title: NMDA receptor binding is reduced within mesocorticolimbic regions following chronic inhalation of toluene in adolescent rats.
abstract: The purposeful inhalation of volatile solvents, such as toluene, to induce self-intoxication is prevalent, particularly within adolescent populations. Chronic misuse results in cognitive and neurobiological impairments, as well as an increased risk for addictive behaviours in adulthood. Toluene-induced neuroadaptations within mesocorticolimbic circuitry are thought, in part, to mediate some of the adverse outcomes of toluene misuse, however our understanding of the neuroadaptive processes remains equivocal. An understanding of these processes is particularly important relative to exposure that occurs during adolescence and at concentrations that reflect various patterns of use. Therefore, we exposed male adolescent Wistar rats (postnatal day [PN] 27) to either air or low or high concentrations of inhaled toluene in a chronic and intermittent fashion (CIT, 3,000 or 10,000ppm) for 1 h/day, 3-5 times per week for 4 weeks to model different patterns of human inhalant abuse. Brains were subsequently analysed using autoradiography, qPCR and immunohistochemistry 3 days following the exposure period to investigate toluene-induced neuroadaptations within mesocorticolimbic circuitry. In CIT-exposed rats binding to N-methyl-D-aspartate (NMDA) receptors containing the GluN2B subunit, as determined using [(3)H]-ifenprodil, was decreased in a concentration-related manner in the caudal cingulate cortex, dorsal striatum and accumbens; however, this was not associated with changes in GluN2B protein expression. There were no differences in [(3)H]-epibatidine binding to heteromeric neuronal nicotinic acetylcholine (nACh) receptors. Relative expression of mRNA transcripts encoding NMDA, nACh, γ-aminobutyric acid type-A (GABAA) and dopamine receptor subunits was unchanged in all regions assessed following CIT. Our data suggest that adolescent CIT exposure impacts NMDA receptors within regions of corticostriatal circuitry, possibly via post-translational mechanisms. Dysfunctional glutamatergic signalling within corticostriatal regions may contribute to the adverse outcomes observed following adolescent toluene abuse.
authors.affiliation: Division of Behavioural Neuroscience, Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria 3010, Australia; Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, 80804 Munich, Germany.
authors.forename: Alec Lindsay Ward
authors.initials: ALW
authors.lastname: Dick
authors.affiliation: Division of Behavioural Neuroscience, Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria 3010, Australia.
authors.forename: Tine
authors.initials: T
authors.lastname: Pooters
authors.affiliation: Division of Behavioural Neuroscience, Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria 3010, Australia.
authors.forename: Sarah
authors.initials: S
authors.lastname: Gibbs
authors.affiliation: Division of Behavioural Neuroscience, Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria 3010, Australia.
authors.forename: Emma
authors.initials: E
authors.lastname: Giles
authors.affiliation: Division of Behavioural Neuroscience, Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria 3010, Australia.
authors.forename: Ashleigh
authors.initials: A
authors.lastname: Qama
authors.affiliation: Division of Behavioural Neuroscience, Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria 3010, Australia.
authors.forename: Andrew John
authors.initials: AJ
authors.lastname: Lawrence
authors.affiliation: Division of Behavioural Neuroscience, Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria 3010, Australia; Department Anatomy & Neuroscience, University of Melbourne, Melbourne, Victoria 3010, Australia. Electronic address: Jhodie.duncan@florey.edu.au.
authors.forename: Jhodie Rubina
authors.initials: JR
authors.lastname: Duncan
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001345:Autoradiography; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000493:pharmacokinetics; D018683:Excitatory Amino Acid Agents / Q000493:pharmacokinetics; D015870:Gene Expression / Q000187:drug effects; D008032:Limbic System / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D018722:Nicotinic Agonists / Q000493:pharmacokinetics; D010880:Piperidines / Q000493:pharmacokinetics; D011485:Protein Binding / Q000187:drug effects; D011725:Pyridines / Q000493:pharmacokinetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D012997:Solvents / Q000494:pharmacology*; D013003:Somatosensory Cortex / Q000187:drug effects / Q000378:metabolism; D014050:Toluene / Q000008:administration & dosage / Q000494:pharmacology*; D014316:Tritium / Q000493:pharmacokinetics
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D018683:Excitatory Amino Acid Agents; D018722:Nicotinic Agonists; D010880:Piperidines; D011725:Pyridines; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D012997:Solvents; D014316:Tritium; D014050:Toluene; C082748:epibatidine; C010739:ifenprodil
keywords: Animal model; Autoradiography; GluN2B; Inhalant abuse; NMDA; qPCR