Inhibition of neuronal nicotinic acetylcholine receptors by the abused solvent, toluene

Toluene is a representative example of a class of industrial solvents that are voluntarily inhaled as drugs of abuse. Previous data from this lab and others has shown that toluene modulates the function of N‐methyl‐ D ‐aspartate (NMDA), γ‐aminobutyric acid (GABA) and glycine receptors at concentrations that do not affect non‐NMDA receptors. We utilized two‐electrode voltage‐clamp and whole cell patch‐clamp techniques to assess the effects of toluene on neuronal nicotinic acetylcholine receptors expressed in oocytes and cultured hippocampal neurons. Toluene (50 μ M to 10 m M ) produced a reversible, concentration‐dependent inhibition of acetylcholine‐induced current in Xenopus oocytes expressing various nicotinic receptor subtypes. The α4β2 and α3β2 subunit combinations were significantly more sensitive to toluene inhibition than the α4β4, α3β4 and α7 receptors. Receptors composed of α4 and β2(V253F) subunits showed α4β4‐like toluene sensitivity while those containing α4 and β4(F255V) subunits showed α4β2‐like sensitivity. In hippocampal neurons, toluene (50 μ M to 10 m M ) dose‐dependently inhibited ACh‐mediated responses with an IC 50 of 1.1 m M . Taken together, these results suggest that nicotinic receptors, like NMDA receptors, show a subunit‐dependent sensitivity to toluene and may represent an important site of action for some of the neurobehavioural effects of toluene.British Journal of Pharmacology (2002) 137 , 375–383. doi: 10.1038/sj.bjp.0704874