The use of volatile organic solvents as drugs of abuse is a significant and understudied health problem. These agents, also termed abused inhalants, are voluntarily inhaled or """"""""huffed"""""""" for their intoxicating effects and their use is especially prevalent among children and adolescents. Volatile solvents are legal and are found in a wide variety of household and commercial products including glues, adhesives and paint thinners. Exposure to these compounds is associated with a variety of adverse effects ranging from reduced social and academic performance, brain abnormalities and a sudden-death syndrome resulting from solvent-induced cardiac arrhythmia. Although abused inhalants can produce ethanol-like signs of intoxication, the sites and mechanisms of action that underlie these effects are largely unknown. Research carried out under this NIDA funded grant has focused on defining the sites and mechanisms of action of volatile solvents and how these compounds affect brain areas involved in addiction. During the initial period of funding of this project, we generated data that revealed a surprising degree of selectivity for the effects of abused inhalants on both voltage-gated and ligand- gated ion channels that regulate neuronal excitability. These findings clearly established that abused inhalants such as toluene have important and specific actions on channels implicated in mediating the actions of a wide variety of drugs of abuse. During the current funding period, we examined the effects of toluene on neurons within the addiction neurocircuitry including those in the medial prefrontal cortex and ventral tegmental area. Results from these studies show that toluene reduces glutamatergic EPSCs in mPFC neurons via both direct actions on ionotropic GluRs and via a novel endocannabinoid mediated depression of signaling. We also showed that a brief exposure of adolescent animals to toluene vapor robustly enhances the AMPA/NMDA ratio in mesolimbic DA neurons while having little effect on those that project to the prefrontal cortex. Moreover, these changes in DA neuron excitability were dependent on the output of prefrontal cortex suggesting an important role for this region in regulating the rewarding effects of abused inhalants. In this application, we propose three specific aims to extend these exciting findings.
Aim 1 will determine how acute toluene affects the function of medium spiny neurons in the nucleus accumbens and DA neurons in the VTA with a focus on the role of endocannabinoids in mediating these actions. Studies in Aim 2 will examine the age-dependence of toluene action on VTA DA neuron excitability and how brief exposures to toluene vapor during adolescence affects neuronal function and behavior in the adult animal.
Aim 3 will test the hypothesis that the mPFC dependent regulation of VTA DA neuron excitability is endocannabinoid dependent and studies will map the neurocircuitry beween mPFC and VTA to clearly establish a mechanism for these effects. Overall, results from these studies will fill an important gap in our knowledge regarding the actions of abused inhalants on the addiction neurocircuitry.
Abused inhalants are an important class of drugs of abuse that have received relatively little attention with respect to their mechanisms of action. Research to be carried out in this proposal will provide a detailed analysis of the effects of abused inhalants on neurons within brain areas involved in addiction.
|Beckley, Jacob T; Randall, Patrick K; Smith, Rachel J et al. (2016) Phenotype-dependent inhibition of glutamatergic transmission on nucleus accumbens medium spiny neurons by the abused inhalant toluene. Addict Biol 21:530-46|
|Nimitvilai, Sudarat; You, Chang; Arora, Devinder S et al. (2016) Differential Effects of Toluene and Ethanol on Dopaminergic Neurons of the Ventral Tegmental Area. Front Neurosci 10:434|
|Mahler, Stephen V; Vazey, Elena M; Beckley, Jacob T et al. (2014) Designer receptors show role for ventral pallidum input to ventral tegmental area in cocaine seeking. Nat Neurosci 17:577-85|
|Cruz, Silvia L; Rivera-GarcÃa, MarÃa Teresa; Woodward, John J (2014) Review of toluene action: clinical evidence, animal studies and molecular targets. J Drug Alcohol Res 3:|
|Woodward, John J; Beckley, Jacob (2014) Effects of the abused inhalant toluene on the mesolimbic dopamine system. J Drug Alcohol Res 3:|
|Beckley, Jacob T; Woodward, John J (2013) Volatile solvents as drugs of abuse: focus on the cortico-mesolimbic circuitry. Neuropsychopharmacology 38:2555-67|
|Beckley, Jacob T; Evins, Caitlin E; Fedarovich, Hleb et al. (2013) Medial prefrontal cortex inversely regulates toluene-induced changes in markers of synaptic plasticity of mesolimbic dopamine neurons. J Neurosci 33:804-13|
|Beckley, Jacob T; Woodward, John J (2011) The abused inhalant toluene differentially modulates excitatory and inhibitory synaptic transmission in deep-layer neurons of the medial prefrontal cortex. Neuropsychopharmacology 36:1531-42|
|Smothers, C Thetford; Woodward, John J (2007) Pharmacological characterization of glycine-activated currents in HEK 293 cells expressing N-methyl-D-aspartate NR1 and NR3 subunits. J Pharmacol Exp Ther 322:739-48|
|Del Re, Angelo M; Dopico, Alejandro M; Woodward, John J (2006) Effects of the abused inhalant toluene on ethanol-sensitive potassium channels expressed in oocytes. Brain Res 1087:75-82|
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