2. Academic Validation
  3. Pitolisant Inhibits Alcohol Drinking and Improves Withdrawal Negative Affect Through Lateral Habenula Histaminergic Signaling in Mice

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

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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