinil-coated nanoparticle has neuroprotective effects by increasing neurotrophic factors and reducing apoptosis after MCAO in the CA1 area of the hippocampus. However, further studies are needed especially, in human samples.
Topics: Animals; Apoptosis; Brain-Derived Neurotrophic Factor; Glial Cell Line-Derived Neurotrophic Factor; Hippocampus; Infarction, Middle Cerebral Artery; Male; Modafinil; Nanoparticles; Neurons; Neuroprotective Agents; Nuclear Proteins; Rats; Rats, Wistar
PubMed: 33345406
DOI: 10.1002/ar.24581