Psychostimulant Use Disorder, an Unmet Therapeutic Goal: Can Modafinil Narrow the Gap?

The number of individuals affected by psychostimulant use disorder (PSUD) has increased rapidly over the last few decades resulting in economic, emotional, and physical burdens on our society. Further compounding this issue is the current lack of clinically approved medications to treat this disorder. The dopamine transporter (DAT) is a common target of psychostimulant actions related to their use and dependence, and the recent availability of atypical DAT inhibitors as a potential therapeutic option has garnered popularity in this research field.

Cocaine-induced locomotor stimulation involves autophagic degradation of the dopamine transporter.

Cocaine exerts its stimulant effect by inhibiting dopamine reuptake leading to increased dopamine signaling. This action is thought to reflect binding of cocaine to the dopamine transporter (DAT) to inhibit its function. However, cocaine is a relatively weak inhibitor of DAT, and many DAT inhibitors do not share the behavioral actions of cocaine.

Structure-activity relationships for a series of (Bis(4-fluorophenyl)methyl)sulfinylethyl-aminopiperidines and -piperidine amines at the dopamine transporter: Bioisosteric replacement of the piperazine improves metabolic stability.

Despite considerable efforts to develop medications to treat psychostimulant use disorders, none have proven effective, leaving an underserved patient population and unanswered questions as to what mechanism(s) of action should be targeted for developing pharmacotherapies. Atypical dopamine transporter (DAT) inhibitors, based on (±)modafinil, have shown therapeutic potential in preclinical models of psychostimulant abuse. However, metabolic instability among other limitations to piperazine analogues 1-3 have impeded further development.

Modafinil potentiates cocaine self-administration by a dopamine-independent mechanism: possible involvement of gap junctions.

Modafinil and methylphenidate are medications that inhibit the neuronal reuptake of dopamine, a mechanism shared with cocaine. Their use as "smart drugs" by healthy subjects poses health concerns and requires investigation. We show that methylphenidate, but not modafinil, maintained intravenous self-administration in Sprague-Dawley rats similar to cocaine.

Structure-Activity Relationships for a Series of (Bis(4-fluorophenyl)methyl)sulfinyl Alkyl Alicyclic Amines at the Dopamine Transporter: Functionalizing the Terminal Nitrogen Affects Affinity, Selectivity, and Metabolic Stability.

Atypical dopamine transporter (DAT) inhibitors have shown therapeutic potential in preclinical models of psychostimulant abuse. In rats, 1-(4-(2-((bis(4-fluorophenyl)methyl)sulfinyl)ethyl)-piperazin-1-yl)-propan-2-ol () was effective in reducing the reinforcing effects of both cocaine and methamphetamine but did not exhibit psychostimulant behaviors itself. While further development of is ongoing, diastereomeric separation, as well as improvements in potency and pharmacokinetics were desirable for discovering pipeline drug candidates.

Effect of systemically administered oxytocin on dose response for methylphenidate self-administration and mesolimbic dopamine levels.

The neuropeptide oxytocin (OT) alters behaviors related to the administration of drugs of abuse, including stimulants. OT also plays a key role in social bonding, which involves an interaction between OT and dopamine (DA) in the nucleus accumbens (NAc). The nature of the interaction between OT and DA in the striatum in the context of psychostimulants is unclear.

Effects of ( R)-Modafinil and Modafinil Analogues on Dopamine Dynamics Assessed by Voltammetry and Microdialysis in the Mouse Nucleus Accumbens Shell.

Recent discoveries have improved our understanding of the physiological and pathological roles of the dopamine transporter (DAT); however, only a few drugs are clinically available for DAT-implicated disorders. Among those drugs, modafinil (MOD) and its ( R)-enantiomer (R-MOD) have been used off-label as therapies for psychostimulant use disorders, but they have shown limited effectiveness in clinical trials. Recent preclinical studies on MOD and R-MOD have led to chemically modified structures aimed toward improving their neurobiological properties that might lead to more effective therapeutics for stimulant use disorders.

Distinct effects of (R)-modafinil and its (R)- and (S)-fluoro-analogs on mesolimbic extracellular dopamine assessed by voltammetry and microdialysis in rats.

Psychostimulant use disorders remain an unabated public health concern worldwide, but no FDA approved medications are currently available for treatment. Modafinil (MOD), like cocaine, is a dopamine reuptake inhibitor and one of the few drugs evaluated in clinical trials that has shown promise for the treatment of cocaine or methamphetamine use disorders in some patient subpopulations. Recent structure-activity relationship and preclinical studies on a series of MOD analogs have provided insight into modifications of its chemical structure that may lead to advancements in clinical efficacy.

Lack of Specific Involvement of (+)-Naloxone and (+)-Naltrexone on the Reinforcing and Neurochemical Effects of Cocaine and Opioids.

Effective medications for drug abuse remain a largely unmet goal in biomedical science. Recently, the (+)-enantiomers of naloxone and naltrexone, TLR4 antagonists, have been reported to attenuate preclinical indicators of both opioid and stimulant abuse. To further examine the potential of these compounds as drug-abuse treatments, we extended the previous assessments to include a wider range of doses and procedures.

Human embryonic stem cells which express hrGFP in the undifferentiated state and during dopaminergic differentiation.

Purpose: Human embryonic stem cells (hESCs) which express a reporter gene consistently during all phases of differentiation would be valuable for basic research on cell transplantation. In this study, we describe karyotypically-abnormal variant hESCs, BGO1V2-EFG, which express hrGFP driven by the EF1 promoter.

Methods: BGO1V2-EFG cells were analyzed by using immunocytochemistry, single cell-based confocal image, and in vitro differentiation, including dopaminergic differentiation.

An immortalized rat ventral mesencephalic cell line, RTC4, is protective in a rodent model of stroke.

One therapeutic approach to stroke is the transplantation of cells capable of trophic support, reinnervation, and/or regeneration. Previously, we have described the use of novel truncated isoforms of SV40 large T antigen to generate unique cell lines from several primary rodent tissue types. Here we describe the generation of two cell lines, RTC3 and RTC4, derived from primary mesencephalic tissue using a fragment of mutant T antigen, T155c (cDNA) expressed from the RSV promoter.

Truncated N-terminal mutants of SV40 large T antigen as minimal immortalizing agents for CNS cells.

Immortalized central nervous system (CNS) cell lines are useful as in vitro models for innumerable purposes such as elucidating biochemical pathways, studies of effects of drugs, and ultimately, such cells may also be useful for neural transplantation. The SV40 large T (LT) oncoprotein, commonly used for immortalization, interacts with several cell cycle regulatory factors, including binding and inactivating p53 and retinoblastoma family cell-cycle regulators. In an attempt to define the minimal requirements of SV40 T antigen for immortalizing cells of CNS origin, we constructed T155c, encoding the N-terminal 155 amino acids of LT.

Stable expression of hrGFP by mouse embryonic stem cells: promoter activity in the undifferentiated state and during dopaminergic neural differentiation.

Three promoters, cellular polypeptide chain elongation factor 1 alpha (EF1), cytomegalovirus (CMV), and Rous sarcoma virus (RSV) were examined for stable transgene expression in mouse embryonic stem (ES) cells and their progeny during dopaminergic neural differentiation. In undifferentiated ES cells the EF1 promoter was highly effective, while CMV had moderate activity. After 3 months in culture, expression of humanized renilla green fluorescent protein (hrGFP) was unchanged for the EF1 promoter and decreased for CMV.

T155g-immortalized kidney cells produce growth factors and reduce sequelae of cerebral ischemia.

Fetal rat kidney cells produce high levels of glial-derived neurotrophic factor (GDNF) and exert neuroprotective effects when transplanted into the brain in animal models of Parkinson's disease and stroke. The purpose of the present experiment was to produce kidney cell lines that secrete GDNF. Genes encoding two truncated N-terminal fragments of SV40 large T antigen, T155g and T155c, which does not code for small t antigen, were used.

Gene expression profile in early stage of retinoic acid-induced differentiation of human SH-SY5Y neuroblastoma cells.

Purpose: The human SH-SY5Y cell line is an established model for retinoic acid (RA)-induced neural differentiation. We employed a broad human 15K microarray (15,000 genes) and focused Neuroarray (1152 genes) to examine changes in gene expression early in the process of differentiation (6 hr), before morphology or growth changes are observed.

Methods: 33 P-labeled CDNA probes prepared from RNA extracts of RA-treated and control cultures were hybridized to array membranes, and levels of expression were quantified and compared.

Human cortical neuronal cell line: a model for HIV-1 infection in an immature neuronal system.

HCN-1A is a human cerebral cortical neuronal cell line having properties consistent with cells of immature neuronal origin. This article details evidence for productive low-level infection of HCN-1A cells with human immunodeficiency virus type 1 (HIV-1). In vitro exposure to HCN-1A monolayers to a high titer of either LAV/HTLV-IIIB or HTLV-IIIMN resulted in HIV-1 p24 antigen production and a moderate increase in reverse transcriptase activity in cell-free supernatants.

The continued search for evidence of retroviral infection in schizophrenic patients.

Retroviral infection has been proposed as an etiologic factor in schizophrenia. In an effort to unmask a latent retrovirus, short term cultures of peripheral lymphocytes from 15 schizophrenic subjects and nine normal controls were exposed to ionizing radiation and co-cultured with indicator cells. Reverse transcriptase activity, a marker of retroviral infection, could not be detected in any of the cultures.

Failure to find interference between anti-HLA antibodies and chlorpromazine.

Chlorpromazine has been reported to interfere with the action of alloantibodies directed against HLA-A1. We attempted to replicate this finding using peripheral blood lymphocytes from 3 healthy donors in a complement-mediated lymphocytotoxicity assay. We were unable to find evidence of interference between chlorpromazine and the anti-HLA sera tested.

HLA antigens in schizophrenia.

Human leukocyte antigen (HLA) typing was performed on 55 white schizophrenic patients, who were subdivided into groups on the basis of clinical subtype, response to neuroleptic treatment, enlargement of the lateral ventricles, presence of increased prefrontal or parieto-occipital markings, and presence of reversed frontal or occipital lobe asymmetry. No observed differences in antigen frequencies between the group as a whole and controls or between any subgroup and the remaining group or controls remained significant after correction for the number of antigens tested.

Binding of 3H-spiperone to human peripheral lymphocytes: absence of stereospecific high-affinity binding.

The binding of 3H-spiperone to human peripheral lymphocytes (PBL) was characterized. The (+)-butaclamol displaceable binding of 3H-spiperone was not saturable, and both (+) and (-)-butaclamol were equally potent in displacing 3H-spiperone binding. We did not find evidence for the existence of a high-affinity specific binding site of 3H-spiperone on human PBL.

Reverse transcriptase activity in 5-azacytidine-treated lymphocyte cultures of patients with schizophrenia.

We investigated the involvement of human lymphotropic retroviruses in the etiology of schizophrenia. Short-term cultures of peripheral lymphocytes of 11 chronic schizophrenic patients and six controls were established and treated with 2.5 and 5 microM 5-azacytidine.