Abstract Experimentation with volatile substances (inhalants) is common during early adolescence, yet limited work has been conducted examining the neurobiological impact of regular binge use during this key stage of development. Human studies consistently demonstrate that chronic use is associated with significant toxic effects, including neurological and neuropsychological impairment, as well as diffuse and subtle changes in white matter. However, most preclinical research has tended to focus on acute exposure, with limited work examining the neuropharmacological or toxicological mechanisms underpinning these changes or their potential reversibility with abstinence. Nevertheless, there is growing evidence that commonly abused inhalants share common cellular mechanisms, and have similar actions to other drugs of abuse. Indeed, the majority of acute behavioural effects appear to be underpinned by changes in receptor and/or ion channel activity (for example, GABA A , glycine and 5HT 3 receptor activation, NMDA receptor inhibition), although nonspecific interactions can also arise at high concentrations. Recent studies examining the effects of toluene exposure during the early postnatal period are suggestive of long-term alterations in the function of NMDA and GABA A receptors, although limited work has been conducted investigating exposure during adolescence. Given the critical role of neurotransmitter systems in cognitive, emotional and brain development, future studies will need to take account of the substantial neuromaturational changes that are known to occur in the brain during childhood and adolescence, and to specifically investigate the neuropharmacological and toxicological profile of inhalant exposure during this period of development. Keywords: inhalants, toluene, organic solvents, adolescence, development, neuroimaging, cognition, toxicity

Introduction The deliberate inhalation of volatile substances (‘inhalants') can cause serious harm to the integrity of the CNS and disrupt normal trajectories of psychological, emotional and neurobiological development (Balster, 1998; Kurtzman et al., 2001; Bowen et al., 2006; Lubman et al., 2006). Historically, volatile substances (for example, nitrous oxide, chloroform and ether) were popularly inhaled by adult populations for intoxication in the late nineteenth and early twentieth centuries. However in recent times, inhalant use has emerged as a relatively common problem among children and adolescents. Adolescent glue sniffing was first noted in the United States during the 1940s, with reports of petrol sniffing subsequently appearing during the following decade. Today, the inhalation of volatile substances by adolescents is practiced worldwide, although there is marked variability in the type and pattern of substances abused. Sniffing the fumes of aerosol spray paint or ‘chroming' is the most popular form of inhalant abuse within Australia, whereas petrol sniffing remains a significant problem for indigenous communities, especially within remote settings (Cairney et al., 2002; Lubman et al., 2006). In Britain, inhalant abuse frequently involves butane gas from lighter refills, and has been associated with numerous deaths (Field-Smith et al., 2001). However, preventing and treating affected youth is difficult due to the complex psychosocial issues that these individuals typically face (for example, unstable and dysfunctional families, state-based care, school absenteeism, forensic issues, comorbid drug use and mental health problems) (Lubman et al., 2006). Despite long-standing awareness of the significant morbidity and mortality associated with inhalant abuse, neuropharmacological research has been comparatively sparse until recently, with limited data available on neurobiological sequelae or effective treatment approaches. For these reasons, inhalant abuse is increasingly gaining the attention of researchers, health providers, politicians and the public.

Compounds abused Inhalants encompass a broad range of volatile compounds (see ), such as nitrites, anaesthetic gases and organic solvents. This review particularly focuses on the latter category, as these compounds are most commonly misused by adolescents. However, a number of excellent early reviews discussing the neuropharmacology of nitrites and anaesthetic gases are available for the interested reader (Evans and Balster, 1991; Dinwiddie, 1994; Balster, 1998). Box 1 Volatile solvents Correction fluids (1,1,1-trichloroethane) Dry-cleaning fluids (trichloroethylene, 1,1,1-trichloroethane) Glues (n-hexane, toluene, xylene) Nail polish remover (acetone, esters) Paint thinners and removers (dichloromethane, toluene, xylene) Petrol (benzene, n-hexane, toluene, xylene) Aerosols (may contain chlorofluorocarbons and fluorocarbon propellants) Deodorants and hairsprays Fabric protector sprays Spray paints (toluene, methyl isobutyl ketone) Vegetable oil sprays Gases Bottled gas (propane) Cigarette lighter fluid (butane) Medical anaesthetics (ether, chloroform, nitrous oxide) Whipped cream (nitrous oxide) Nitritesa Amyl nitrites Open in a separate window Organic solvents are easily accessible to young people, as they are found in numerous readily available household and commercial products (for example, paint products, glues, petrol, correction fluid, lighter fuel and aerosols), and are cheap and legal. Such products typically contain a mixture of solvents, including aliphatic hydrocarbons (for example, iso-butane, n-butane, n-hexane and propane), aromatic hydrocarbons (for example, toluene and xylene), chlorinated hydrocarbons (for example, tetrachloroethylene, 1,1,1-trichloroethane and trichloroethylene) and ketones (for example, acetone, butanone and methyl iso-butyl ketone) (Ramsey et al., 1989). However, it is toluene (also known as methylbenzene or phenylmethane), a clear and colourless flammable liquid commonly used as an industrial solvent in the manufacturing of paints, chemicals, pharmaceuticals and rubber, that appears to have the highest potential for abuse. Given their highly lipophilic nature, organic solvents have rapid access to the brain (peaking within 1–3 min in primates and rodents), although the brain/blood ratio remains high for an extended period (Gerasimov, 2004; Gerasimov et al., 2005). Animal imaging studies also report high uptake and slower clearance in white matter compared with other brain regions (Gerasimov, 2004), indicating higher levels of exposure. Aliphatic hydrocarbons are generally eliminated unchanged via respiration, whereas aromatic hydrocarbons tend to be converted to hydrophilic metabolites, via the hepatic microsomal system, before being excreted in the urine. However, the psychopharmacology of inhalants has been largely characterized in workers following occupational exposure, and it is unclear whether the pharmacokinetics are similar in young users simultaneously exposed to high concentrations of multiple solvents (Dinwiddie, 1994). Young people typically abuse volatile substances by deliberately inhaling available vapours 15–20 times over a relatively brief period (for example, 10–15 min). This results in very high concentrations being inhaled (>6000 p.p.m.), although the exact concentration typically varies by compound (Bowen et al., 2006). ‘Sniffing' involves direct inhalation from a container or a piece of clothing sprayed with the substance. Some users attempt to increase the amount of available vapours by heating the substance first, or by holding a soaked cloth over the nose or mouth (that is, ‘huffing'). ‘Bagging' further increases the concentration of inhaled vapours, and involves breathing from a paper or plastic bag containing the volatile substance. Typically, experimental use begins with the sniffing of inhalants, gradually progressing through huffing and bagging as their misuse escalates (Henretig, 1996).

Concluding remarks There has been a substantial increase in research examining the neurobiology of inhalants, although the bulk of preclinical work has largely focused on acute exposure to toluene, with limited emphasis on examining neuropharmacological differences across volatile substances. Many of these studies have utilized non-inhalation methods of administration (particularly neurochemical and electrophysiological research), and such approaches may produce distinct biobehavioural sequelae (Bowen et al., 2006). Further, the relevance of such findings to human abuse requires further delineation, and more animal studies that attempt to robustly model the human experience (brief, high concentrations of inhalation exposure) are clearly necessary. Nevertheless, there is growing evidence that commonly abused solvents share common cellular mechanisms, and appear to have similar actions to other drugs of abuse, particularly CNS depressants. Despite clear evidence of neuropsychological impairments in chronic users, as well as diffuse and subtle changes in white matter, limited animal work has been conducted examining the neuropharmacological or toxicological mechanisms underpinning these changes or their potential reversibility with abstinence. Although there is often a marked variability in the type and pattern of inhalants used by adolescents, most epidemiological and clinical studies tend to describe inhalant users as a homogenous group, with little attention paid to differences in the chemical composition or toxic profile of substances inhaled. In addition, many of these studies include small samples of adult populations, with only limited neuropsychological and/or neuroimaging assessment. The lack of appropriately matched control groups and consideration of background educational, psychological, emotional and social factors further hinders the interpretation of the available data. Indeed, the failure to utilize longitudinal designs has meant that the natural course of inhalant abuse is largely uncharted, with limited data available on the correlates and consequences of use over the short- and long-term, including the nature of recovery with abstinence. Future studies will need to take account of the substantial neuromaturational changes that are known to occur in the brain during childhood and adolescence, and to specifically investigate the neuropharmacological and toxicological profile of inhalant exposure during this developmental period. Prospective human studies will also be needed to determine to what extent the neuropsychological and neurobiological abnormalities found in chronic abusers are present premorbidly, and/or relate to previous trauma or mental disorder. Although the recent increase in inhalant-related neuroscience research is encouraging, more comprehensive programmes that examine the impact of chronic inhalant binges during adolescence are essential for addressing the dearth of effective prevention and treatment approaches.

Acknowledgments Dr Yücel is supported by a National Health and Medical Research Council (NHMRC) Clinical Career Development Award (ID 509345). We acknowledge the support of the Colonial Foundation and the Alcohol Education Rehabilitation (AER) Foundation.

Abbreviations MRI magnetic resonance imaging PN postnatal day VTA ventral tegmental area