Vincent S. Setola, PhD

Research Interests

1) Many drugs of abuse (e.g. amphetamine, cocaine, MDMA) and psychiatric medications (e.g., Prozac, Trintellix) exert their actions through monoamine neurotransmitter transporters, such as the dopamine transporter (DAT), the serotonin transporter (SERT), and the norepinephrine transporter (NET). Our group has discovered that mice lacking the protein RGS12 exhibit blunted responses to psychostimulants that target the aforementioned neurotransmitter transporters. For instance, wild-type mice treated with amphetamine exhibit a marked hyperlocomotor response. Mice lacking RGS12 treated with amphetamine exhibit a markedly reduced (compared with wild-type mice) response to amphetamine. The same is true for cocaine. These observations led us to discover that RGS12 is a previously unknown regulator of neurotransmitter transporter function. We are currently conducting studies to elucidate why the absence of RGS12 affects neurotransmitter transporters.

2) Prescription opioid painkillers (morphine, oxycodone, hydrocodone) are among the best treatments for severe pain; however, their addiction liability renders them very high-risk prescription drugs. We have devised an approach that increases the antinociceptive properties of opioid painkillers and decreases (if not eliminates) their rewarding properties in mice. This approach, if translatable to humans, would allow for the use of lower doses of opioid painkillers and the reduction/elimination of their euphoric properties. While our previous studies have focused on an adjuvant called nalfurafine, which is a kappa opioid receptor (KOR)-selective agonist, we are currently exploring adjuvants targeting other receptors.

3) Humans with schizophrenia (SCZ) often develop substance use disorder (SUD). We have mutant mice that are a novel model for features of human SCZ. Specifically, our mutant mice exhibit positive symptoms (e.g., sensorimotor gating deficits), negative symptoms (e.g., reduced social interaction), and cognitive symptoms (e.g., impaired novel object recognition memory) of SCZ. We are studying whether these SCZ-like phenotypes of our mutant mice are “cured” by different classes of antipsychotic medications, as well as potentially novel antipsychotics. We are also trying to understand the molecular mechanisms underlying the SCZ-like phenotypes of these mutant mice. Further, we are assessing whether (and why), like humans with SCZ, our mutant mice are susceptible to the development of SUD.

Publications

Tian G, Bartas K, Hui M, Chen L, Vasquez JJ, Azouz G, Derdeyn P, Manville RW, Ho EL, Fang AS, Li Y, Tyler I, Setola V, Aoto J, Abbott GW, Beier KT. Molecular and circuit determinants in the globus pallidus mediating control of cocaine-induced behavioral plasticity. Neuron 2024:S0896-6273(24)00540-3. Epub ahead of print. PMID: 39153478. DOI: 10.1016/j.neuron.2024.07.018 

PubMed

[2021]

• Zhou Y, Freeman K, Setola V, Cao D, Kaski S, Kreek MJ, Liu-Chen LY.  (2021). Preclinical Studies on Nalfurafine (TRK-820), a Clinically Used KOR Agonist. Handb Exp Pharmacol. 

[2020]

• White AN, Gross JD, Kaski SW, Trexler KR, Wix KA, Wetsel WC, Kinsey SG, Siderovski DP, Setola V. (2020). Genetic deletion of Rgs12 in mice affects serotonin transporter expression and function in vivo and ex vivo. J Psychopharmacol. 34(12):1393-1407.

[2019]

• Kaski SW, White AN, Gross JD, Trexler KR, Wix K, Harland AA, Prisinzano TE, Aubé J, Kinsey SG, Kenakin T, Siderovski DP, Setola V. (2019). Preclinical Testing of Nalfurafine as an Opioid-sparing Adjuvant that Potentiates Analgesia by the Mu Opioid Receptor-targeting Agonist Morphine. J Pharmacol Exp Ther. 371(2):487-499. doi: 10.1124/jpet.118.255661. Epub 2019 Sep 6. PMID: 31492823
• Schroer, A. B., Mohamed, J. S., Willard, M. D., Setola, V., Oestreich, E., & Siderovski, D. P. (2019). A role for Regulator of G protein Signaling-12 (RGS12) in the balance between myoblast proliferation and differentiation. PloS one, 14(8), e0216167.
• Gross JD, Kaski SW, Schmidt KT, Cogan ES, Boyt KM, Wix K, Schroer AB, McElligott ZA, Siderovski DP, Setola V. (2019). Role of RGS12 in the differential regulation of kappa opioid receptor-dependent signaling and behavior. Neuropsychopharmacology. 44(10):1728-1741. doi: 10.1038/s41386-019-0423-7. Epub 2019 May 29. PMID: 31141817
• Purnell, P. R., Addicks, B. L., Zalzal, H. G., Shapiro, S., Wen, S., Ramadan, H. H., Setola, V., & Siderovski, D. P. (2019). Single Nucleotide Polymorphisms in Chemosensory Pathway Genes GNB3, TAS2R19, and TAS2R38 Are Associated with Chronic Rhinosinusitis. International archives of allergy and immunology, 180(1), 72–78.
• Kaski SW, Brooks S, Wen S, Haut MW, Siderovski DP, Berry JH, Lander LR, Setola V. (2019). Four single nucleotide polymorphisms in genes involved in neuronal signaling are associated with Opioid Use Disorder in West Virginia. J Opioid Manag. 15(2):103-109. doi: 10.5055/jom.2019.0491. PMID: 31057342 

[2018]

• Gross JD, Kaski SW, Schroer AB, Wix KA, Siderovski DP, Setola V. (2018). Regulator of G protein signaling-12 modulates the dopamine transporter in ventral striatum and locomotor responses to psychostimulants. J Psychopharmacol. 32(2):191-203. 
• Schroer AB, Gross JD, Kaski SW, Wix KA, Siderovski DP, Vandenbeuch A, Setola V (2018). Development of Full Sweet, Umami, and Bitter Taste Responsiveness Requires Regulator of G protein Signaling-21 (RGS21). Chem. Senses. 43(5):367-378.

[2016]

• Gall BJ, Schroer AB, Gross JD, Setola V, Siderovski DP. (2016) Reduction of GPSM3 expression akin to the arthritis-protective SNP rs204989 differentially affects migration in a neutrophil model. Genes Immun. 17(6):321-7.
• Nicolson SC, Li C, Hirsch ML, Setola V, Samulski RJ. (2016) Identification and Validation of Small Molecules That Enhance Recombinant Adeno-associated Virus Transduction following High- Throughput Screens. J Virol. 27;90(16):7019-31.
• Gall BJ, Wilson A, Schroer AB, Gross JD, Stoilov P, Setola V, Watkins CM, Siderovski DP. (2016) Genetic variations in GPSM3 associated with protection from rheumatoid arthritis affect its transcript abundance. Genes Immun. 17(2):139-47.