About

Marco Bortolato, M.D., Ph.D., joined the UF College of Pharmacy in November 2024 as a professor of cellular and systems pharmacology. He previously served eight years at the University of Utah, four years at the University of Kansas, and seven years at the University of Southern California. A native of Italy, he earned his B.S., M.D., and Ph.D. from the University of Cagliari. His research has focused on translational studies aimed at understanding the pathophysiology of tic disorders (TDs) and other neurodevelopmental disorders, including autism spectrum disorder and disruptive behavior disorders. His key research interest lies in generating animal models of these conditions to develop novel therapies, utilizing behavioral and neurochemical analyses to study their underlying mechanisms. Additionally, he has conducted clinical studies to validate new therapeutic approaches for these disorders.

Research topics

• Psychology
• Biology
• Internal medicine
• Medicine
• Psychiatry
• Genetics
• Neuroscience
• Medical emergency
• Pharmacology
• Clinical psychology
• Endocrinology
• Developmental psychology

Selected publications

• Targeting serotonin 5-HT2A receptors in the treatment of aggression: From antipsychotics to psychedelics

  Aggression and Violent Behavior · 2026-02-10

  articleSenior authorCorresponding
  PublisherDOI

• Sleep deprivation impairs information processing via dysregulation of chloride homeostasis in the prefrontal cortex

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-03-18

  articleOpen accessSenior authorCorresponding

  Sleep deprivation (SD) impairs information processing through alterations of prefrontal cortex (PFC) function, yet the molecular underpinnings of this process remain poorly understood. We previously showed that SD disrupts sensorimotor gating by elevating prefrontal levels of the neurosteroid allopregnanolone (AP), a positive allosteric modulator of GABA-A receptors. Here we identify a complementary, mechanistically independent process whereby SD alters GABA-A currents in the PFC of mice and rats. SD reduced membrane expression of the chloride exporter KCC2, leading to intracellular chloride accumulation and a depolarizing shift in GABA-A receptor reversal potential that weakened GABAergic inhibition. Pharmacological normalization of chloride homeostasis with bumetanide fully rescued SD-induced deficits in sensorimotor gating and information encoding. SD also upregulated BDNF, and intra-PFC antagonism of its receptor TrkB restored KCC2 expression and normalized information processing, identifying BDNF-TrkB signaling as an upstream driver of chloride dysregulation. Notably, blocking AP synthesis rescued behavioral deficits without correcting chloride imbalance, confirming mechanistic independence. Finally, combined administration of AP and a KCC2 blocker produced information-processing deficits akin to those induced by SD. These findings identify TrkB-dependent disruption of prefrontal chloride homeostasis as a druggable mechanism underlying sleep loss-induced cognitive dysfunction.

  PublisherOA PDFDOI

• Prefrontal 5-HT _2A receptors directly contribute to tic ontogeny: translational evidence

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-12-29

  articleOpen accessSenior authorCorresponding

  Abstract Tourette syndrome (TS) is a neuropsychiatric disorder characterized by motor and vocal tics and frequently accompanied by comorbidities such as obsessive-compulsive disorder (OCD) and pathological aggression. Although approved pharmacotherapies often reduce tic severity, they frequently cause adverse effects and are insufficient for managing comorbid symptoms, underscoring the need for improved treatments. Recent evidence indicates that the serotonin 5-HT 2A receptor (5-HT 2A R) antagonist pimavanserin reduces tic severity and improves quality of life, yet its mechanism of action in TS remains unclear. Here, we combine postmortem human and preclinical approaches to gain insight into the role of 5-HT 2A Rs in TS. Western-blot analyses of postmortem prefrontal cortex (PFC) samples obtained from individuals with TS revealed a pronounced, male-specific elevation of 5-HT 2A R protein levels in Brodmann Area (BA) 10. We then tested pimavanserin and the selective 5-HT 2A R antagonist volinanserin in two mouse models of TS: D1CT-7 transgenic mice and mice with early-life depletion of striatal cholinergic interneurons. Systemic administration of pimavanserin (1–2 mg·kg⁻¹, IP) or volinanserin (0.1–0.3 mg·kg⁻¹, IP) robustly reduced tic-like movements and stereotypies in both models. Local infusion of pimavanserin into the medial PFC, but not the dorsal striatum, recapitulated these effects, indicating a cortical locus of action. Pimavanserin also reduced resident-intruder aggression, but not locomotion or anxiety-like behavior. Together, these findings identify elevated prefrontal 5-HT 2A Rs as a key mechanistic contributor to TS and a promising therapeutic target for individuals with TS and pathological aggression.

  PublisherOA PDFDOI

• Prefrontal 5α-reductase 2 mediates male-specific acute stress response

  Science Advances · 2025-01-22 · 5 citations

  articleOpen accessSenior authorCorresponding

  A key response to acute stress is the increased brain synthesis of the neurosteroid allopregnanolone (AP). Although the rate-limiting step of this reaction is catalyzed by 5α-reductase (5αR), the role of its two primary isoenzymes, 5αR1 and 5αR2, in stress reactivity remains unclear. Here, we found that acute stress led to increased levels of 5αR2, but not 5αR1, in the medial prefrontal cortex (mPFC) of male, but not female, rats. Down-regulation of 5αR2 in the mPFC significantly reduced stress response in males, and similar sexual dimorphic effects were observed in a novel line of 5αR2 knockout rats. Notably, 5αR1 regulated baseline AP synthesis, whereas 5αR2 enabled AP production under stress. Acute AP administration restored stress response in 5αR2 knockdown rats. Single-nucleus transcriptomics showed that 5αR2 enabled stress-induced protein translation in neurons and glia. These results highlight the crucial role of 5αR2 in mediating sex-specific differences in acute stress reactivity.

  PublisherDOI

• The role of neuroactive steroids in psychiatric and neurological disorders: Neurobiology and therapeutic perspectives

  Neuroscience & Biobehavioral Reviews · 2025-10-24 · 5 citations

  articleOpen accessSenior authorCorresponding
  PublisherOA PDFDOI

• Tic-related behaviors in Celsr3 mutant mice are contributed by alterations of striatal D3 dopamine receptors

  Molecular Psychiatry · 2025-03-28 · 7 citations

  articleSenior author
  PublisherDOI

• Decoding the bidirectional links between alcohol misuse and aggression: toward a unified translational framework

  Psychopharmacology · 2025-10-31 · 2 citations

  articleCorresponding
  PublisherDOI

• Pregnenolone Reduces L‐Dopa‐Induced Dyskinesias in Female Parkinsonian Monkeys

  Movement Disorders · 2025-07-05

  articleOpen access

  BACKGROUND: Pregnenolone is the first neurosteroid synthesized from cholesterol in the brain. Previous studies showed that it reduces the development of levodopa (L-dopa)-induced dyskinesias (LIDs) in rat models of Parkinson's disease (PD). OBJECTIVE: To examine whether pregnenolone mitigates established LIDs in a non-human primate model. METHODS: Ovariectomized female macaques, modeling the postmenopausal hormonal status of most women with PD, were lesioned with MPTP and treated with L-dopa to induce LIDs. Pregnenolone was administered subcutaneously (SC) at 6 or 18 mg/kg or orally (36 mg/kg). RESULTS: Pregnenolone reduced established LIDs in MPTP-lesioned monkeys while preserving L-dopa's antiparkinsonian effects. The antidyskinetic effect was dose-dependent, with the greatest reduction observed at 18 mg/kg SC, followed by 6 mg/kg SC, and a lesser effect at 36 mg/kg orally, likely due to first-pass metabolism. CONCLUSIONS: Pregnenolone reduces established LIDs in parkinsonian monkeys and may represent a safe, novel therapeutic candidate for dyskinesia treatment in PD. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

  PublisherOA PDFDOI

• An exploratory analysis of 5‐alpha reductase inhibitors and risk of opioid use disorder among male Medicare beneficiaries receiving prescription opioid medications

  American Journal on Addictions · 2025-07-13

  articleOpen access

  BACKGROUND: Opioid use disorder (OUD) imposes a significant socioeconomic burden, highlighting the need for new interventions. OBJECTIVE: This study investigated whether exposure to 5-alpha reductase inhibitors (5αRIs) is associated with a lower risk of developing OUD. METHODS: A cohort study was conducted using Medicare data from 2017 to 2019. Male subjects identified as receiving at least one opioid medication were propensity score matched based on exposure to a 5αRI medication. The primary outcome of interest was a diagnosis of OUD occurring following opioid exposure. Additionally, the study compared the number of morphine milliequivalents (MME) and the count of opioid prescription claims between the groups. RESULTS: We identified 467,399 subjects who had received at least one opioid prescription. Among these, 19,176 beneficiaries were receiving a 5αRI before opioid medication exposure and were matched 1:1 to non-users. Use of 5αRI was associated with a reduced risk of OUD (OR = 0.63, 95% CI: 0.53-0.75). MME for subjects exposed to 5αRI was significantly lower than for those without 5αRI exposure (p < .001). Furthermore, there was a significant difference in the number of opioid prescription claims between the groups, with those taking a 5αRI having an average of 6.0 (SD = 10.1) prescriptions as compared to 6.7 (SD = 13.0) for those not receiving a 5αRI (p < .001). CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: This first of its kind in humans study suggests that concomitant use of opioids and 5αRI is associated with a reduction in OUD and maybe a preventive therapy for patients at risk of OUD. Our findings align with animal models that have shown similar findings.

  PublisherOA PDFDOI

• Sex-Dependent Effects of <i>MAOA</i> Genotypes on the Relations Between Childhood Sexual Abuse, Aggression, and Cannabis Use in Emerging Adults

  Journal of Child Sexual Abuse · 2025-05-19

  articleOpen accessSenior author

  in moderating the relationship between trauma, substance use, and aggression. If validated by further studies, these results could inform the development of targeted pharmacological and behavioral treatments for individuals with trauma histories and genetic predispositions to aggression.

  PublisherOA PDFDOI

Recent grants

• Mechanisms of information-processing and executive deficits caused by sleep deprivation

  NIH · $511k · 2023–2025

• Exploring the role of neuroactive steroids in Tourette syndrome

  NIH · $459k · 2022–2025

• Exploring steroid-based therapies to reduce opioid abuse

  NIH · $419k · 2020–2023

• Exploring the role of neurosteroids in tic modulation

  NIH · $428k · 2018–2021

• NIH Grant R21HD070611

  NIH · $434k · 2014

Frequent coauthors

• Roberto Frau

  University of Cagliari

  98 shared

• Sean C. Godar

  University of Utah

  50 shared

• Paola Devoto

  University of Cagliari

  50 shared

• Laura J. Mosher

  University of Utah

  34 shared

• Francesco Marrosu

  University of Cagliari

  31 shared

• Jean C. Shih

  University of Southern California

  29 shared

• Paula J. Fite

  Temple University

  29 shared

• Gabriele Floris

  Indiana University School of Medicine

  29 shared