Gianluigi Tanda, Ph.D.

@article{TANDA202113,

title = {Modafinil and its structural analogs as atypical dopamine uptake inhibitors and potential medications for psychostimulant use disorder},

author = {Gianluigi Tanda and Melinda Hersey and Briana Hempel and Zheng-Xiong Xi and Amy Hauck Newman},

url = {https://pubmed.ncbi.nlm.nih.gov/32927246/},

doi = {https://doi.org/10.1016/j.coph.2020.07.007},

issn = {1471-4892},

year  = {2021},

date = {2021-01-01},

journal = {Current Opinion in Pharmacology},

volume = {56},

pages = {13 - 21},

abstract = {Pharmacotherapeutics for treatment of psychostimulant use disorder are still an unmet medical goal. Recently, off label use of modafinil (MOD), an approved medication for treatment of sleep disturbances, has been tested as a therapeutic for cocaine and methamphetamine use disorder. Positive results have been found in subjects dependent on psychostimulants without concurrent abuse of other substances. Novel structural analogs of MOD have been synthesized in the search for compounds with potentially broader therapeutic efficacy than the parent drug. In the present report we review their potential efficacy as treatments for psychostimulant abuse and dependence assessed in preclinical tests. Results from these preclinical proof of concept studies reveal that some modafinil analogs do not possess typical cocaine-like neurochemical and behavioral effects. Further, they might blunt the reinforcing effects of psychostimulants in animal models, suggesting their potential efficacy as pharmacotherapeutics for treatment of psychostimulant use disorders.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Slack:2020aa,

title = {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},

author = {Rachel D Slack and Therese C Ku and Jianjing Cao and JoLynn B Giancola and Alessandro Bonifazi and Claus J Loland and Alexandra Gadiano and Jenny Lam and Rana Rais and Barbara S Slusher and Mark Coggiano and Gianluigi Tanda and Amy Hauck Newman},

url = {https://pubmed.ncbi.nlm.nih.gov/31661268/},

doi = {10.1021/acs.jmedchem.9b01188},

isbn = {0022-2623},

year  = {2020},

date = {2020-03-12},

booktitle = {Journal of Medicinal Chemistry},

journal = {Journal of Medicinal Chemistry},

volume = {63},

number = {5},

pages = {2343--2357},

publisher = {American Chemical Society},

abstract = {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 (3b) was effective in reducing the reinforcing effects of both cocaine and methamphetamine but did not exhibit psychostimulant behaviors itself. While further development of 3b is ongoing, diastereomeric separation, as well as improvements in potency and pharmacokinetics were desirable for discovering pipeline drug candidates. Thus, a series of bis(4-fluorophenyl)methyl)sulfinyl)alkyl alicyclic amines, where the piperazine-2-propanol scaffold was modified, were designed, synthesized, and evaluated for binding affinities at DAT, as well as the serotonin transporter and σ1 receptors. Within the series, 14a showed improved DAT affinity (Ki = 23 nM) over 3b (Ki = 230 nM), moderate metabolic stability in human liver microsomes, and a hERG/DAT affinity ratio = 28. While 14a increased locomotor activity relative to vehicle, it was significantly lower than activity produced by cocaine. These results support further investigation of 14a as a potential treatment for psychostimulant use disorders.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Yue:2020aa,

title = {A further assessment of a role for Toll-like receptor 4 in the reinforcing and reinstating effects of opioids},

author = {Kai Yue and Gianluigi Tanda and Jonathan L Katz and Claudio Zanettini},

url = {https://pubmed.ncbi.nlm.nih.gov/30741729/},

doi = {10.1097/FBP.0000000000000474},

isbn = {0955-8810},

year  = {2020},

date = {2020-01-01},

journal = {Behavioural Pharmacology},

volume = {31},

number = {2&3},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{GIANCOLA2020112674,

title = {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},

author = {JoLynn B Giancola and Alessandro Bonifazi and Jianjing Cao and Therese Ku and Alexandra J Haraczy and Jenny Lam and Rana Rais and Mark A Coggiano and Gianluigi Tanda and Amy Hauck Newman},

url = {https://pubmed.ncbi.nlm.nih.gov/32947229/},

doi = {https://doi.org/10.1016/j.ejmech.2020.112674},

issn = {0223-5234},

year  = {2020},

date = {2020-01-01},

journal = {European Journal of Medicinal Chemistry},

volume = {208},

pages = {112674},

abstract = {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 ($pm$)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. Herein, bioisosteric substitutions of the piperazine ring were explored with a series of aminopiperidines (A) and piperidine amines (B) wherein compounds with either a terminal tertiary amine or amide were synthesized. Several lead compounds showed high to moderate DAT affinities and metabolic stability in rat liver microsomes. Aminopiperidines 7 (DAT Ki = 50.6 nM), 21b (DAT Ki = 77.2 nM) and 33 (DAT Ki = 30.0 nM) produced only minimal stimulation of ambulatory activity in mice, compared to cocaine, suggesting an atypical DAT inhibitor profile.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Mereu:2020aa,

title = {Modafinil potentiates cocaine self-administration by a dopamine-independent mechanism: possible involvement of gap junctions},

author = {Maddalena Mereu and Takato Hiranita and Chloe J Jordan and Lauren E Chun and Jessica P Lopez and Mark A Coggiano and Juliana C Quarterman and Guo-Hua Bi and Jacqueline D Keighron and Zheng-Xiong Xi and Amy Hauck Newman and Jonathan L Katz and Gianluigi Tanda},

url = {https://pubmed.ncbi.nlm.nih.gov/32340023/},

doi = {10.1038/s41386-020-0680-5},

isbn = {1740-634X},

year  = {2020},

date = {2020-01-01},

journal = {Neuropsychopharmacology},

volume = {45},

number = {9},

pages = {1518--1526},

abstract = {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. Both modafinil and methylphenidate pretreatments potentiated cocaine self-administration. Cocaine, at self-administered doses, stimulated mesolimbic dopamine levels. This effect was potentiated by methylphenidate, but not by modafinil pretreatments, indicating dopamine-dependent actions for methylphenidate, but not modafinil. Modafinil is known to facilitate electrotonic neuronal coupling by actions on gap junctions. Carbenoxolone, a gap junction inhibitor, antagonized modafinil, but not methylphenidate potentiation of cocaine self-administration. Our results indicate that modafinil shares mechanisms with cocaine and methylphenidate but has a unique pharmacological profile that includes facilitation of electrotonic coupling and lower abuse liability, which may be exploited in future therapeutic drug design for cocaine use disorder.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Newman:2019aa,

title = {Translating the atypical dopamine uptake inhibitor hypothesis toward therapeutics for treatment of psychostimulant use disorders.},

author = {Amy Hauck Newman and Jianjing Cao and Jacqueline D Keighron and Chloe J Jordan and Guo-Hua Bi and Ying Liang and Ara M Abramyan and Alicia J Avelar and Christopher W Tschumi and Michael J Beckstead and Lei Shi and Gianluigi Tanda and Zheng-Xiong Xi},

url = {https://www.ncbi.nlm.nih.gov/pubmed/30858517},

doi = {10.1038/s41386-019-0366-z},

issn = {1740-634X (Electronic); 0893-133X (Linking)},

year  = {2019},

date = {2019-07-01},

journal = {Neuropsychopharmacology},

volume = {44},

number = {8},

pages = {1435--1444},

address = {Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, 333 Cassell Drive, Baltimore, MD, 21224, USA. anewman@intra.nida.nih.gov.},

abstract = {Medication-assisted treatments are unavailable to patients with cocaine use disorders. Efforts to develop potential pharmacotherapies have led to the identification of a promising lead molecule, JJC8-091, that demonstrates a novel binding mode at the dopamine transporter (DAT). Here, JJC8-091 and a structural analogue, JJC8-088, were extensively and comparatively assessed to elucidate neurochemical correlates to their divergent behavioral profiles. Despite sharing significant structural similarity, JJC8-088 was more cocaine-like, increasing extracellular DA concentrations in the nucleus accumbens shell (NAS) efficaciously and more potently than JJC8-091. In contrast, JJC8-091 was not self-administered and was effective in blocking cocaine-induced reinstatement to drug seeking. Electrophysiology experiments confirmed that JJC8-091 was more effective than JJC8-088 at inhibiting cocaine-mediated enhancement of DA neurotransmission. Further, when VTA DA neurons in DAT-cre mice were optically stimulated, JJC8-088 produced a significant leftward shift in the stimulation-response curve, similar to cocaine, while JJC8-091 shifted the curve downward, suggesting attenuation of DA-mediated brain reward. Computational models predicted that JJC8-088 binds in an outward facing conformation of DAT, similar to cocaine. Conversely, JJC8-091 steers DAT towards a more occluded conformation. Collectively, these data reveal the underlying molecular mechanism at DAT that may be leveraged to rationally optimize leads for the treatment of cocaine use disorders, with JJC8-091 representing a compelling candidate for development.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Keighron:2019aa,

title = {Effects of (R)-Modafinil and Modafinil Analogues on Dopamine Dynamics Assessed by Voltammetry and Microdialysis in the Mouse Nucleus Accumbens Shell},

author = {Jacqueline D Keighron and Juliana C Quarterman and Jianjing Cao and Emily M DeMarco and Mark A Coggiano and Apre Gleaves and Rachel D Slack and Claudio Zanettini and Amy Hauck Newman and Gianluigi Tanda},

url = {https://pubmed.ncbi.nlm.nih.gov/30645944/},

doi = {10.1021/acschemneuro.8b00340},

year  = {2019},

date = {2019-04-17},

booktitle = {ACS Chemical Neuroscience},

journal = {ACS Chemical Neuroscience},

volume = {10},

number = {4},

pages = {2012--2021},

publisher = {American Chemical Society},

abstract = {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. This study examines three MOD analogues (JJC8-016, JJC8-088, and JJC8-091) with improved DAT affinities compared to their parent compound. These compounds were investigated for their effects on the neurochemistry (brain microdialysis and FSCV) and behavior (ambulatory activity) of male Swiss-Webster mice. Our data indicate that these compounds have dissimilar effects on tonic and phasic dopamine in the nucleus accumbens shell and variability in producing ambulatory activity. These results suggest that small changes in the chemical structure of a DAT inhibitor can cause compounds such as JJC8-088 to produce effects similar to abused psychostimulants like cocaine. In contrast, other compounds like JJC8-091 do not share cocaine-like effects and have a more atypical DAT-inhibitor profile, which may prove to be an advancement in the treatment of psychostimulant use disorders.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{doi:10.1111/nyas.14101,

title = {Effect of systemically administered oxytocin on dose response for methylphenidate self-administration and mesolimbic dopamine levels},

author = {Mary R Lee and Matthew C H Rohn and Claudio Zanettini and Mark A Coggiano and Lorenzo Leggio and Gianluigi Tanda},

url = {https://pubmed.ncbi.nlm.nih.gov/31074517/},

doi = {10.1111/nyas.14101},

year  = {2019},

date = {2019-01-01},

journal = {Annals of the New York Academy of Sciences},

volume = {1455},

number = {1},

pages = {173-184},

abstract = {Abstract 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. We investigated the effect of OT, delivered intraperitoneally, on the methylphenidate (MP) dose--response function for self-administration in rats. Food was used as a control condition. In a microdialysis study, we measured the effect of intraperitoneal OT on MP-stimulated striatal DA levels. Systemic OT pretreatment caused a downward shift in the MP dose--response function for self-administration, while having no effect on motor activity. OT also caused a reduction in food self-administration, although a significantly higher dose of OT was required for this effect compared with that required for a reduction of MP self-administration. Systemic OT pretreatment caused a potentiation of MP-stimulated DA levels in the NAc shell but not in the core. The significance of these findings is discussed, including the potential of OT as a therapeutic agent for addictive disorders.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{ZANETTINI2019107446,

title = {Pharmacological classification of centrally acting drugs using EEG in freely moving rats: an old tool to identify new atypical dopamine uptake inhibitors},

author = {Claudio Zanettini and Alessandro Scaglione and Jacqueline D Keighron and JoLynn B Giancola and Shih-Chieh Lin and Amy H Newman and Gianluigi Tanda},

url = {https://pubmed.ncbi.nlm.nih.gov/30481526/},

doi = {https://doi.org/10.1016/j.neuropharm.2018.11.034},

issn = {0028-3908},

year  = {2019},

date = {2019-01-01},

journal = {Neuropharmacology},

volume = {161},

pages = {107446},

abstract = {Atypical dopamine uptake inhibitors (DUIs) bind to the dopamine transporter and inhibit the reuptake of dopamine but have lower abuse potential than psychostimulants. Several atypical DUIs can block abuse-related effects of cocaine and methamphetamine, thus making them potential medication candidates for psychostimulant use disorders. The aim of the current study is to establish an in-vivo assay using EEG for the rapid identification of atypical DUIs with potential for medication development. The typical DUIs cocaine and methylphenidate dose-dependently decreased the power of the alpha, beta, and gamma bands. The atypical DUI modafinil and its F-analog, JBG1-049, decreased the power of beta, but in contrast to cocaine, none of the other frequency bands, while JHW007 did not significantly alter the EEG spectrum. The mu-opioid receptor agonists heroin and morphine dose-dependently decreased the power of gamma and increased power of the other bands. The effect of morphine on EEG power bands was antagonized by naltrexone. The NMDA receptor antagonist ketamine increased the power of all frequency bands. Therefore, typical and atypical DUIs and drugs of other classes differentially affected EEG spectra, showing distinctive features in the magnitude and direction of their effects on EEG. Comparative analysis of the effects of test drugs on EEG indicates a potential atypical profile of JBG1-049 with similar potency and effectiveness to its parent compound modafinil. These data suggest that EEG can be used to rapidly screen compounds for potential activity at specific pharmacological targets and provide valuable information for guiding the early stages of drug development. This article is part of the issue entitled `Special Issue on Neurotransmitter Transporters'.},

note = {Neurotransmitter Transporters},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{doi:10.1111/ejn.14256,

title = {Distinct effects of (R)-modafinil and its (R)- and (S)-fluoro-analogs on mesolimbic extracellular dopamine assessed by voltammetry and microdialysis in rats},

author = {Jacqueline D Keighron and JoLynn B Giancola and Rachel J Shaffer and Emily M DeMarco and Mark A Coggiano and Rachel D Slack and Amy Hauck Newman and Gianluigi Tanda},

url = {https://pubmed.ncbi.nlm.nih.gov/30402972/},

doi = {10.1111/ejn.14256},

year  = {2019},

date = {2019-01-01},

journal = {European Journal of Neuroscience},

volume = {50},

number = {3},

pages = {2045-2053},

abstract = {Abstract 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. Here, we have tested the effects of the clinically available (R)-enantiomer of MOD on extracellular dopamine levels in the nucleus accumbens shell, a mesolimbic dopaminergic projection field that plays significant roles in various aspects of psychostimulant use disorders, measured in vivo by fast-scan cyclic voltammetry and by microdialysis in Sprague-Dawley rats. We have compared these results with those obtained under identical experimental conditions with two novel and enantiopure bis(F) analogs of MOD, JBG1-048 and JBG1-049. The results show that (R)-modafinil (R-MOD), JBG1-048, and JBG1-049, when administered intravenously with cumulative drug-doses, will block the dopamine transporter and reduce the clearance rate of dopamine, increasing its extracellular levels. Differences among the compounds in their maximum stimulation of dopamine levels, and in their time course of effects were also observed. These data highlight the mechanistic underpinnings of R-MOD and its bis(F) analogs as pharmacological tools to guide the discovery of novel medications to treat psychostimulant use disorders.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Secci:2019aa,

title = {Astrocytic Mechanisms Involving Kynurenic Acid Control Δ9-Tetrahydrocannabinol-Induced Increases in Glutamate Release in Brain Reward-Processing Areas},

author = {Maria E Secci and Paola Mascia and Claudia Sagheddu and Sarah Beggiato and Miriam Melis and Andrea C Borelli and Maria C Tomasini and Leigh V Panlilio and Charles W Schindler and Gianluigi Tanda and Sergi Ferré and Charles W Bradberry and Luca Ferraro and Marco Pistis and Steven R Goldberg and Robert Schwarcz and Zuzana Justinova},

url = {https://pubmed.ncbi.nlm.nih.gov/30151725/},

doi = {10.1007/s12035-018-1319-y},

isbn = {1559-1182},

year  = {2019},

date = {2019-01-01},

journal = {Molecular Neurobiology},

volume = {56},

number = {5},

pages = {3563--3575},

abstract = {The reinforcing effects of Δ9-tetrahydrocannabinol (THC) in rats and monkeys, and the reinforcement-related dopamine-releasing effects of THC in rats, can be attenuated by increasing endogenous levels of kynurenic acid (KYNA) through systemic administration of the kynurenine 3-monooxygenase inhibitor, Ro 61-8048. KYNA is a negative allosteric modulator of α7 nicotinic acetylcholine receptors (α7nAChRs) and is synthesized and released by astroglia, which express functional α7nAChRs and cannabinoid CB1 receptors (CB1Rs). Here, we tested whether these presumed KYNA autoreceptors (α7nAChRs) and CB1Rs regulate glutamate release. We used in vivo microdialysis and electrophysiology in rats, RNAscope in situ hybridization in brain slices, and primary culture of rat cortical astrocytes. Acute systemic administration of THC increased extracellular levels of glutamate in the nucleus accumbens shell (NAcS), ventral tegmental area (VTA), and medial prefrontal cortex (mPFC). THC also reduced extracellular levels of KYNA in the NAcS. These THC effects were prevented by administration of Ro 61-8048 or the CB1R antagonist, rimonabant. THC increased the firing activity of glutamatergic pyramidal neurons projecting from the mPFC to the NAcS or to the VTA in vivo. These effects were averted by pretreatment with Ro 61-8048. In vitro, THC elicited glutamate release from cortical astrocytes (on which we demonstrated co-localization of the CB1Rs and α7nAChR mRNAs), and this effect was prevented by KYNA and rimonabant. These results suggest a key role of astrocytes in interactions between the endocannabinoid system, kynurenine pathway, and glutamatergic neurotransmission, with ramifications for the pathophysiology and treatment of psychiatric and neurodegenerative diseases.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Scherma:2019aa,

title = {Brain activity of anandamide: a rewarding bliss?},

author = {Maria Scherma and Paolo Masia and Valentina Satta and Walter Fratta and Paola Fadda and Gianluigi Tanda},

url = {https://pubmed.ncbi.nlm.nih.gov/30050084/},

doi = {10.1038/s41401-018-0075-x},

isbn = {1745-7254},

year  = {2019},

date = {2019-01-01},

journal = {Acta Pharmacologica Sinica},

volume = {40},

number = {3},

pages = {309--323},

abstract = {Anandamide is a lipid mediator that acts as an endogenous ligand of CB1 receptors. These receptors are also the primary molecular target responsible for the pharmacological effects of Δ9-tetrahydrocannabinol, the psychoactive ingredient in Cannabis sativa. Several studies demonstrate that anandamide exerts an overall modulatory effect on the brain reward circuitry. Several reports suggest its involvement in the addiction-producing actions of other abused drugs, and it can also act as a behavioral reinforcer in animal models of drug abuse. Importantly, all these effects of anandamide appear to be potentiated by pharmacological inhibition of its metabolic degradation. Enhanced brain levels of anandamide after treatment with inhibitors of fatty acid amide hydrolase, the main enzyme responsible for its degradation, seem to affect the rewarding and reinforcing actions of many drugs of abuse. In this review, we will provide an overview from a preclinical perspective of the current state of knowledge regarding the behavioral pharmacology of anandamide, with a particular emphasis on its motivational/reinforcing properties. We will also discuss how modulation of anandamide levels through inhibition of enzymatic metabolic pathways could provide a basis for developing new pharmaco-therapeutic tools for the treatment of substance use disorders.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Scherma2018,

title = {New Perspectives on the Use of Cannabis in the Treatment of Psychiatric Disorders},

author = {Maria Scherma and Paolo Masia and Matteo Deidda and Walter Fratta and Gianluigi Tanda and Paola Fadda},

url = {https://pubmed.ncbi.nlm.nih.gov/30279403/},

doi = {https://doi.org/10.3390/medicines5040107},

year  = {2018},

date = {2018-10-02},

journal = {Medicines},

volume = {5},

number = {4},

pages = {107},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{TUNSTALL201896b,

title = {Atypical dopamine transporter inhibitors attenuate compulsive-like methamphetamine self-administration in rats},

author = {Brendan J Tunstall and Chelsea P Ho and Jianjing Cao and Jana 'i and Brooke E Schmeichel and Rachel D Slack and Gianluigi Tanda and Alexandra J Gadiano and Rana Rais and Barbara S Slusher and George F Koob and Amy H Newman and Leandro F Vendruscolo},

url = {https://pubmed.ncbi.nlm.nih.gov/29217282/},

doi = {https://doi.org/10.1016/j.neuropharm.2017.12.006},

issn = {0028-3908},

year  = {2018},

date = {2018-01-01},

journal = {Neuropharmacology},

volume = {131},

pages = {96 - 103},

abstract = {Methamphetamine (METH) is a highly addictive drug, but no pharmacological treatment is yet available for METH use disorders. Similar to METH, the wake-promoting drug (R)-modafinil (R-MOD) binds to the dopamine transporter (DAT). Unlike METH, R-MOD is not a substrate for transport by DAT and has low abuse potential. We tested the hypothesis that the atypical DAT inhibitor R-MOD and compounds that are derived from modafinil would decrease METH intake by reducing the actions of METH at the DAT. We tested the effects of systemic injections of R-MOD and four novel modafinil-derived ligands with increased DAT affinity (JJC8-016, JJC8-088, JJC8-089, and JJC8-091) on intravenous (i.v.) METH self-administration in rats that were allowed short access (ShA; 1 h) or long access (LgA; 6 h) to the drug. ShA rats exhibited stable METH intake over sessions, whereas LgA rats exhibited an escalation of drug intake. R-MOD decreased METH self-administration in ShA and LgA rats (in the 1st hour only). JJC8-091 and JJC8-016 decreased METH self-administration in both ShA and LgA rats. JJC8-089 decreased METH self-administration in LgA rats only, whereas JJC8-088 had no effect on METH self-administration in either ShA or LgA rats. These findings support the potential of atypical DAT inhibitors for the treatment of METH use disorders and suggest several novel compounds as candidate drugs.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{TUNSTALL201896,

title = {Atypical dopamine transporter inhibitors attenuate compulsive-like methamphetamine self-administration in rats},

author = {Brendan J Tunstall and Chelsea P Ho and Jianjing Cao and Jana 'i and Brooke E Schmeichel and Rachel D Slack and Gianluigi Tanda and Alexandra J Gadiano and Rana Rais and Barbara S Slusher and George F Koob and Amy H Newman and Leandro F Vendruscolo},

url = {https://pubmed.ncbi.nlm.nih.gov/29217282/},

doi = {https://doi.org/10.1016/j.neuropharm.2017.12.006},

issn = {0028-3908},

year  = {2018},

date = {2018-01-01},

journal = {Neuropharmacology},

volume = {131},

pages = {96 - 103},

abstract = {Methamphetamine (METH) is a highly addictive drug, but no pharmacological treatment is yet available for METH use disorders. Similar to METH, the wake-promoting drug (R)-modafinil (R-MOD) binds to the dopamine transporter (DAT). Unlike METH, R-MOD is not a substrate for transport by DAT and has low abuse potential. We tested the hypothesis that the atypical DAT inhibitor R-MOD and compounds that are derived from modafinil would decrease METH intake by reducing the actions of METH at the DAT. We tested the effects of systemic injections of R-MOD and four novel modafinil-derived ligands with increased DAT affinity (JJC8-016, JJC8-088, JJC8-089, and JJC8-091) on intravenous (i.v.) METH self-administration in rats that were allowed short access (ShA; 1 h) or long access (LgA; 6 h) to the drug. ShA rats exhibited stable METH intake over sessions, whereas LgA rats exhibited an escalation of drug intake. R-MOD decreased METH self-administration in ShA and LgA rats (in the 1st hour only). JJC8-091 and JJC8-016 decreased METH self-administration in both ShA and LgA rats. JJC8-089 decreased METH self-administration in LgA rats only, whereas JJC8-088 had no effect on METH self-administration in either ShA or LgA rats. These findings support the potential of atypical DAT inhibitors for the treatment of METH use disorders and suggest several novel compounds as candidate drugs.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Zhang:2017aa,

title = {The Novel Modafinil Analog, JJC8-016, as a Potential Cocaine Abuse Pharmacotherapeutic.},

author = {Hai-Ying Zhang and Guo-Hua Bi and Hong-Ju Yang and Yi He and Gilbert Xue and Jianjing Cao and Gianluigi Tanda and Eliot L Gardner and Amy Hauck Newman and Zheng-Xiong Xi},

url = {https://www.ncbi.nlm.nih.gov/pubmed/28266501},

doi = {10.1038/npp.2017.41},

issn = {1740-634X (Electronic); 0893-133X (Linking)},

year  = {2017},

date = {2017-03-29},

journal = {Neuropsychopharmacology},

volume = {42},

number = {9},

pages = {1871--1883},

address = {Neuropsychopharmacology Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.},

abstract = {(+/-)Modafinil ((+/-)MOD) and its R-enantiomer (R-modafinil; R-MOD) have been investigated for their potential as treatments for psychostimulant addiction. We recently reported a series of (+/-)MOD analogs, of which JJC8-016 (N-(2-((bis(4-fluorophenyl)methyl)thio)ethyl)-3-phenylpropan-1-amine) was selected for further development. JJC8-016 and R-MOD were evaluated for binding across ~70 receptors, transporters, and enzymes. Although at a concentration of 10 muM, there were many hits for JJC8-016, binding affinities in the range of its DAT affinity were only observed at the serotonin transporter (SERT), dopamine D2-like, and sigma1 receptors. R-MOD was more selective, but had much lower affinity at the DAT (Ki=3 muM) than JJC8-016 (Ki=116 nM). In rats, systemic administration of R-MOD alone (10-30 mg/kg i.p.) dose-dependently increased locomotor activity and electrical brain-stimulation reward, whereas JJC8-016 (10-30 mg/kg i.p.) did not produce these effects. Strikingly, pretreatment with JJC8-016 dose-dependently inhibited cocaine-enhanced locomotion, cocaine self-administration, and cocaine-induced reinstatement of drug-seeking behavior, whereas R-MOD inhibited cocaine-induced reinstatement only at the high dose of 100 mg/kg. Notably, JJC8-016 alone neither altered extracellular dopamine in the nucleus accumbens nor maintained self-administration. It also failed to induce reinstatement of drug-seeking behavior. These findings suggest that JJC8-016 is a unique DAT inhibitor that has no cocaine-like abuse potential by itself. Moreover, pretreatment with JJC8-016 significantly inhibits cocaine-taking and cocaine-seeking behavior likely by interfering with cocaine binding to DAT. In addition, off-target actions may also contribute to its potential therapeutic utility in the treatment of cocaine abuse.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Mereu2017,

title = {The unique psychostimulant profile of (+/-)-modafinil: investigation of behavioral and neurochemical effects in mice.},

author = {Maddalena Mereu and Lauren E Chun and Thomas E Prisinzano and Amy Hauck Newman and Jonathan L Katz and Gianluigi Tanda},

url = {https://www.ncbi.nlm.nih.gov/pubmed/27545285},

doi = {10.1111/ejn.13376},

issn = {1460-9568 (Electronic); 0953-816X (Linking)},

year  = {2017},

date = {2017-01-01},

journal = {Eur J Neurosci},

volume = {45},

number = {1},

pages = {167--174},

address = {Medication Development Program, Molecular Targets and Medications Discovery Branch, Department of Health and Human Services, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, 333 Cassell Drive, Baltimore, MD, 21224, USA.},

abstract = {Blockade of dopamine (DA) reuptake via the dopamine transporter (DAT) is a primary mechanism identified as underlying the therapeutic actions of (+/-)-modafinil (modafinil) and its R-enantiomer, armodafinil. Herein, we explored the neurochemical and behavioral actions of modafinil to better characterize its psychostimulant profile. Swiss-Webster mice were implanted with microdialysis probes in the nucleus accumbens shell (NAS) or core (NAC) to evaluate changes in DA levels related to acute reinforcing actions of drugs of abuse. Additionally, subjective effects were studied in mice trained to discriminate 10 mg/kg cocaine (i.p.) from saline. Modafinil (17-300 mg/kg, i.p.) significantly increased NAS and NAC DA levels that at the highest doses reached ~300% at 1 h, and lasted > 6 h in duration. These elevated DA levels did not show statistically significant regional differences between the NAS and NAC. Modafinil produced cocaine-like subjective effects at 56-100 mg/kg when administered at 5 and 60 min before the start of the session, and enhanced cocaine effects when the two were administered in combination. Despite sharing subjective effects with cocaine, modafinil's psychostimulant profile was unique compared to that of cocaine and like compounds. Modafinil had lower potency and efficacy than cocaine in stimulating NAS DA. In addition, the cocaine-like subjective effects of modafinil were obtained at lower doses and earlier onset times than expected based on its dopaminergic effects. These studies suggest that although inhibition of DA reuptake may be a primary mechanism underlying modafinil's therapeutic actions, non DA-dependent actions may be playing a role in its psychostimulant profile.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Bonaventura2017,

title = {Key role of the dopamine D_{4} receptor in the modulation of corticostriatal glutamatergic neurotransmission.},

author = {Jordi Bonaventura and Cesar Quiroz and Ning-Sheng Cai and Marcelo Rubinstein and Gianluigi Tanda and Sergi Ferre},

url = {https://www.ncbi.nlm.nih.gov/pubmed/28097219},

doi = {10.1126/sciadv.1601631},

issn = {2375-2548 (Electronic); 2375-2548 (Linking)},

year  = {2017},

date = {2017-01-01},

journal = {Sci Adv},

volume = {3},

number = {1},

pages = {e1601631},

address = {Integrative Neurobiology Section, National Institute on Drug Abuse, Intramural research Program, National Institutes of Health, Baltimore, MD 21224, USA.},

abstract = {Polymorphic variants of the dopamine D4 receptor gene (DRD4) have been repeatedly associated with numerous neuropsychiatric disorders. Yet, the functional role of the D4 receptor and the functional differences of the products of DRD4 polymorphic variants remained enigmatic. Immunohistochemical and optogenetic-microdialysis experiments were performed in knock-in mice expressing a D4 receptor with the long intracellular domain of a human DRD4 polymorphic variant associated with attention deficit hyperactivity disorder (ADHD). When compared with the wild-type mouse D4 receptor, the expanded intracellular domain of the humanized D4 receptor conferred a gain of function, blunting methamphetamine-induced cortical activation and optogenetic and methamphetamine-induced corticostriatal glutamate release. The results demonstrate a key role of the D4 receptor in the modulation of corticostriatal glutamatergic neurotransmission. Furthermore, these data imply that enhanced D4 receptor-mediated dopaminergic control of corticostriatal transmission constitutes a vulnerability factor of ADHD and other neuropsychiatric disorders.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Talbot2016,

title = {Rapid and sustained antidepressant properties of an NMDA antagonist/monoamine reuptake inhibitor identified via transporter-based virtual screening.},

author = {Jeffery N Talbot and Laura M Geffert and Jessica E Jorvig and Ruben I Goldstein and Cienna L Nielsen and Nicholas E Wolters and Mary Ellen Amos and Caitlin A Munro and Elizabeth Dallman and Maddalena Mereu and Gianluigi Tanda and Jonathan L Katz and Martin Indarte and Jeffry D Madura and Hailey Choi and Rehana K Leak and Christopher K Surratt},

url = {https://www.ncbi.nlm.nih.gov/pubmed/27569602},

doi = {10.1016/j.pbb.2016.08.007},

issn = {1873-5177 (Electronic); 0091-3057 (Linking)},

year  = {2016},

date = {2016-11-01},

journal = {Pharmacol Biochem Behav},

volume = {150-151},

pages = {22--30},

address = {Research Center on Substance Abuse and Depression, College of Pharmacy, Roseman University of Health Sciences, 11 Sunset Way, Henderson, NV 89014, USA. Electronic address: jtalbot@roseman.edu.},

abstract = {Rational design of lead compounds targeting monoamine transporters (MATs) is critical to developing novel therapeutics to treat psychiatric disorders including depression and substance abuse. A 3-D dopamine transporter (DAT) computer model was used to virtually screen a commercially available small molecule library for high DAT affinity drug-like compounds. One hit, coded "MI-4", inhibited human dopamine, norepinephrine, and serotonin transporters in vitro. In vivo administration in mice induced robust, dose-dependent antidepressant-like behaviors in learned helplessness models (tail suspension and forced swim tests). Moreover, chronic administration (21day, 10mg/kg, bid) reduced drinking latencies comparable to fluoxetine (10mg/kg, bid) in the novelty-induced hypophagia test, which requires chronic treatment to produce antidepressant-like effects. MI-4 (10mg/kg, bid) produced rapid (three-day) antidepressant-like effects in the social avoidance test following 10days of social defeat stress. Unlike ketamine, chronic administration of MI-4 increased social interaction scores while improving resiliency to the mood-altering effects of stress to over 70%. Importantly, MI-4 exhibited minimal abuse liability in behavioral and neurological models (conditioned place preference and dopamine in vivo microdialysis). MI-4 was found to be Ro-25-6981, an ifenprodil analog and reputed NMDA antagonist. The data suggest that Ro-25-6981, previously known for rapid-acting glutamatergic antidepressant actions, may also functionally inhibit monoamine reuptake and produces sustained antidepressant effects in vivo. This demonstrates, as proof of principle, the viability of combining these mechanisms to produce rapid and sustained antidepressant-like effects. Overall, these findings suggest MAT computational model-based virtual screening is a viable method for identifying antidepressant lead compounds of unique scaffold.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}