Pitolisant Inhibits Alcohol Drinking and Improves Withdrawal Negative Affect Through Lateral Habenula Histaminergic Signaling in Mice

Sep 29, 2026

Uploaded by Adam

Alcohol use disorder is a chronic relapsing condition driven by compulsive drinking and withdrawal-related negative affect. Histamine signaling via the histamine H3 receptor may shape alcohol-related behaviors, motivating this study of pitolisant, an FDA-approved H3R antagonist. In adult C57BL/6J mice exposed to acute or chronic intermittent ethanol, pitolisant pretreatment was followed by behavioral, histologic, and molecular analyses. Results indicate reduced ethanol reward and intake, improved 24-h withdrawal anxiety/depression-like behaviors, and mechanistic changes in lateral habenula neuronal signaling.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages15

Reading Time38 min

AccessFree to download

ABSTRACT

Introduction

Materials and Methods

Results

Behavioral effects

Withdrawal-related negative affect

Lateral habenula signaling mechanisms

Discussion

Conclusion

CNS Neuroscience & Therapeutics |
ORIGINAL ARTICLE OPEN ACCESS
Pitolisant Inhibits Alcohol Drinking and Improves Withdrawal Negative Affect Through Lateral Habenula Histaminergic Signaling in Mice
Yan Zhao1 | Yixin Fu2 | Tianhao Liu2 | Zanhao Yang2 | Zhengzhong Yang2 | Bingqing Chen2 | Lipeng Zhou2 | Juntao Yang2 Duo Chen3 | Xiaojiao Han2 | Ying Tang4 | Jiang-Hong Ye5 | Chao-Yu Miao1 | Rao Fu2,6
1Department of Pharmacology, Naval Medical University/Second Military Medical University, Shanghai, China | 2Department of Anatomy, School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Sun Yat-Sen University, Shenzhen, Guangdong, China | 3Department of Anesthesiology, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China | 4Clinical Skills Training Center, School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Sun Yat-Sen University, Shenzhen, Guangdong, China | 5Department of Anesthesiology, Pharmacology, Physiology & Neuroscience, Rutgers, The State University of New Jersey, New Jersey Medical School, Newark, New Jersey, USA | 6Shenzhen Key Laboratory for Systems Medicine in
Inflammatory Diseases, School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Sun Yat-Sen University, Shenzhen, China Correspondence: Rao Fu ([furao5@mail.sysu.edu.cn](furao5@mail.sysu.edu.cn))
Received: 14 August 2025 | Revised: 15 November 2025 | Accepted: 19 December 2025
Keywords: alcohol use disorder | alcohol withdrawal | histamine H3 receptor (H3R) | lateral habenula (LHb) | negative mood | pitolisant | | | --- | --- | | ABSTRACT
Background: Alcohol use disorder (AUD) is a chronic condition marked by compulsive drinking and withdrawal-related negative affect. Histamine (HA) signaling, particularly via the histamine H3 receptor (H3R), may modulate alcohol-related behaviors. We investigated the effects of pitolisant, an FDA-approved H3R antagonist, on ethanol (EtOH)-related behaviors in mice. Method: Adult male C57BL/6J mice underwent acute or chronic (2 or >8 weeks) intermittent alcohol exposure. Pitolisant pretreatment was administered, and then pharmacological behavior, histologic, and molecular assays were conducted.
Result: Pitolisant administration reduced acute EtOH-induced locomotor activation, conditioned place preference, and sedative effects, and also curtailed EtOH intake. It alleviated anxiety and depression-like behavior during 24-h withdrawal (Post-EtOH) . Mechanistically, the Post-EtOH condition was featured by complicated brain cFos expression mapping, including elevated cFos,[HA] and [glutamine]/[glutamate] ratio in the lateral habenula (LHb) . However, systemic pitolisant treatment significantly increased [norepinephrine]/[normetanephrine] ratio, and restored the diminished phosphorylated CREB and BDNF levels in the LHb. Intra-LHb H2R antagonist cimetidine infusion partly blocked the pitolisant therapeutic effect on alcohol-related behavior. Conclusion: These findings highlight the HAergic system as a critical regulator of alcohol-related behaviors. The LHb HA signaling and norepinephrine neurotransmission might underlie pitolisant's potential novel therapeutic strategy for AUD. | | | 1 | Introduction | withdrawal-induced negative affect [1] . Current FDA-approved | | Alcohol use disorder (AUD) is a chronic relapsing condition marked by compulsive alcohol consumption, loss of control, and | treatments, such as naltrexone and acamprosate, offer limited efficacy and fail to adequately address affective symptoms, highlighting the need for novel therapeutic targets [2] . | | Yan Zhao and Yixin Fu authors contributed equal to this work. | | | This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
© 2026 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd. | | CNS Neuroscience & Therap

FAQs

What is pitolisant, and why was it tested for alcohol-related behaviors?

Pitolisant is an FDA-approved histamine H3 receptor (H3R) inverse agonist. It was tested because histamine signaling, particularly through H3R, may regulate behaviors linked to alcohol use and withdrawal.

How does pitolisant affect ethanol-induced behaviors in mice?

Pitolisant reduced acute ethanol-related locomotor activation, conditioned place preference, sedative effects, and also curtailed ethanol intake.

What mechanisms involving the lateral habenula were implicated during withdrawal?

The 24-hour post-ethanol condition showed altered cFos expression patterns in the lateral habenula, alongside changes in CREB/BDNF signaling. Pitolisant restored diminished phosphorylated CREB and BDNF levels, and intra-LHb cimetidine partially blocked its therapeutic effect.

Sep 29, 2026

Uploaded by Adam