Rationale

Toluene is a misused inhalant with hallucinogenic properties and complex effects. Toluene blocks N-methyl-d-aspartate (NMDA) receptors, releases dopamine (DA), and modifies several neurotransmitter levels; nonetheless, the mechanism by which it produces hallucinations is not well characterized.

Objectives

This study aims (a) to study toluene’s effects on the 5-HT 2A -mediated head-twitch response (HTR), dopamine (DA), and serotonin (5-HT) tissue levels in discrete brain regions; (b) to compare the actions of toluene, ketamine, and 1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane (DOI) on HTR; and (c) to study the pharmacological blockade of toluene’s and ketamine’s effects by selective drugs.

Methods

Independent groups of rats inhaled toluene (500–12,000 ppm) for 30 min during which the occurrence of serotonergic signs was analyzed. Brains were obtained after exposure to determine DA and 5-HT levels by HPLC.

Results

Toluene concentration-dependently induced HTR. Other serotonin syndrome signs were evident at high concentrations. Toluene (4000 and 8000 ppm), and ketamine (3 and 10 mg/kg), significantly increased 5-HT levels in the frontal cortex (FC) striatum, hippocampus, and brain stem, as well as DA levels in the striatum and FC. Pretreatment with ketanserin (5HT 2A/2C receptor antagonist), M100907 (selective 5-HT 2A receptor antagonist), D-serine (co-agonist of the NMDA receptor glycine site), and haloperidol (D 2 receptor antagonist) significantly decreased toluene’s and ketamine’s actions. The 5HT 1A receptor antagonist WAY100635 had no effect.

Conclusion