N-acetylcysteine decreases toluene conditioned place preference and modulates corticostriatal activity in adolescent rats.

Inhalant (toluene) use disorder (IUD) continues to be a public health problem especially among Filipino adolescents. Animal models of IUD have not explored neurobiological changes from chronic toluene exposure, or possible treatments for long-lasting toluene-induced deficits. In rats repeatedly exposed to 3000 ppm of toluene vapor over 12 days, we report that daily administration of N-acetylcysteine (NAC; 100 mg/kg i.p. or 0.9 g/l oral), but not melatonin (10 mg/kg i.p.), during 8 days of abstinence reduced toluene conditioned place preference in both male and female adolescent Sprague-Dawley rats. Using immunofluorescence, we found that toluene-exposed rats showed decreased c-Fos densities in the dorsomedial striatum (DMS), dorsolateral striatum, and ventrolateral orbitofrontal cortex (vlOFC) after 8 days of abstinence. NAC partially rescued c-Fos expression in vlOFC. We found that c-Fos densities in both vlOFC and prelimbic cortex were significantly correlated with CPP values and with c-Fos densities in the DMS across treatment groups, suggesting that a history of toluene exposure may act by reducing cortical modulation of the dorsal striatum to promote long-lasting drug context-seeking. Our findings suggest that N-acetylcysteine may be a promising treatment for IUD in adolescent males and females.