The intentional exposure to volatile organic solvents in order to achieve a state of intoxication constitutes a health problem throughout the world, which mainly affects children and adolescents. In spite of its importance, the study of the molecular mechanisms of action of abused solvents was not addressed until lately. This paper reviews some of the relevant recent advances in this field. During the last three decades, behavioral studies have provided evidence that solvents have similar effects on the central nervous system as depressant drugs such as ethanol, barbiturates and benzodiazepines. Based on this evidence, it was first hypothesized that abused solvents could share some of the cellular mechanisms of action of other depressant drugs. Using recombinant receptors expressed in Xenopus oocytes and the two-electrode voltage clamp technique, Cruz et al. studied the effects of several commonly abused solvents on the cationic currents elicited through glutamatergic receptors. These studies showed that toluene produces a non-competitive, rapid, complete and reversible inhibition of NMDA receptor ion currents. The NR1/2B NMDA receptor subtype is more sensitive that the NR1/2A and NR1/2C subtypes. The inhibitory concentration at 50% (IC50) for toluene on NR1/2B receptors is 0.17mM. At the same range of concentrations, toluene has no effect on non-NMDA (AMPA and kainate) receptors. These findings were soon extended to 1,1,1, trichlorothane (TCE) and a series of alkylbenzenes (benzene, m-xylene, ethylbenzene and propylbenzene), all of which were found to inhibit NMDA-induced currents in a dose-dependent manner, at sub-millimolar concentrations. Interestingly, flurothyl, a convulsive solvent with physicochemical properties similar to those of many abused solvents (high lipophilicity and volatility), has no effect on glutamatergic receptors. It is worth noting that the range of solvent concentrations tested in these studies does not affect the stability of cellular membranes. Taken together, these findings strongly suggested a specificity of action for abused solvents, which encouraged further research on the effects these compounds at other neurotransmitter receptors. Thus, in 2000, Beckstead and coworkers studied the effects of toluene, TCE and trichloroethylene on the ionic currents mediated by GABA(A) and glycine receptors in Xenopus oocytes. They found out that all three solvents increase these currents at 0.2 - 09mM, acting as allosteric modulators of these channels. More recently, Bale et al. showed that toluene has also inhibitory effects on different cholinergic nicotinic receptor subtypes in vitro, the most sensitive of which is the alpha(4),beta(2) receptor subtype (toluene's IC50 = 0.2mM). Moreover, in cultured neuronal cells, toluene inhibits the calcium response to acetylcholine with an IC50 = 0.5mM. In a recent paper, Lopreato and coworkers reproted that toluene, TCE and trichloroethylene increase the ionic currents activated by serotonin through 5-HT3 receptors at concentrations lower that 1 mM. All these effects occur at a range of concentrations thta does not compromise the integrity of cell membranes and that is relevant to human exposure to solvents during intoxication. The actions of abused solvents on voltage-gated ion channels have also been a focus of attention in the last few years. According to Tillar et al. toluene inhibits Ca2+ currents in KCl-depolarized pheochromocytoma cells, but other authors have found that toluene might activate these channels. Another solvent, TCE, reduces Ca2+ currents in dorsal root ganglion cells, although this effect is only seen at relatively high concentrations (IC50 = 4-6 mM). In a recent report, our group showed that toluene blocks human cardiac sodium channels transfected into Xenopus oocytes. This effect occurs at micromolar concentrations and depends on the dose and on the frequency of stimulation of the channel. The so far described mechanisms of action of solvents are similar to those described for alcohol. A compromise of the potencies of toluene and ethanol to produce similar effects reveals that toluene is, in general, 10-1000 times more potent that ethanol. In the last years an increasing interest has emerged on the effects of abused solvents in the mesolimbic dopaminergic system. According to several researches toluene, like other drugs of abuse, increases dopamine release in selected brain areas. Finally, the information of free radicals has been proposed as a mechanism that might be involved in the harmful chronic effects of solvents, such as neurotoxicity. In summary, basic research on the cellular effects of solvents has experienced an important increase in the last decade. As a result, it is now clear that these substances do not act through a non-specific membrane fluidization as it was once proposed, but through interactions with several receptor systems at sub-millimolar concentrations.
