Volatile organic solvents, part of the abused inhalants drug class, are compounds found in common household products, such as paints, paint thinners, lacquers and glues. The use of these agents for intoxicating purposes is particularly prevalent among children and adolescents. Inhalant abuse can have profound adverse consequences, such as cognitive impairment, brain abnormalities, organ damage, and even sudden death, a result of inhalant-induced cardiac dysrhythmia. Toluene, a prototypical abused inhalant, inhibits NMDA mediated currents and has an excitatory effect on GABA synaptic transmission, among other effects. Evidence from rodent behavioral studies indicates that toluene has positive-reinforcing properties, similar to other drugs of abuse. In the ventral tegmental area (VTA), a region responsible for encoding the salience of stimuli, toluene increases dopaminergic (DA) cell firing, and exposure to abuse levels of toluene induces an increase in extracellular DA in the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC). Preliminary studies for this proposal suggest that toluene applied in vitro induces long-term depression (LTD) in mPFC pyramidal neurons. Together, these findings indicate that toluene exposure impacts regions of the brain responsible for reward (VTA:NAc) and cognition (mPFC). This proposal extends these findings by examining the effect of acute in vivo toluene exposure on markers of neuroplasticity.
Aim 1 will use whole-cell patch clamp electrophysiology and acute brain slices to determine whether acute toluene vapor exposure induces persistent physiological alterations in excitatory synapses of mPFC pyramidal neurons and VTA DA neurons.
Aim 2 will determine whether acute toluene exposure induces long-term changes in markers of structural plasticity in the mPFC and VTA by using the diolistic cell labeling method and analyzing dendritic spines. Results from these experiments will help determine the neurological substrates of toluene's abuse potential.
About 16% of 8th grade students in the US have used inhalants to get intoxicated and for many first-time drug users, the first drug experience is an abused inhalant. Data collected from experiments contained in this proposal will provide insight into the mechanisms of how toluene, a prototypical inhalant found in glues, lacquers and spray paints, can co-opt brain reward and cognitive systems. These results will clarify the danger of using toluene and similar inhalants so that ultimately education and prevention strategies can be improved.
|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|
|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|
|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; 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 (2013) Volatile solvents as drugs of abuse: focus on the cortico-mesolimbic circuitry. Neuropsychopharmacology 38:2555-67|
|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|