# 4‐HIAA Blocks Methamphetamine‐Induced Conditioned Place Preference in Mice Through Modulation of the 5‐HT Pathway in the Nucleus Accumbens

## TL;DR

4-HIAA, a psilocin metabolite, crosses the blood-brain barrier and reduces methamphetamine's rewarding effects in mice by affecting serotonin in the nucleus accumbens.

## Contribution

This study reveals 4-HIAA's novel ability to block methamphetamine-induced CPP through serotonin pathway modulation in the nucleus accumbens.

## Key findings

- 4-HIAA crosses the blood–brain barrier and inhibits methamphetamine-induced CPP acquisition.
- 4-HIAA promotes extinction and prevents relapse of methamphetamine-induced CPP in mice.
- 4-HIAA's effects correlate with altered serotonin expression in the nucleus accumbens.

## Abstract

4‐hydroxyindole‐3‐acetic acid (4‐HIAA) is a metabolite of psilocin. Here, we explored the ability of 4‐HIAA to cross the blood–brain barrier and its potential effects on methamphetamine (METH)‐induced conditioned place preference (CPP) in mice. Treatment with 1‐mg/kg 4‐HIAA inhibited CPP formation during the acquisition phase, promoted METH extinction and inhibited METH relapse. Furthermore, the regulatory effect of 4‐HIAA on METH was underscored by altered 5‐HT expression in the nucleus accumbens. Collectively, our findings provide novel insights into the molecular mechanisms of the 4‐HIAA‐induced blockade of the acquisition, extinction and reinstatement of METH‐induced CPP.

4‐HIAA crosses the blood–brain barrier. Treatment (1‐mg/kg) inhibited CPP acquisition, promoted extinction and prevented relapse. These behavioural effects were associated with changes in nucleus accumbens 5‐HT expression.