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

## TL;DR

Pitolisant, a drug approved for other uses, reduces alcohol drinking and withdrawal symptoms in mice by affecting brain signaling in the lateral habenula.

## Contribution

This study reveals a novel therapeutic mechanism for treating alcohol use disorder via histaminergic signaling in the lateral habenula.

## Key findings

- Pitolisant reduced ethanol-induced locomotor activation, sedation, and alcohol intake in mice.
- The drug alleviated anxiety and depression-like behaviors during alcohol withdrawal.
- Pitolisant restored phosphorylated CREB and BDNF levels in the lateral habenula.

## Abstract

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.

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.

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.

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.

Pitolisant, an FDA‐approved H3R antagonist, counteracts the rewarding and sedative effects of ethanol, reduces alcohol intake, and alleviates the negative affect during withdrawal. This might occur via the antagonism of presynaptic autoreceptors and heteroreceptors H3Rs in the lateral habenula, thereby activating the H2R/p‐CREB/BDNF signaling and modulating norepinephrine neurotransmission.