Juan L. Gomez, Ph.D.

@article{pmid34750356c,

title = {Synaptic Zn potentiates the effects of cocaine on striatal dopamine neurotransmission and behavior},

author = {Juan L Gomez and Jordi Bonaventura and Jacqueline Keighron and Kelsey M Wright and Dondre L Marable and Lionel A Rodriguez and Sherry Lam and Meghan L Carlton and Randall J Ellis and Chloe J Jordan and Guo-Hua Bi and Oscar Solis and Marco Pignatelli and Michael J Bannon and Zheng-Xiong Xi and Gianluigi Tanda and Michael Michaelides},

url = {https://pubmed.ncbi.nlm.nih.gov/34750356/},

doi = {10.1038/s41398-021-01693-0},

issn = {2158-3188},

year  = {2021},

date = {2021-11-01},

urldate = {2021-11-01},

journal = {Transl Psychiatry},

volume = {11},

number = {1},

pages = {570},

abstract = {Cocaine binds to the dopamine (DA) transporter (DAT) to regulate cocaine reward and seeking behavior. Zinc (Zn) also binds to the DAT, but the in vivo relevance of this interaction is unknown. We found that Zn concentrations in postmortem brain (caudate) tissue from humans who died of cocaine overdose were significantly lower than in control subjects. Moreover, the level of striatal Zn content in these subjects negatively correlated with plasma levels of benzoylecgonine, a cocaine metabolite indicative of recent use. In mice, repeated cocaine exposure increased synaptic Zn concentrations in the caudate putamen (CPu) and nucleus accumbens (NAc). Cocaine-induced increases in Zn were dependent on the Zn transporter 3 (ZnT3), a neuronal Zn transporter localized to synaptic vesicle membranes, as ZnT3 knockout (KO) mice were insensitive to cocaine-induced increases in striatal Zn. ZnT3 KO mice showed significantly lower electrically evoked DA release and greater DA clearance when exposed to cocaine compared to controls. ZnT3 KO mice also displayed significant reductions in cocaine locomotor sensitization, conditioned place preference (CPP), self-administration, and reinstatement compared to control mice and were insensitive to cocaine-induced increases in striatal DAT binding. Finally, dietary Zn deficiency in mice resulted in decreased striatal Zn content, cocaine locomotor sensitization, CPP, and striatal DAT binding. These results indicate that cocaine increases synaptic Zn release and turnover/metabolism in the striatum, and that synaptically released Zn potentiates the effects of cocaine on striatal DA neurotransmission and behavior and is required for cocaine-primed reinstatement. In sum, these findings reveal new insights into cocaine's pharmacological mechanism of action and suggest that Zn may serve as an environmentally derived regulator of DA neurotransmission, cocaine pharmacodynamics, and vulnerability to cocaine use disorders.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid31604917,

title = {High-potency ligands for DREADD imaging and activation in rodents and monkeys},

author = {Jordi Bonaventura and Mark A G Eldridge and Feng Hu and Juan L Gomez and Marta Sanchez-Soto and Ara M Abramyan and Sherry Lam and Matthew A Boehm and Christina Ruiz and Mitchell R Farrell and Andrea Moreno and Islam Mustafa Galal Faress and Niels Andersen and John Y Lin and Ruin Moaddel and Patrick J Morris and Lei Shi and David R Sibley and Stephen V Mahler and Sadegh Nabavi and Martin G Pomper and Antonello Bonci and Andrew G Horti and Barry J Richmond and Michael Michaelides},

url = {https://pubmed.ncbi.nlm.nih.gov/31604917/},

doi = {10.1038/s41467-019-12236-z},

issn = {2041-1723},

year  = {2019},

date = {2019-10-01},

urldate = {2019-10-01},

journal = {Nat Commun},

volume = {10},

number = {1},

pages = {4627},

abstract = {Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) are a popular chemogenetic technology for manipulation of neuronal activity in uninstrumented awake animals with potential for human applications as well. The prototypical DREADD agonist clozapine N-oxide (CNO) lacks brain entry and converts to clozapine, making it difficult to apply in basic and translational applications. Here we report the development of two novel DREADD agonists, JHU37152 and JHU37160, and the first dedicated F positron emission tomography (PET) DREADD radiotracer, [F]JHU37107. We show that JHU37152 and JHU37160 exhibit high in vivo DREADD potency. [F]JHU37107 combined with PET allows for DREADD detection in locally-targeted neurons, and at their long-range projections, enabling noninvasive and longitudinal neuronal projection mapping.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid30872534,

title = {Ultrapotent chemogenetics for research and potential clinical applications},

author = {Christopher J Magnus and Peter H Lee and Jordi Bonaventura and Roland Zemla and Juan L Gomez and Melissa H Ramirez and Xing Hu and Adriana Galvan and Jayeeta Basu and Michael Michaelides and Scott M Sternson},

url = {https://pubmed.ncbi.nlm.nih.gov/30872534/},

doi = {10.1126/science.aav5282},

issn = {1095-9203},

year  = {2019},

date = {2019-04-01},

urldate = {2019-04-01},

journal = {Science},

volume = {364},

number = {6436},

abstract = {Chemogenetics enables noninvasive chemical control over cell populations in behaving animals. However, existing small-molecule agonists show insufficient potency or selectivity. There is also a need for chemogenetic systems compatible with both research and human therapeutic applications. We developed a new ion channel-based platform for cell activation and silencing that is controlled by low doses of the smoking cessation drug varenicline. We then synthesized subnanomolar-potency agonists, called uPSEMs, with high selectivity for the chemogenetic receptors. uPSEMs and their receptors were characterized in brains of mice and a rhesus monkey by in vivo electrophysiology, calcium imaging, positron emission tomography, behavioral efficacy testing, and receptor counterscreening. This platform of receptors and selective ultrapotent agonists enables potential research and clinical applications of chemogenetics.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Gomez2017,

title = {Chemogenetics revealed: DREADD occupancy and activation via converted clozapine.},

author = {Juan L Gomez and Jordi Bonaventura and Wojciech Lesniak and William B Mathews and Polina Sysa-Shah and Lionel A Rodriguez and Randall J Ellis and Christopher T Richie and Brandon K Harvey and Robert F Dannals and Martin G Pomper and Antonello Bonci and Michael Michaelides},

url = {https://www.ncbi.nlm.nih.gov/pubmed/28774929},

doi = {10.1126/science.aan2475},

issn = {1095-9203 (Electronic); 0036-8075 (Linking)},

year  = {2017},

date = {2017-08-04},

urldate = {2017-08-04},

journal = {Science},

volume = {357},

number = {6350},

pages = {503--507},

address = {Biobehavioral Imaging and Molecular Neuropsychopharmacology Unit, National Institute on Drug Abuse (NIDA) Intramural Research Program, Baltimore, MD 21224, USA.},

abstract = {The chemogenetic technology DREADD (designer receptors exclusively activated by designer drugs) is widely used for remote manipulation of neuronal activity in freely moving animals. DREADD technology posits the use of "designer receptors," which are exclusively activated by the "designer drug" clozapine N-oxide (CNO). Nevertheless, the in vivo mechanism of action of CNO at DREADDs has never been confirmed. CNO does not enter the brain after systemic drug injections and shows low affinity for DREADDs. Clozapine, to which CNO rapidly converts in vivo, shows high DREADD affinity and potency. Upon systemic CNO injections, converted clozapine readily enters the brain and occupies central nervous system-expressed DREADDs, whereas systemic subthreshold clozapine injections induce preferential DREADD-mediated behaviors.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}