Review of Toluene Actions: Clinical Evidence, Animal Studies, and Molecular Targets

Abstract

It has long been known that individuals will engage in voluntary inhalation of volatile solvents for their rewarding effects. However, research into the neurobiology of these agents has lagged behind that of more commonly used drugs of abuse such as psychostimulants, alcohol and nicotine. This imbalance has begun to shift in recent years as the serious effects of abused inhalants, especially among children and adolescents, on brain function and behavior have become appreciated and scientifically documented. In this review, we discuss the physicochemical and pharmacological properties of toluene, a representative member of a large class of organic solvents commonly used as inhalants. This is followed by a brief summary of the clinical and pre-clinical evidence showing that toluene and related solvents produce significant effects on brain structures and processes involved in the rewarding aspects of drugs. This is highlighted by tables highlighting toluene’s effect on behaviors (reward, motor effects, learning, etc.) and cellular proteins (e.g. voltage and ligand-gated ion channels) closely associated the actions of abused substances. These sections demonstrate not only the significant progress that has been made in understanding the neurobiological basis for solvent abuse but also reveal the challenges that remain in developing a coherent understanding of this often overlooked class of drugs of abuse.

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.…”

Developmental Exposure to Environmental Toxicants

“…Chronic solvent abusers are at risk for leukoencephalopathy, hearing loss, cognitive impairment, cerebellar atrophy, ataxia, and hepatic and renal dysfunction. 91 …”

“…Inhalational use typically begins during childhood, peaks at age 14 to 25 years, and typically declines by late adolescence. 91,92 Toxic effects…”

“…Solvents are lipophilic, cross the placenta readily, and can affect developing fetuses. 90,91 Solvents are known to rapidly impart a feeling of euphoria after inhalation, and are used as recreational drugs (they are inexpensive and easily attainable). Inhalational use typically begins during childhood, peaks at age 14 to 25 years, and typically declines by late adolescence.…”

Challenges to Neuroscience and Public Policy Derived from New Trends and Patterns of Inhalant Misuse

“…Toluene has potent psychoactive effects, interacts directly with specific molecular targets [8,14,30], and releases dopamine in the mesolimbic system [2,46,64]. As it occurs with other drugs, inhalant misuse is a medical disease modulated by the environment.…”