The abused inhalant toluene is a potent activator of the rat mesolimbic dopamine system: Extracellular studies in brain slices with neurobehavioral correlates

Abstract

This dissertation represents some of the first work to associate the behavioral stimulant and electrophysiological effects of the putative psychotropic component of many inhalants of abuse, the organic solvent toluene, with changes in mesolimbic dopamine (DA) neurotransmission. To test if the locomotor stimulant properties of toluene are dependent on mesolimbic DA neurotransmission, rats received focal injections of 6-hydroxydopamine (6OHDA) or vehicle into the NaCC, and following recovery received injections of toluene, amphetamine, scopolamine, and vehicle. In 6OHDA-treated animals, the locomotor hyperactivity evoked by toluene and amphetamine, but not scopolamine or vehicle were reduced, and the DA concentration in the NaCC declined ∼90%. To test if toluene directly stimulated ventral tegmental area (VTA) neuronal activity, rat in vitro brain slices containing the VTA were superfused with behaviorally relevant concentrations of toluene. Regions outside the VTA were either mildly stimulated or inhibited by toluene. Toluene was very efficacious at activating DA neurons in the rostral VTA regions, which project to the NaCC. These stimulatory effects appeared unrelated to NMDA receptors, and persisted in ACSF media designed to inhibit synaptic transmission. To examine the effects of repeated exposure to toluene, locomotor hyperactivity in response to daily injections of either toluene or vehicle was assessed. Toluene-induced hyperactivity progressively declined over the 7 days of exposure suggesting the development of tolerance. To determine if these changes involved alterations in the mesolimbic DA system, the same rats were challenged with amphetamine, cocaine and scopolamine. Animals tolerant to toluene were also cross-tolerant to cocaine and amphetamine, but not to scopolamine. Brain slices from similarly treated animals revealed comparatively increased numbers of spontaneously active non-DA neurons with an ∼400 fold increased sensitivity to stimulation by NMDA. In contrast, both the firing rates and the number of spontaneously active VTA DA cells were reduced. VTA DA cells also exhibited hyperpolarized action potential waveforms and a significantly reduced sensitivity to toluene. Taken together it appears that the abuse potential of inhalants containing toluene may stem from the stimulatory actions of this solvent on the mesolimbic dopamine system, a circuit intimately tied to the rewarding effects of most drugs of abuse.