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.

Negative allosteric modulation of GABAA receptors inhibits facilitation of brain stimulation reward by drugs of abuse in C57BL6/J mice

“…In contrast, Ro15-4513 completely blocked d-methamphetamine, toluene and diazepam- facilitated ICSS. While toluene has positive GABA A modulatory effects (Beckstead et al 2000; Williams et al 2005; Shelton and Nicholson 2013; Beckley and Woodward 2013), d-methamphetamine does not (Hondebrink et al 2011), supporting our hypothesis that negative allosteric GABA A modulation via the BDZ site can strongly affect the reward-related effects of drugs of abuse, regardless of their specific pharmacological mechanism of action.…”

Phenotype-dependent inhibition of glutamatergic transmission on nucleus accumbens medium spiny neurons by the abused inhalant toluene

“…Abused inhalants are substances that are voluntarily inhaled for intoxication effects, such as behavioral disinhibition and euphoria (Beckley and Woodward, 2013). The most commonly abused inhalants are volatile solvents, such as toluene, that are contained in a wide range of household and industrial solutions.…”

“…NAc neurons receive inputs from other brain regions implicated in the response to drugs of abuse including glutamatergic neurons in the prefrontal cortex (PFC) and dopaminergic neurons in the ventral tegmental area (VTA) (Sesack and Grace, 2010). In previous studies, we showed that the volatile solvent toluene alters glutamatergic signaling in accumbens-projecting VTA DA neurons (Beckley et al, 2013) and induces an endocannabinoid (eCB) mediated long-term depression (LTD) of glutamatergic transmission in deep layer pyramidal neurons of the medial prefrontal cortex (mPFC) (Beckley and Woodward, 2011). Endocannabinoid modulation of glutamatergic neurotransmission is also present in NAc neurons (Robbe et al, 2002; Wang et al, 2010), but appears to be restricted to D2 MSNs (Kreitzer and Malenka, 2007) suggesting that toluene may induce LTD only in these neurons.…”

Sexual behaviour is impaired by the abused inhalant toluene in adolescent male rats

“…In addition, toluene exposure might have altered testosterone synthesis at the brain and this neurosteroid is a positive modulator of GABA A receptor function (Wang, ); therefore, the inhibition of sexual behaviour caused by toluene might involve GABAergic transmission. Actually, it is well established that the complex action mechanism of toluene (Beckley & Woodward, ; Cruz et al., ; Lubman, Yücel, & Lawrence, ) includes GABA A receptor‐positive allosteric modulation (Beckstead, Weiner, Eger, Gong, & Mihic, ). Moreover, repeated exposure to 8,000 ppm toluene (30 min daily for 10 days) decreases α1 GABA A subunit levels in the ventral tegmental area (VTA) of rats (Williams, Stafford, & Steketee, ), a brain region critically involved in the rewarding effects of drugs and natural stimuli such as mating.…”