title: Toluene inhalation in adolescent rats reduces flexible behaviour in adulthood and alters glutamatergic and GABAergic signalling.
abstract: Toluene is a commonly abused inhalant that is easily accessible to adolescents. Despite the increasing incidence of use, our understanding of its long-term impact remains limited. Here, we used a range of techniques to examine the acute and chronic effects of toluene exposure on glutameteric and GABAergic function, and on indices of psychological function in adult rats after adolescent exposure. Metabolomics conducted on cortical tissue established that acute exposure to toluene produces alterations in cellular metabolism indicative of a glutamatergic and GABAergic profile. Similarly, in vitro electrophysiology in Xenopus oocytes found that acute toluene exposure reduced NMDA receptor signalling. Finally, in an adolescent rodent model of chronic intermittent exposure to toluene (10 000 ppm), we found that, while toluene exposure did not affect initial learning, it induced a deficit in updating that learning when response-outcome relationships were reversed or degraded in an instrumental conditioning paradigm. There were also group differences when more effort was required to obtain the reward; toluene-exposed animals were less sensitive to progressive ratio schedules and to delayed discounting. These behavioural deficits were accompanied by changes in subunit expression of both NMDA and GABA receptors in adulthood, up to 10 weeks after the final exposure to toluene in the hippocampus, prefrontal cortex and ventromedial striatum; regions with recognized roles in behavioural flexibility and decision-making. Collectively, our data suggest that exposure to toluene is sufficient to induce adaptive changes in glutamatergic and GABAergic systems and in adaptive behaviour that may underlie the deficits observed following adolescent inhalant abuse, including susceptibility to further drug-use.
authors.affiliation: Brain & Mind Centre, University of Sydney, Sydney, New South Wales, Australia.|School of Psychology, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Teri M
authors.initials: TM
authors.lastname: Furlong
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia.|Department of Anatomy and Neuroscience, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Jhodie R
authors.initials: JR
authors.lastname: Duncan
authors.affiliation: School of Psychology, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Laura H
authors.initials: LH
authors.lastname: Corbit
authors.affiliation: Neuroscience Research Australia, Randwick, New South Wales, Australia.|School of Medical Sciences, University of NSW, Kensington, New South Wales, Australia.
authors.forename: Caroline D
authors.initials: CD
authors.lastname: Rae
authors.affiliation: Neuroscience Research Australia, Randwick, New South Wales, Australia.|School of Medical Sciences, University of NSW, Kensington, New South Wales, Australia.
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Rowlands
authors.affiliation: Neuroscience Research Australia, Randwick, New South Wales, Australia.
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Maher
authors.affiliation: Neuroscience Research Australia, Randwick, New South Wales, Australia.
authors.forename: Fatima A
authors.initials: FA
authors.lastname: Nasrallah
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Carol J
authors.initials: CJ
authors.lastname: Milligan
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Steven
authors.initials: S
authors.lastname: Petrou
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Lawrence
authors.affiliation: Brain & Mind Centre, University of Sydney, Sydney, New South Wales, Australia.|School of Psychology, University of NSW, Kensington, New South Wales, Australia.
authors.forename: Bernard W
authors.initials: BW
authors.lastname: Balleine
mesh_terms: D000280:Administration, Inhalation; D000367:Age Factors; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006168:Guinea Pigs; D007858:Learning / Q000187:drug effects / Q000502:physiology; D008297:Male; D009924:Organ Culture Techniques; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D012997:Solvents / Q000008:administration & dosage / Q000633:toxicity; D014050:Toluene / Q000008:administration & dosage* / Q000633:toxicity*; D014982:Xenopus laevis
chemical_list: D011963:Receptors, GABA-A; D016194:Receptors, N-Methyl-D-Aspartate; D012997:Solvents; D014050:Toluene; C121001:NR2B NMDA receptor
keywords: NMDA receptor; glutamatergic dysfunction; inhalant abuse; instrumental conditioning; metabolomics; oocyte