Volatile solvents as drugs of abuse: focus on the cortico-mesolimbic circuitry

Abstract

Volatile solvents such as those found in fuels, paints, and thinners are found throughout the world and are used in a variety of industrial applications. However, these compounds are also often intentionally inhaled at high concentrations to produce intoxication. While solvent use has been recognized as a potential drug problem for many years, research on the sites and mechanisms of action of these compounds lags behind that of other drugs of abuse. In this review, we first discuss the epidemiology of voluntary solvent use throughout the world and then consider what is known about their basic pharmacology and how this may explain their use as drugs of abuse. We next present data from preclinical and clinical studies indicating that these substances induce common addiction sequelae such as dependence, withdrawal, and cognitive impairments. We describe how toluene, the most commonly studied psychoactive volatile solvent, alters synaptic transmission in key brain circuits such as the mesolimbic dopamine system and medial prefrontal cortex (mPFC) that are thought to underlie addiction pathology. Finally, we make the case that activity in mPFC circuits is a critical regulator of the mesolimbic dopamine system's ability to respond to volatile solvents like toluene. Overall, this review provides evidence that volatile solvents have high abuse liability because of their selective effects on critical nodes of the addiction neurocircuitry, and underscores the need for more research into how these compounds induce adaptations in neural circuits that underlie addiction pathology.

Figure 1

Trends in 30-day prevalence for voluntary use of various drugs among American 8th grade students. Solvents are indicated by triangles with the final point being encircled. Data from Johnston et al (2013).

Figure 2

Toluene dose-dependently alters the activity of a wide range of ion channels. Color bar indicates relative range of concentrations of toluene with odor threshold and huffing concentration indicated. Position of ion channel along the x-direction indicates relative sensitivity of individual ion channels to toluene while position along the y-direction indicates inhibition (below dotted line) or potentiation (above dotted line). Toluene has no appreciable effect on ion channels that overlay the dotted line. Underline indicates data collected in the author's laboratory.

Figure 3

Toluene enhances excitatory transmission onto mesolimbic neurons. (a) Example of a VTA neuron that expresses red retrobeads. (b) Representative example of a recorded neuron in the VTA that is TH+. (c) Summary effects of in vivo toluene on AMPA/NMDA ratio from mesoaccumbens core neurons. (i) Dose-depedency of toluene's actions on the AMPA/NMDA ratio (*p<0.05). (ii) Toluene's effect persists for at most 6 days (*p<0.05). (iii) Representative AMPA and NMDA traces from mesoaccumbens core neurons. (d) Summary of effects on mesolimbic shell neurons. (i) Toluene's effect on AMPA/NMDA ratio persists at least 21 days (*p<0.05). (ii) Representative AMPA and NMDA traces from mesolimbic shell neurons. From Beckley et al, 2013; with permission from the Journal of Neuroscience.

Figure 4

The medial prefrontal cortex inhibits the mesolimbic DA pathway through several different transsynaptic circuits. This wiring diagram is overlaying a sagittal section ∼1 mm from midline, stained with cresyl violet Nissl stain (Paxinos and Watson, 2005). Black—glutamate, red—GABA, blue—dopamine, green—mix (acetylcholine, substance P). IPN, interpeduncular nucleus; LDTg, lateral dorsal tegmentum; LHb, lateral habenula; mHB, medial habenula; mPFC, medial prefrontal cortex; NAc, nucleus accumbens; RMTg, rostromedial tegmentum; VTA, ventral tegmental area.