Volatile solvents such as toluene, benzene and trichloroethane are widely distributed in a variety of products encountered in both industrial and home settings. These include glues, thinners, rubber cements, aerosol sprays, nail polish removers, correction fluid and dry cleaning solvents. Although the occupational hazards of exposure to these solvents have been previously examined in a variety of toxicological studies, the cellular and molecular sites of action that account for their intoxicating effects are virtually unknown. Surveys of drug use show that a significant percentage of the population has used volatile solvents for their intoxicating properties and such use is especially prevalent among adolescents and teens who may have easy access to these products. Previous behavioral studies show that toluene and other abused volatile solvents display actions similar to that observed for CNS depressants such as ethanol, barbiturates, benzodiazepines, and anesthetics. Thus, we hypothesize that abused solvents, like other CNS depressants, may exert some of its neurobehavioral effects by altering the function of specific ion channels that are involved in mediating and modulating neuronal transmission. We have generated data to support this hypothesis and have demonstrated that toluene and other volatile solvents inhibit the function of recombinant and native NMDA and acetylcholine receptors expressed in oocytes and cultured neurons. This inhibition was dose-dependent and was influenced by the subunit composition expressed. In contrast to ethanol, toluene had negligible effects on currents mediated by non-NMDA receptors or on G-protein coupled potassium channels. These results suggest that abused solvents may show greater selectivity than alcohol with respect to their ability to modulate the activity of neuronal ion channels. Studies outlined in this proposal will test this hypothesis by determining the sensitivity of recombinant and native ion channels to toluene and other volatile solvents that are subject to abuse. Two-electrode voltage-clamp and patch-clamp electrophysiology will be used to analyze the solvent sensitivity of recombinant ionotropic receptors expressed in oocytes and HEK cells. The molecular sites of action for toluene will be explored by testing whether sites known to regulate the alcohol/anesthetic sensitivity of these channels also regulate solvent sensitivity. Finally, the relevance of the findings obtained in recombinant receptor systems will be assessed by measuring the effects of toluene and other abused solvents on ion channels expressed in cultured brain neurons using whole-cell patch clamp and calcium imaging. Results obtained from these studies outlined are expected to greatly expand our knowledge of the cellular and molecular targets of these important drugs of abuse.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA013951-05
Application #
7024517
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Purohit, Vishnudutt
Project Start
2002-04-15
Project End
2009-02-28
Budget Start
2006-03-01
Budget End
2009-02-28
Support Year
5
Fiscal Year
2006
Total Cost
$280,573
Indirect Cost
Name
Medical University of South Carolina
Department
Neurosciences
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
Wayman, Wesley N; Woodward, John J (2018) Exposure to the Abused Inhalant Toluene Alters Medial Prefrontal Cortex Physiology. Neuropsychopharmacology 43:912-924
Gioia, Dominic A; Xu, Minfu; Wayman, Wesley N et al. (2018) Effects of drugs of abuse on channelrhodopsin-2 function. Neuropharmacology 135:316-327
Wayman, Wesley N; Woodward, John J (2018) Chemogenetic Excitation of Accumbens-Projecting Infralimbic Cortical Neurons Blocks Toluene-Induced Conditioned Place Preference. J Neurosci 38:1462-1471
Braunscheidel, K M; Gass, J T; Mulholland, P J et al. (2017) Persistent cognitive and morphological alterations induced by repeated exposure of adolescent rats to the abused inhalant toluene. Neurobiol Learn Mem 144:136-146
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
Woodward, John J; Beckley, Jacob (2014) Effects of the abused inhalant toluene on the mesolimbic dopamine system. J Drug Alcohol Res 3:
Cruz, Silvia L; Rivera-García, María Teresa; Woodward, John J (2014) Review of toluene action: clinical evidence, animal studies and molecular targets. 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

Showing the most recent 10 out of 17 publications