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

  • CNS Neurosci Ther. 2026 Jan;32(1):e70732. doi: 10.1002/cns.70732.
Yan Zhao  1 ,  Yixin Fu  2 ,  Tianhao Liu  2 ,  Zanhao Yang  2 ,  Zhengzhong Yang  2 ,  Bingqing Chen  2 ,  Lipeng Zhou  2 ,  Juntao Yang  2 ,  Duo Chen  3 ,  Xiaojiao Han  2 ,  Ying Tang  4 ,  Jiang-Hong Ye  5 ,  Chao-Yu Miao  1 ,  Rao Fu  2  6
Affiliations
  • 1. Department of Pharmacology, Naval Medical University/Second Military Medical University, Shanghai, China.
  • 2. Department of Anatomy, School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Sun Yat-Sen University, Shenzhen, Guangdong, China.
  • 3. Department of Anesthesiology, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China.
  • 4. Clinical Skills Training Center, School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Sun Yat-Sen University, Shenzhen, Guangdong, China.
  • 5. Department of Anesthesiology, Pharmacology, Physiology & Neuroscience, Rutgers, The State University of New Jersey, New Jersey Medical School, Newark, New Jersey, USA.
  • 6. Shenzhen Key Laboratory for Systems Medicine in Inflammatory Diseases, School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Sun Yat-Sen University, Shenzhen, China.
PMID: 41492821 DOI: 10.1002/cns.70732
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.

Keywords
alcohol use disorder; alcohol withdrawal; histamine H3 receptor (H3R); lateral habenula (LHb); negative mood; pitolisant.
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