Preclinical characterization of toluene as a non-classical hallucinogen drug in rats: participation of 5-HT, dopamine and glutamate systems

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. This study aims (a) to study toluene's effects on the 5-HT2A-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. 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. 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-HT2A 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. Toluene stimulates 5HT(2A) and 5HT(2C) receptors, and increases 5-HT and DA levels. These actions are similar to those produced by ketamine and involve activation of a complex neurotransmitter network that includes NMDA receptor antagonism.