title: The abused inhalant toluene increases dopamine release in the nucleus accumbens by directly stimulating ventral tegmental area neurons.
abstract: Recreational abuse of toluene-containing volatile inhalants by adolescents is a significant public health problem. The mechanisms underlying the abuse potential of such substances remain unclear, but could involve increased activity in mesoaccumbal dopamine (DA) afferents innervating the nucleus accumbens (ACB). Here, using in vitro electrophysiology, we show that application of behaviorally relevant concentrations of toluene directly stimulates DA neurons in the ventral tegmental area (VTA), but not surrounding midbrain regions. Toluene stimulation of VTA neurons persists when synaptic transmission is reduced. Moreover, unlike non-DA neurons, the magnitude of VTA DA neuron firing does not decline during longer exposures designed to emulate 'huffing'. Using dual-probe in vivo microdialysis, we show that perfusion of toluene directly into the VTA increases DA concentrations in the VTA (somatodendritic release) and its terminal projection site, the ACB. These results provide the first demonstration that even brief exposure to toluene increases action potential drive onto mesoaccumbal VTA DA neurons, thereby enhancing DA release in the ACB. The finding that toluene stimulates mesoaccumbal neurotransmission by activating VTA DA neurons directly (independently of transynaptic inputs) provide insights into the neural substrates that may contribute to the initiation and pathophysiology of toluene abuse.
authors.affiliation: Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ, USA. Riegela@OHSU.edu
authors.forename: Arthur C
authors.initials: AC
authors.lastname: Riegel
authors.forename: Agustin
authors.initials: A
authors.lastname: Zapata
authors.forename: Toni S
authors.initials: TS
authors.lastname: Shippenberg
authors.forename: Edward D
authors.initials: ED
authors.lastname: French
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D004298:Dopamine / Q000378:metabolism*; D045604:Extracellular Fluid / Q000187:drug effects / Q000378:metabolism; D019570:Inhalation Exposure / Q000009:adverse effects*; D008297:Male; D017551:Microdialysis; D009434:Neural Pathways / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism; D009924:Organ Culture Techniques; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012201:Reward; D012997:Solvents / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D014050:Toluene / Q000494:pharmacology*; D017557:Ventral Tegmental Area / Q000187:drug effects* / Q000378:metabolism
chemical_list: D012997:Solvents; D014050:Toluene; D004298:Dopamine