The major goal of this R21 Exploratory/Developmental grant proposal is to determine the actions of inhaled substances of abuse (inhalants) such as toluene on ventral tegmental area (VTA) dopaminergic neurons, part of the mesoaccumbens dopaminergic system. Inhalants are abused due to their ability to promote euphoria. Increased activity in the mesoaccumbens dopaminergic pathway is believed to be important for the reinforcing properties of drugs leading to their abuse. As inhalants induce euphoria and have been shown to be chronically abused, it is likely that they activate the mesoaccumbens system. However, the current literature is lacking in studies of the effects of inhalants in the mesoaccumbens system and on dopamine release. In addition, little information is available on the mechanisms of action of inhalants. As toluene is frequently present in inhaled solvents, our studies will focus initially on the actions of toluene. From the sparse information available about the effects of toluene, we have formed the hypothesis that toluene stimulates the mesoaccumbens pathway but that the actions are dose dependent. At low concentrations toluene enhances activity in the VTA dopaminergic neurons, while at high concentrations toluene effects become inhibitory. We will test this hypothesis in slices of the midbrain containing the VTA using patch clamp recording methods. The first specific aim will determine the effects of a range of concentrations of toluene on the membrane properties of the VTA dopaminergic neurons. The second specific aim will determine the ionic basis of the membrane responses. It is anticipated that the results from this study will provide fundamental information about the effects of inhalants on VTA dopaminergic neurons, creating a basis for future studies aimed at understanding the mechanisms by which inhalants are reinforced leading to their abuse. ? ?
