1. ¹Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ, USA
2. ²Vollum Institute, Oregon Health & Science University, Portland, OR, USA
3. ³Intramural Research Program, Integrative Neuroscience Section, US Department of Health and Human Services, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, USA

Correspondence: AC Riegel, Vollum Institute, Oregon Health & Sciences University, 3181 SW Sam Jackson Park Road, Mail Stop L474, Portland, OR 85724-5050, USA. Tel: +1 503 494 4723; Fax: +1 503 494 6972; E-mail: Riegela@OHSU.edu

⁴These authors contributed equally to this work.

Received 24 May 2006; Accepted 6 October 2006; Published online 10 January 2007.

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.