Adolescent Toluene Inhalation in Rats Affects White Matter Maturation with the Potential for Recovery Following Abstinence

Abstract

Inhalant misuse is common during adolescence, with ongoing chronic misuse associated with neurobiological and cognitive abnormalities. While human imaging studies consistently report white matter abnormalities among long-term inhalant users, longitudinal studies have been lacking with limited data available regarding the progressive nature of such abnormalities, including the potential for recovery following periods of sustained abstinence. We exposed adolescent male Wistar rats (postnatal day 27) to chronic intermittent inhaled toluene (3,000 ppm) for 1 hour/day, 3 times/week for 8 weeks to model abuse patterns observed in adolescent and young adult human users. This dosing regimen resulted in a significant retardation in weight gain during the exposure period (p<0.05). In parallel, we performed longitudinal magnetic resonance imaging (T2-weighted) and diffusion tensor imaging prior to exposure, and after 4 and 8 weeks, to examine the integrity of white matter tracts, including the anterior commissure and corpus callosum. We also conducted imaging after 8 weeks of abstinence to assess for potential recovery. Chronic intermittent toluene exposure during adolescence and early adulthood resulted in white matter abnormalities, including a decrease in axial (p<0.05) and radial (p<0.05) diffusivity. These abnormalities appeared region-specific, occurring in the anterior commissure but not the corpus callosum and were not present until after at least 4 weeks of exposure. Toluene-induced effects on both body weight and white matter parameters recovered following abstinence. Behaviourally, we observed a progressive decrease in rearing activity following toluene exposure but no difference in motor function, suggesting cognitive function may be more sensitive to the effects of toluene. Furthermore, deficits in rearing were present by 4 weeks suggesting that toluene may affect behaviour prior to detectable white matter abnormalities. Consequently, exposure to inhalants that contain toluene during adolescence and early adulthood appear to differentially affect white matter maturation and behavioural outcomes, although recovery can occur following abstinence.

Chronic intermittent toluene inhalation initiated during adolescence in rats does not alter voluntary consumption of ethanol in adulthood

“…Previous work has demonstrated that pathological and behavioral abnormalities are present following 8 but not 4 weeks of CIT exposure in this model (Duncan et al, 2012). Furthermore, the duration of abuse history is associated with the severity of cognitive and pathological abnormalities in human abusers (Rosenberg, Grigsby, Dreisbach, Busenbark, & Grigsby, 2002), supporting the idea of increased adverse affects with continued exposure.…”

“…Exposure to toluene inhalation was conducted as previously described (Duncan et al, 2012). Briefly, rats were acclimatized to the laboratory at least 1 h prior to exposure to toluene or air during which time their body weights were recorded.…”

“…The vulnerability of the adolescent brain to substances of abuse is believed to be driven, in part, by the fact that adolescence encompasses a significant maturational period in which dynamic reorganization occurs within the brain (for review see Lubman, Yücel, & Hall, 2007;Spear, 2000). As such, the long-term adverse consequences of inhalant abuse are associated with the age of abuse onset (Wu et al, 2004), as well as the duration of abuse history in humans and rodents (Duncan et al, 2012).…”

“…As it has been previously demonstrated that the duration of CIT exposure results in differential neuropathological and behavioral effects in this model (Duncan et al, 2012), this study investigated the effects of ethanol following exposure confined primarily to adolescence (PN 27e52) or both adolescence and early adulthood (PN 27e80). As age-dependent effects on voluntary ethanol consumption have been observed in rats (Schramm-Sapyta et al, 2013), this paradigm also enabled the investigation of the effects of age upon voluntary ethanol consumption.…”

Adolescent Inhalant Abuse Results in Adrenal Dysfunction and a Hypermetabolic Phenotype with Persistent Growth Impairments

“…Rats were exposed to CIT as described [20]. Briefly, exposure was undertaken in toluene-resistant chambers (17.6 cm wide × 16.5 cm high × 16.4 cm deep; Alternative Plastics Pty Ltd., Melbourne, VIC, Australia; fittings by Swagelok, Broadmeadows, VIC, Australia) with toluene concentration maintained at 10,000 ± 100 ppm (verified by calibrated inline gas chromatography; Shimadzu Corporation, Kyoto, Japan).…”