The predominant route of administration of volatile solvents is through inhalation of fumes, known in street terms as ‘huffing,' or ‘chroming' (Lubman et al, 2008). Toluene is detectable by humans at concentrations as low as 11 p.p.m. (World Health Organization, 2000), and a low-detectable concentration is probably common among other volatile solvents. In contrast, those who intentionally inhale volatile solvents for intoxication usually expose themselves for a short duration (around 15 min) to extremely high vapor concentrations, up to 15 000 p.p.m. (Hathaway and Proctor, 2004).

Toluene likely has the most well-documented pharmacological profile of all the volatile solvents studied. While the majority of the toluene vapor exhaled is unchanged, the rest enters the bloodstream through the alveoli and distributes throughout the body (Garcia, 1996). Ten minutes following initiation of vapor inhalation, the blood concentration of toluene in rats reaches about 60% of maximum, and then drops to around 30% of maximum 40 min following cessation of inhalation (Benignus, 1981). Due to excretion from lungs and metabolism, it is estimated that about 3% of the original vapor concentration of toluene reaches the brain (Benignus et al, 1981).

Toluene acts as a central nervous system depressant, and it is likely that all volatile solvents act similarly, although potency and sites of action may differ between solvent type. Like ethanol, the most commonly used CNS depressant, toluene, benzene, m-xylene, ethylbenzene and 1,1,1-trichloroethane (TCE) dose-dependently and reversibly inhibit NMDA receptors, with a higher potency on GluN1/2B than GluN1/2A receptors (Cruz et al, 1998, 2000). Toluene, TCE, and trichloroethylene (TCY) also enhance GABAA and glycine receptor function (Beckstead et al, 2000, 2001). In the hippocampal CA1 synapses, toluene enhances GABAergic neurotransmission by increasing the intracellular calcium concentration in the presynaptic terminal, leading to an increased release of GABA (MacIver, 2009). While volatile solvents pharmacologically inhibit NMDARs and enhance GABAA activity, prolonged exposure to inhalants leads to a homeostatic process whereby NMDA-mediated currents are enhanced and GABAA currents are diminished (Bale et al, 2005). NMDA and GABAA receptor subunit expression follows this homeostatic response as well, with an increase in GluN1 expression in the medial prefrontal cortex (mPFC), GluN2B in the NAc and VTA, and a decrease in GABAA α1 subunit expression in the VTA and substantia nigra (Williams et al, 2005). Therefore, toluene and likely other volatile solvents bi-directionally affect inhibitory and excitatory synaptic transmission depending on whether exposure is acute or chronic.

While toluene's action on the GABA and glutamate neurotransmitter systems likely underlies much of its CNS depressant effects, toluene has also been shown to act on a number of other ion channels and modulatory processes. Thus, toluene affects synaptic signaling by increasing intracellular levels of calcium in both glutamatergic and GABAergic neurons, and this action is blocked by dantrolene, a ryanodine receptor antagonist, or thapsigargin, a SERCA inhibitor (Beckley and Woodward, 2011; MacIver, 2009), suggesting an interaction with intracellular receptors that gate calcium stores. Toluene also dose-dependently inhibits nicotinic acetylcholine receptors, with α4β2 and α3β2 subtypes being particularly sensitive (Bale et al, 2002). Toluene, along with TCE and TCY and ethanol, also enhances serotonin 5HT3 function (Sung et al, 2000; Lopreato et al, 2003). Toluene's effect on 5HT3 receptors may be important in mediating its rewarding properties, as 5HT3 activation synergizes with systemic administration of ethanol in enhancing extracellular DA in the NAc (Campbell and McBride, 1995), and in alcohol-dependent individuals, ondansetron, a 5HT3 antagonist, reduces BOLD changes due to alcohol cues in the ventral striatum (Myrick et al, 2008). In contrast to ethanol, toluene inhibits the calcium-activated potassium BK channel and also the G-protein coupled inwardly rectifying potassium channel GIRK2 (Del Re et al, 2006). On the other hand, ethanol, anesthetics, toluene, TCE, and tetrachloroethylene, also known as perchloroethylene (PERC), all inhibit voltage-sensitive calcium current-mediated voltage-gated calcium channels (Shafer et al, 2005; Tillar et al, 2002). Toluene also inhibits voltage-gated sodium channels, with cardiac subtypes being more sensitive than those expressed in neurons (Cruz et al, 2003; Gauthereau et al, 2005). This mechanism may relate to an abuser's development of ‘Sudden Sniffing Death Syndrome,' which is a form of cardiac failure resulting from acute, high concentration exposure to volatile solvents (Kurtzman et al, 2001). Toluene has a complex interaction with ATP-sensitive P2X receptors, producing inhibition of P2X2 and P2X4 receptors activated by low, but not maximal, ATP concentrations, and potentiating currents in P2X3 receptors at all tested ATP concentrations (Woodward et al, 2004). Other effects of toluene include inhibition of gap junction connexin channels involved in intercellular communication (Del Re and Woodward, 2005). These diverse actions are summarized in Figure 2 and illustrate the wide range of potential targets for toluene in the CNS. Based on these findings, it can be hypothesized that toluene and other volatile solvents would have profound effects on fast synaptic transmission mediated by calcium-dependent release of neurotransmitters and activation of ligand-gated ion channels with less effect on axonal conduction. Differences in the expression of toluene-sensitive and insensitive targets between brain regions and during development would also be expected to determine the sensitivity of various behaviors or brain processes to volatile solvents. As discussed below, some of these actions have been examined using animal models of drug discrimination/reinforcement and single neuron electrophysiological approaches.