Principal Investigator

​Our laboratory integrates computational structural biology, advanced neuropharmacology, and neurophysiology to elucidate the complex dynamics of cholinergic and dopaminergic neuromodulation underlying substance abuse within basal ganglia microcircuits.

 

I conducted my doctoral studies at the University of Puerto Rico, where I performed biophysical studies on nicotinic acetylcholine receptors (nAChRs) to elucidate the structural and functional mechanisms underlying their molecular dynamics. I learned techniques such as recombinant DNA, molecular biology, confocal microscopy, and electrophysiology in heterologous expression systems. Our work resulted in publications demonstrating that nicotine pharmacodynamics at the α4β2 nAChR depends on the stoichiometric ratio and that lipid-protein interactions are critical for receptor assembly and gating. As part of my thesis work, we also expressed and purified a truncated β2 extracellular binding site with the aim of producing crystals suitable for structural analysis.

 

During my postdoctoral training at Columbia University Medical Center, I shifted my focus from Biophysics to Neurophysiology and Neuropharmacology. I worked on projects aimed at understanding the mechanisms that regulate acetylcholine and dopamine neurotransmission in the striatum. As a result, I developed expertise in ex vivo electrophysiology and electrochemistry, as well as in Igor and Python programming. We conducted studies on the physiological roles of muscarinic acetylcholine receptor subtype 5 (M5R) and dopamine receptor subtype 2 (D2R). We elucidated how M5R internalization modulates dopamine release and developed a novel positive allosteric modulator of M5R. For D2R, we found that signaling in a specific striatal neuron population exclusively modulates discrete limbic-associated behaviors and general movement processes. Additionally, I contributed to a study on glycine-mediated mechanisms of dopaminergic reinnervation in the striatum.

 

Later, I was promoted to Associate Research Scientist, which allowed me to lead my own projects as a principal investigator while continuing my collaborations with other laboratories. Our collaborations demonstrated that D2R in cholinergic interneurons mediates antipsychotic drug-induced catalepsy and that glutamate co-release from dopamine neurons in the ventral tegmental area is required for attribution of motivational salience. In addition, we contributed to the development of false-fluorescent neurotransmitters to study release mechanisms at the single-synapse level. As principal investigator, we published a study showing that α7 nAChRs bind amphetamine and are essential for locomotor effects.

 

This experience broadened my technical expertise in methodologies such as confocal microscopy, calcium imaging, molecular docking, molecular dynamics, and behavioral paradigms. I have also acquired skills in ex vivo two-photon microscopy and have applied my knowledge of electrophysiology and electrochemistry to in vivo recordings. Additionally, I have incorporated photometry into my research work.

 

Operating as an Adjunct Professor at the Institute of Neurobiology, I have implemented all these techniques, aiming to bridge the translational gap between the pharmacodynamics of amphetamine-like stimulants (ATS) and the low efficacy of currently proposed therapeutic approaches based on substitution therapy. Furthermore, our laboratory seeks to fill the lack of knowledge about the specific synergistic molecular mechanisms driving ATS and alcohol co-abuse. By leveraging high-resolution structural models, AI-accelerated drug screening, and protein engineering, coupled with functional insights from transcriptomics and neurophysiological processes, we aim to drive the rational, structure-based design of novel and effective pharmacotherapies for this psychiatric condition.

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​My overall experience has resulted in 12 peer-reviewed publications. These publications have been cited over 586 times (h-index 9). We are currently writing three additional studies (one as first author, one as co-principal investigator, and one as principal investigator) that are expected to be submitted for publication in 2026.

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Past Appointments:

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Associate Research Scientist

Columbia University, New York, NY

Department of Psychiatry

 

Education & Training:​

 

Postdoctoral Research Fellow

T32 Fellowship in Schizophrenia Research

Columbia University, New York, NY

Department of Psychiatry

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Postdoctoral Research Fellow

T32 Training Program in Basic Neuroscience and Addiction

Columbia University, New York, NY

Department of Neurology

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Doctor of Philosophy

Biochemsitry/Biophysics

University of Puerto Rico, Río Piedras, PR

Department of Chemistry

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Bachelor Degree

Chemistry

University of Puerto Rico, Río Piedras, PR

School of Natural Sciences

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High School Diploma

De La Salle School, Bayamón, PR

Class of '92

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Past Support:

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FEMA Fund PW11325
Research Equipment and Materials Support Program
Lizardi-Ortiz, José E (PI)
June 2026
AI-Driven Discovery of Novel Pharmacotherapies for Amphetamine-Type Stimulants.
The primary goal of this project is to employ AI-driven protein conformation prediction and molecular dynamics simulations to identify hidden binding sites in two physiologically relevant signaling targets for ATS use disorder: the Trace Amine-Associated Receptor 1 and the α7 nicotinic acetylcholine receptor.

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Title V Grant Award P031S200104, US Department of Education

Pilot Projects for Established Researchers (PiPs-ER)

Lizardi-Ortiz, José E (PI)

Valdés-Fernández, Bianca N (Co-PI)

05/20/2024-09/30/2025

10/01/2025-06/30/2026 (No-cost Extension)

Structure-activity of Amphetamine-type Stimulants on Nicotinic Receptors.

The major goal of this project is to determine the binding mechanisms of amphetamine-type stimulants in the α7 nAChR/AChBP chimera as a model describing the binding on the native α7 nicotinic receptor

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University of Puerto Rico, Medical Sciences Campus

Deanship of Research Pilot Program

Lizardi-Ortiz, José E (PI)

07/01/2022-06/30/2023

Pharmacological Characterization of Amphetamine-type Stimulants on β2 Nicotinic Receptors.

The major goal of this project is to determine the pharmacological parameters of amphetamine-type stimulants in α4β2, α4α5β2, and α6β2β3 nicotinic receptors as a potential therapeutic approach for psychostimulant addiction.

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5P20GM103642, NIH–National Institute of General Medical Sciences

COBRE Pilot Project Program (CP3)

Lizardi-Ortiz, José E (PI)

07/01/2019-06/30/2022

Role of Nicotinic Alpha 7 Autoreceptors in Striatal Cholinergic Interneurons.

The major goal of this project is the uncovering of an α7-mediated response with potential modulatory action on the mesolimbic circuitry.

 

Ongoing Support:

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