Contact
Triad Technology Center333 Cassell Drive
Room 3301
Baltimore, MD 21224
Phone: 667-312-5409
Email: Gianluigi.Tanda@nih.gov
Education
University Diploma as Doctor in Pharmacy, and National Board Certification as Professional Pharmacist, University of Cagliari, Italy. (Advisor: Prof. G. DiChiara)
Diploma of Doctoral Specialization in Toxicology, School of Toxicology, University of Cagliari, Italy; Summa cum Laude. (Advisor: Prof. G. DiChiara)
Research Interests
Past research at the University of Cagliari, Italy, has been focusing on interactions among brain amine systems in psychiatric diseases, depression, schizophrenia, and addictions. In collaboration with Prof. DiChiara and Prof. Pontieri, we have been the first to characterize the pharmacological effects of addictive substances in the shell and core of the Nucleus Accumbens in rodents.
After moving to NIDA/IRP, NIH, in collaboration with Dr. Steven Goldberg we have also been the first to provide clear preclinical demonstration that THC maintains drug-taking behavior in squirrel monkeys at doses comparable to those smoked by humans. This finding demonstrated that THC is a reinforcer, and it has potential for misuse comparable to that of nicotine, cocaine and heroin. This discovery facilitated studies of the neurobiology underlying marijuana and cannabinoid misuse, including the complex pharmacology of the endogenous cannabinoid system and its relationship with systems underlying nicotine dependence.
Our current research is focused on understanding neurochemical, behavioral and molecular differences among typical and atypical blockers of the membrane dopamine transporter that can lead to pharmacotherapeutics for the treatment of cocaine and other psychostimulant use disorders.
We are currently characterizing the effects of modafinil, its enantiomers and several newly synthetized structural analogs of modafinil, alone and in combination with addictive psychostimulants on dopamine dynamics, via neuro-electrochemistry procedures, and on reward-related behavior in rodents. Our goal is to find potential medications for treatment of psychostimulant use disorder.
Publications
Selected Publications
Slack, Rachel D; Ku, Therese C; Cao, Jianjing; Giancola, JoLynn B; Bonifazi, Alessandro; Loland, Claus J; Gadiano, Alexandra; Lam, Jenny; Rais, Rana; Slusher, Barbara S; Coggiano, Mark; Tanda, Gianluigi; Newman, Amy Hauck In: Journal of Medicinal Chemistry, vol. 63, no. 5, pp. 2343–2357, 2020, ISBN: 0022-2623. Yue, Kai; Tanda, Gianluigi; Katz, Jonathan L; Zanettini, Claudio A further assessment of a role for Toll-like receptor 4 in the reinforcing and reinstating effects of opioids Journal Article In: Behavioural Pharmacology, vol. 31, no. 2&3, 2020, ISBN: 0955-8810. Mereu, Maddalena; Hiranita, Takato; Jordan, Chloe J; Chun, Lauren E; Lopez, Jessica P; Coggiano, Mark A; Quarterman, Juliana C; Bi, Guo-Hua; Keighron, Jacqueline D; Xi, Zheng-Xiong; Newman, Amy Hauck; Katz, Jonathan L; Tanda, Gianluigi Modafinil potentiates cocaine self-administration by a dopamine-independent mechanism: possible involvement of gap junctions Journal Article In: Neuropsychopharmacology, vol. 45, no. 9, pp. 1518–1526, 2020, ISBN: 1740-634X. Giancola, JoLynn B; Bonifazi, Alessandro; Cao, Jianjing; Ku, Therese; Haraczy, Alexandra J; Lam, Jenny; Rais, Rana; Coggiano, Mark A; Tanda, Gianluigi; Newman, Amy Hauck In: European Journal of Medicinal Chemistry, vol. 208, pp. 112674, 2020, ISSN: 0223-5234. Newman, Amy Hauck; Cao, Jianjing; Keighron, Jacqueline D; Jordan, Chloe J; Bi, Guo-Hua; Liang, Ying; Abramyan, Ara M; Avelar, Alicia J; Tschumi, Christopher W; Beckstead, Michael J; Shi, Lei; Tanda, Gianluigi; Xi, Zheng-Xiong Translating the atypical dopamine uptake inhibitor hypothesis toward therapeutics for treatment of psychostimulant use disorders. Journal Article In: Neuropsychopharmacology, vol. 44, no. 8, pp. 1435–1444, 2019, ISSN: 1740-634X (Electronic); 0893-133X (Linking). Keighron, Jacqueline D; Quarterman, Juliana C; Cao, Jianjing; DeMarco, Emily M; Coggiano, Mark A; Gleaves, Apre; Slack, Rachel D; Zanettini, Claudio; Newman, Amy Hauck; Tanda, Gianluigi In: ACS Chemical Neuroscience, vol. 10, no. 4, pp. 2012–2021, 2019. Scherma, Maria; Masia, Paolo; Satta, Valentina; Fratta, Walter; Fadda, Paola; Tanda, Gianluigi Brain activity of anandamide: a rewarding bliss? Journal Article In: Acta Pharmacologica Sinica, vol. 40, no. 3, pp. 309–323, 2019, ISBN: 1745-7254. Secci, Maria E; Mascia, Paola; Sagheddu, Claudia; Beggiato, Sarah; Melis, Miriam; Borelli, Andrea C; Tomasini, Maria C; Panlilio, Leigh V; Schindler, Charles W; Tanda, Gianluigi; Ferré, Sergi; Bradberry, Charles W; Ferraro, Luca; Pistis, Marco; Goldberg, Steven R; Schwarcz, Robert; Justinova, Zuzana In: Molecular Neurobiology, vol. 56, no. 5, pp. 3563–3575, 2019, ISBN: 1559-1182. Keighron, Jacqueline D; Giancola, JoLynn B; Shaffer, Rachel J; DeMarco, Emily M; Coggiano, Mark A; Slack, Rachel D; Newman, Amy Hauck; Tanda, Gianluigi In: European Journal of Neuroscience, vol. 50, no. 3, pp. 2045-2053, 2019. Zanettini, Claudio; Scaglione, Alessandro; Keighron, Jacqueline D; Giancola, JoLynn B; Lin, Shih-Chieh; Newman, Amy Hauck; Tanda, Gianluigi In: Neuropharmacology, vol. 161, pp. 107446, 2019, ISSN: 0028-3908, (Neurotransmitter Transporters).
2020
@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{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{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}
}
2019
@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{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{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{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{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 Hauck 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},
urldate = {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}
}