Gianluigi Tanda, Ph.D.

@article{pmid33414501,

title = {Cocaine-induced locomotor stimulation involves autophagic degradation of the dopamine transporter},

author = {Maged M Harraz and Prasun Guha and In Guk Kang and Evan R Semenza and Adarsha P Malla and Young Jun Song and Luke Reilly and Isaac Treisman and Pedro Cortés and Mark A Coggiano and Vijayabhaskar Veeravalli and Rana Rais and Gianluigi Tanda and Solomon H Snyder},

url = {https://pubmed.ncbi.nlm.nih.gov/33414501/},

doi = {10.1038/s41380-020-00978-y},

issn = {1476-5578},

year  = {2021},

date = {2021-02-01},

urldate = {2021-02-01},

journal = {Mol Psychiatry},

volume = {26},

number = {2},

pages = {370--382},

abstract = {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. We previously showed that toxic levels of cocaine induce autophagic neuronal cell death. Here, we show that subnanomolar concentrations of cocaine elicit neural autophagy in vitro and in vivo. Autophagy inhibitors reduce the locomotor stimulant effect of cocaine in mice. Cocaine-induced autophagy degrades transporters for dopamine but not serotonin in the nucleus accumbens. Autophagy inhibition impairs cocaine conditioned place preference in mice. Our findings indicate that autophagic degradation of DAT modulates behavioral actions of cocaine.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@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{pmid34121988,

title = {Psychostimulant Use Disorder, an Unmet Therapeutic Goal: Can Modafinil Narrow the Gap?},

author = {Melinda Hersey and Amanda K Bacon and Lydia G Bailey and Mark A Coggiano and Amy H Newman and Lorenzo Leggio and Gianluigi Tanda},

url = {https://pubmed.ncbi.nlm.nih.gov/34121988/},

doi = {10.3389/fnins.2021.656475},

issn = {1662-4548},

year  = {2021},

date = {2021-01-01},

urldate = {2021-01-01},

journal = {Front Neurosci},

volume = {15},

pages = {656475},

abstract = {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. Modafinil (MOD), which is approved for clinical use for the treatment of narcolepsy and sleep disorders, blocks DAT just like commonly abused psychostimulants. However, preclinical and clinical studies have shown that it lacks the addictive properties (in both behavioral and neurochemical studies) associated with other abused DAT inhibitors. Clinical availability of MOD has facilitated its off-label use for several psychiatric disorders related to alteration of brain dopamine (DA) systems, including PSUD. In this review, we highlight clinical and preclinical research on MOD and its R-enantiomer, R-MOD, as potential medications for PSUD. Given the complexity of PSUD, we have also reported the effects of MOD on psychostimulant-induced appearance of several symptoms that could intensify the severity of the disease (i.e., sleep disorders and impairment of cognitive functions), besides the potential therapeutic effects of MOD on PSUD.},

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{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{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{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}

}