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Pharmacology, Biochemistry, and Behavior Sep 2023Substance 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...
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.
Topics: Male; Animals; Rats; Rats, Wistar; Exploratory Behavior; Motivation; Modafinil; Atomoxetine Hydrochloride; Dopamine
PubMed: 37595803
DOI: 10.1016/j.pbb.2023.173618 -
The Journal of Physiology Sep 2023The secretion of insulin from β-cells in the islet of Langerhans is governed by a series of metabolic and electrical events, which can fail during the progression of...
The secretion of insulin from β-cells in the islet of Langerhans is governed by a series of metabolic and electrical events, which can fail during the progression of type 2 diabetes (T2D). β-cells are electrically coupled via connexin-36 (Cx36) gap junction channels, which coordinates the pulsatile dynamics of [Ca ] and insulin release across the islet. Factors such as pro-inflammatory cytokines and free fatty acids disrupt gap junction coupling under in vitro conditions. Here we test whether gap junction coupling and coordinated [Ca ] dynamics are disrupted in T2D, and whether recovery of gap junction coupling can recover islet function. We examine islets from donors with T2D, from db/db mice, and islets treated with pro-inflammatory cytokines (TNF-α, IL-1β, IFN-ɣ) or free fatty acids (palmitate). We modulate gap junction coupling using Cx36 over-expression or pharmacological activation via modafinil. We also develop a peptide mimetic (S293) of the c-terminal regulatory site of Cx36 designed to compete against its phosphorylation. Cx36 gap junction permeability and [Ca ] dynamics were disrupted in islets from both human donors with T2D and db/db mice, and in islets treated with pro-inflammatory cytokines or palmitate. Cx36 over-expression, modafinil treatment and S293 peptide all enhanced Cx36 gap junction coupling and protected against declines in coordinated [Ca ] dynamics. Cx36 over-expression and S293 peptide also reduced apoptosis induced by pro-inflammatory cytokines. Critically, S293 peptide rescued gap junction coupling and [Ca ] dynamics in islets from both db/db mice and a sub-set of T2D donors. Thus, recovering or enhancing Cx36 gap junction coupling can improve islet function in diabetes. KEY POINTS: Connexin-36 (Cx36) gap junction permeability and associated coordination of [Ca ] dynamics is diminished in human type 2 diabetes (T2D) and mouse models of T2D. Enhancing Cx36 gap junction permeability protects against disruptions to the coordination of [Ca ] dynamics. A novel peptide mimetic of the Cx36 c-terminal regulatory region protects against declines in Cx36 gap junction permeability. Pharmacological elevation in Cx36 or Cx36 peptide mimetic recovers [Ca ] dynamics and glucose-stimulated insulin secretion in human T2D and mouse models of T2D.
Topics: Humans; Mice; Animals; Islets of Langerhans; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Modafinil; Connexins; Insulin; Gap Junctions; Insulin-Secreting Cells; Cytokines
PubMed: 37578890
DOI: 10.1113/JP282114 -
Frontiers in Pharmacology 2023Drug-induced Behavioral Signature Analysis (DBSA), is a machine learning (ML) method for screening of compounds, inspired by analytical methods quantifying gene...
Drug-induced Behavioral Signature Analysis (DBSA), is a machine learning (ML) method for screening of compounds, inspired by analytical methods quantifying gene enrichment in genomic analyses. When applied to behavioral data it can identify drugs that can potentially reverse behavioral symptoms in animal models of human disease and suggest new hypotheses for drug discovery and repurposing. We present a proof-of-concept study aiming to assess Drug-induced Behavioral Signature Analysis (DBSA) as a systematic approach for drug discovery for rare disorders. We applied Drug-induced Behavioral Signature Analysis to high-content behavioral data obtained with SmartCube, an automated phenotyping platform. The therapeutic potential of several dozen approved drugs was assessed for phenotypic reversal of the behavioral profile of a Huntington's Disease (HD) murine model, the Q175 heterozygous knock-in mice. The Drug-induced Behavioral Signature Analysis predictions were enriched for drugs known to be effective in the symptomatic treatment of Huntington's Disease, including bupropion, modafinil, methylphenidate, and several SSRIs, as well as the atypical antidepressant tianeptine. To validate the method, we tested acute and chronic effects of tianeptine (20 mg/kg) , using Q175 mice and wild type controls. In both experiments, tianeptine significantly rescued the behavioral phenotype assessed with the SmartCube platform. Our target-agnostic method thus showed promise for identification of symptomatic relief treatments for rare disorders, providing an alternative method for hypothesis generation and drug discovery for disorders with huge disease burden and unmet medical needs.
PubMed: 37560472
DOI: 10.3389/fphar.2023.1128562 -
Diabetes Aug 2023
Topics: Mice; Male; Animals; Modafinil; Orexins; Hypoglycemia; Glucose; Neurons
PubMed: 37471600
DOI: 10.2337/dbi22-0038 -
ACS Chemical Neuroscience Aug 2023Understanding the neurochemistry underlying sex differences in psychostimulant use disorders (PSUD) is essential for developing related therapeutics. Many...
Understanding the neurochemistry underlying sex differences in psychostimulant use disorders (PSUD) is essential for developing related therapeutics. Many psychostimulants, like cocaine, inhibit the dopamine transporter (DAT), which is largely thought to account for actions related to their misuse and dependence. Cocaine-like, typical DAT inhibitors preferentially bind DAT in an outward-facing conformation, while atypical DAT inhibitors, like modafinil, prefer a more inward-facing DAT conformation. Modafinil and -modafinil have emerged as potential therapeutic options for selected populations of individuals affected by PSUD. In addition, analogs of modafinil (JJC8-088 and JJC8-091) with different pharmacological profiles have been explored as potential PSUD medications in preclinical models. In this work, we employ fast scan cyclic voltammetry (FSCV) to probe nucleus accumbens shell (NAS) dopamine (DA) dynamics in C57BL/6 male and female mice. We find that cocaine slowed DA clearance in both male and female mice but produced more robust increases in evoked NAS DA in female mice. -Modafinil produced mild increases in evoked NAS DA and slowed DA clearance across the sexes. The modafinil analog JJC8-088, a typical DAT inhibitor, produced increases in evoked NAS DA in female and male mice. Finally, JJC8-091, an atypical DAT inhibitor, produced limited increases in evoked NAS DA and slowed DA clearance in both sexes. In this work we begin to tease out how sex differences may alter the effects of DAT targeting and highlight how this may help focus research toward effective treatment options for PSUD.
Topics: Female; Mice; Male; Animals; Modafinil; Dopamine Plasma Membrane Transport Proteins; Dopamine; Nucleus Accumbens; Mice, Inbred C57BL; Central Nervous System Stimulants; Cocaine; Dopamine Uptake Inhibitors
PubMed: 37466616
DOI: 10.1021/acschemneuro.3c00354 -
Annals of Clinical Psychiatry :... Aug 2023Bipolar depression is a serious neuropsychiatric disorder associated with a high risk of morbidity and suicidality. Standard antidepressants approved for treating major...
BACKGROUND
Bipolar depression is a serious neuropsychiatric disorder associated with a high risk of morbidity and suicidality. Standard antidepressants approved for treating major depressive disorder fail to exert efficacy in bipolar depression. Although 5 agents have been developed for the treatment of bipolar depression, treatment resistance is still observed in some patients, and requires off-label pharmacotherapy. Modafinil and armodafinil have been reported to improve treatment-resistant bipolar depression, but with inconsistent results.
METHODS
We present a case of a 65-year-old woman with severe bipolar depression who failed to respond to electroconvulsive therapy and IV ketamine but later responded to high-dose armodafanil.
RESULTS
The patient responded to high-dose armodafinil (gradually titrated to 1,000 mg/d) and achieved remission with good tolerability for 5 years. Recently, she contracted COVID-19 and developed muscular weakness. After a lengthy workup, we became concerned for myopathy as an adverse effect from armodafinil. The patient's dose of armodafinil was significantly reduced and she subsequently became very depressed and functionally disabled before improving again when armodafinil 1,000 mg/d was reinstated.
CONCLUSIONS
We propose that some of the negative results seen in research of armodafinil for bipolar depression may be due to the use of low doses (100 to 200 mg/d), and higher doses may be needed for adequate response in treatment-resistant bipolar depression.
Topics: Female; Humans; Aged; Modafinil; Bipolar Disorder; Depressive Disorder, Major; Benzhydryl Compounds; COVID-19
PubMed: 37459498
DOI: 10.12788/acp.0113 -
Journal of Psychopharmacology (Oxford,... Jul 2023
PubMed: 37458280
DOI: 10.1177/02698811231187127 -
Molecules (Basel, Switzerland) Jul 2023Psychostimulant 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... (Review)
Review
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.
Topics: Female; Humans; Male; Dopamine Uptake Inhibitors; Modafinil; Sex Characteristics; Benzhydryl Compounds; Central Nervous System Stimulants; Cocaine; Dopamine
PubMed: 37446929
DOI: 10.3390/molecules28135270 -
Journal of Psychopharmacology (Oxford,... Sep 2023
Topics: Modafinil; Central Nervous System Stimulants; Benzhydryl Compounds
PubMed: 37435726
DOI: 10.1177/02698811231187127 -
Current Opinion in Chemical Biology Oct 2023In the review, current status of sulfoxides on the pharmaceutical market is discussed. In the first part of the article, natural sulfoxides will be described with a... (Review)
Review
In the review, current status of sulfoxides on the pharmaceutical market is discussed. In the first part of the article, natural sulfoxides will be described with a special focus on sulforaphane and amanitin, a mushroom toxin which has been developed as payload in antibody drug conjugates in the possible cancer treatment. Controversies associated with the medical use of dimethylsulfoxide are briefly described in the next section. In the part devoted to PPIs, the benefits of using pure enantiomers (chiral switch) are discussed. An interesting approach, repositioning of drugs is exemplified by new possible applications of modafinil and sulindac. The review is concluded by presentation of cenicriviroc and adezmapimod, both with the status of promising drug candidates.
Topics: Sulfoxides; Dimethyl Sulfoxide; Stereoisomerism
PubMed: 37307682
DOI: 10.1016/j.cbpa.2023.102340