Translational Neuropharmacology Unit

The Translational Neuropharmacology Unit within Dr. Zanos’ lab serves as a dynamic nexus at the forefront of neuropharmacology research, specializing in unraveling the complex interplay between substance use disorders and mood-related conditions using rodent models. With a dedicated focus on translational methodologies, including drug repurposing, this unit aims to bridge the gap between preclinical investigations and clinical applications by specifically understanding the complex neurobiological mechanisms underlying comorbidities associated with substance use and mood disorders. Through meticulously designed studies, our team explores the intricate landscape of neuropharmacology, uncovering novel insights into the underlying mechanisms, potential therapeutic interventions, and behavioral manifestations of brain diseases.

Team Members (more details in the Team Members section)

 
 
 
 

 

Current Projects

Efficacy of Ketamine’s Hydroxynorketamine (HNK) Metabolites in Drug Addiction: Our lab investigates (2R,6R)-HNK’s potential in curbing maladaptive responses and relapse in opioid-seeking behaviors during abstinence. Utilizing rodent models, they explore addictive behaviors and create relevant models to comprehend the interplay among stress, drug exposure, and emotional disturbances.

Role of Cytochrome P450 Enzymes in Major Depression: Focusing on depression as a global health concern, the project delves into the functional and molecular mechanisms underlying depression. Specifically, it examines Cytochrome P450 enzymes, particularly their impact on oxidative stress and the generation of bioactive metabolites (20-HETE and EET). This research aims to unveil the neuroprotective and anti-depressant potential of regulating CYPs, both in vitro and in vivo.

Elucidating Ketamine’s Antidepressant Efficacy Using Human-Derived Neural Organoids and Implications for Neural Tube Defects: This project aims to understand how rapid-acting antidepressants, including ketamine, impact neural tube defects during early fetal development. By utilizing human stem cell-derived neural organoids, the study investigates structural, genetic, and protein-level changes induced by various antidepressants. Additionally, it explores the roles of NMDA and AMPA receptors via CRISPR-Cas9 techniques, aiming to uncover how these receptors influence neural tube formation and whether rapid-acting antidepressants like ketamine can mitigate defects caused by receptor knockout.

Identify molecular pathways characterizing protracted opioid withdrawal using RNA sequencing: In our research, we are performing bulk mRNA sequencing and transcriptomic analysis using mouse brain and plasma samples to uncover the precise and unique molecular signatures associated with protracted opioid abstinence. Through this cutting-edge approach, we are examining the comprehensive mRNA profiles within the mouse brain and plasma, enabling us to capture the changes occurring at a genetic level during extended periods of opioid abstinence. By identifying these molecular signatures, we aim to unravel the underlying mechanisms and alterations in gene expression patterns that characterize protracted abstinence. This method empowers us to identify key genetic markers, pathways, and biological processes that play pivotal roles in the prolonged withdrawal phase of opioid addiction cycle, offering invaluable insights into the neurobiological adaptations occurring during this critical period of opioid cessation.

 

Publications (last two years)

 
  • Michael, A.*, Onisiforou, A.*, Georgiou, P., Koumas, M., Mammadov, E., Zanos, P. (2R,6R)-hydroxynorketamine facilitates extinction and prevents emotional impairment and stress-induced reinstatement in morphine abstinent mice. bioRxiv (2023), 12.07.570550. * Equal Contribution. https://doi.org.10.1101/2023.12.07.570550.
 
  • Onisiforou, A., Georgiou, P., Zanos, P. Role of group II metabotropic glutamate receptors in the antidepressant actions of ketamine. Pharmacology, Biochemistry and Behaviour, 2023, In Press (Vol. 223). doi: 10.1016/j.pbb.2023.173531. https://doi.org/10.1016/j.pbb.2023.173531.
 
  • Zanos, P.*, Brown K.A., Georgiou, P., Yuan, P., Zarate, C.A., Thompson, S., Gould, T.D. NMDA receptor activation-dependent antidepressant-relevant behavioral and synaptic actions of ketamine. Journal of Neuroscience, 2023, 43, 1038-1050. * Corresponding Author. https://doi.org/10.1523/JNEUROSCI.1316-22.2022.
 
  • Brown K.A., Zanos, P., Powels, C.F., Fix, C.J., Michaelides, M., Pereira, E.FR., Moaddel, R., Gould, T.D. Ketamine preservative benzethonium chloride potentiates hippocampal synaptic transmission and binds neurotransmitter receptors and transporters. Neuropharmacology, 2023, 225:109403. https://doi.org/10.1016/j.neuropharm.2022.109403.
 
  • Georgiou, P., Zanos, P., Mou, T-C., An, X., Gerhard, D., Dryanovski, I.D., Potter, E.L., Highland, J., Jenne, C., Stewart, B., Pultorak, K., Yuan, P., Powels, C., Lovett, J., Pereira, E., Clark, S., Tonelli, L., Moaddel, R., Zarate, C.A., Duman, R., Thompson, S., Gould, T.D. Experimenters’ sex modulates mouse behaviors and neural responses to ketamine via corticotropin releasing factor. Nature Neuroscience, 2022, 25, 1191-1200. https://doi.org/10.1038/s41593-022-01146-x.
 
  • Moaddel, R., Zanos, P., Farmer, C.A., Kadriu, B., Morris, P., Lovett, J., Acevedo-Diaz, E., Cavanaugh, G., Yuan, P., Yavi, M., Thomas, C., Park, L.T., Ferrucci, L., Gould, T.D., Zarate Jr, C.A. Comparative Metabolomic Analysis in Plasma and Cerebrospinal Fluid of Humans and in Plasma and Brain of Mice Following Antidepressant-dose Ketamine Administration. Translational Psychiatry, 2022, 12, 1-9. https://doi.org/10.1038/s41398-022-01941-x.
 
  • Bonaventura, J., Gomez, J.L., Carlton, M.L., Lam, S., Sanchez-Soto, M., Morris, P.J., Moaddel, R., Kang, H-J., Zanos, P., Gould, T.D., Thomas, C.J., Sibley, D.R., Zarate Jr, C.A., Michaelides, M. Target deconvolution studies of (2R,6R)-hydroxynorketamine: an elusive search. Molecular Psychiatry, 2022, 27, 4144-4156. https://doi.org/10.1038/s41380-022-01673-w.
 
  • Georgiou, P., Zanos, P., Mou, T-C., An, X., Gerhard, D., Dryanovski, I.D., Potter, E.L., Highland, J., Jenne, C., Stewart, B., Pultorak, K., Yuan, P., Powels, C., Lovett, J., Pereira, E., Clark, S., Tonelli, L., Moaddel, R., Zarate, C.A., Duman, R., Thompson, S., Gould, T.D. Experimenter sex modulates mouse biobehavioral and pharmacological responses. BioRxiv, https://doi.org/10.1101/2022.01.09.475572.
 
  • Georgiou, P., Mou, T-C., Potter, L., An, X., Zanos, P., Patton, M., Pultorak, K., Clark, S., Ngyuyen, V., Powels, P., Prokai-Tatrai, K., Merchenthaler, I., Prokai, L., McCarthy, M., Mathur, B., Gould, T.D. Estradiol mediates stress-susceptibility in the male brain. BioRxiv, https://doi.org/10.1101/2022.01.09.475485.
 
  • Highland, J., Morris, P., Konrath, K., Riggs, L., Hagen, N., Zanos, P., Powels, C., Moaddel, R., Thomas, C., Wang, A., Gould, TD. Hydroxynorketamine Pharmacokinetics and Antidepressant Behavioral Effects of (2,6)- and (5R)‑Methyl-(2R,6R)‑hydroxynorketamines. ACS Chemical Neuroscience. 2022, 4, 510-523. https://doi.org/10.1021/acschemneuro.1c00761.
 
  • Troppoli, T., Zanos, P., Georgiou, P., Gould, TD., Rudolph, U., Thompson, S. Negative allosteric modulation of GABAARs at α5 subunit-containing benzodiazepine sites reverses stress-induced anhedonia and weakened synaptic function in mice. Biological Psychiatry, 2022, 92, 216-226. https://doi.org/10.1016/j.biopsych.2021.11.024.
 
  • Highland, J., Farmer, C., Zanos, P., Lovett, J., Zarate, CA., Moaddel, R., Gould, TD. Sex-dependent metabolism of ketamine and (2R,6R)-hydroxynorketamine in mice and humans. Journal of Psychopharmacology. 2022, 36, 170-182. https://doi.org/10.1177/02698811211064922.
 

Current Collaborations

 
 
 
 
 
 
 
 
 

Contact

Email: neuropharmlab@ucy.ac.cy

Phone: +357 22-892243

 

 

 

 

 

 

 

 

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