Alterations in glutamatergic and gabaergic ion channel activity in hippocampal neurons following exposure to the abused inhalant toluene.
Toluene, a representative member of the large class of abused inhalants, decreases neuronal activity and depresses behavior in both animals and humans. The sites of action of toluene are not completely known but recent studies suggest that ion channels that regulate neuronal excitability may be particularly sensitive. Previous studies with recombinant receptors showed that toluene decreases currents carried by N-methyl-D-aspartate (NMDA)-glutamate receptors without affecting those gated by non-NMDA receptors. In addition, toluene increases currents generated by GABA and glycine receptors. In the present study, primary cultures of rat hippocampal neurons were used to investigate the effects of acute and chronic toluene exposure on native excitatory and inhibitory ligand-gated ion channels. Toluene dose-dependently inhibited NMDA-mediated currents (IC50 1.5 mM) but had no effect on responses evoked by the non-NMDA agonist kainic acid. Prolonged treatment of neurons with toluene (1 mM; 4 days) increased whole-cell responses to exogenously applied NMDA, reduced those evoked by GABA but did not alter responses generated by kainic acid. Immunoblot analysis revealed that prolonged toluene exposure increased levels of NR2A and NR2B NMDA receptor subunits with no change in NR1. Immunohistochemical analysis with confocal imaging showed that toluene-treated neurons had significant increases in the density of NR1 subunits as compared with control neurons. Toluene exposure increased the amplitude of synaptic NMDA currents and decreased those activated by GABA. The results from this study suggest that toluene induces compensatory responses in the functional expression of ion channels that regulate neuronal excitability.
Bale
A S
AS
Department of Physiology and Neuroscience, Center for Drug and Alcohol Programs, Medical University of South Carolina, 67 President Street, P.O. Box 250510 IOP471N, Charleston, SC 29425, USA.
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Y
Y
Carpenter-Hyland
E P
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Chandler
L J
LJ
Woodward
J J
JJ
D027322:Amino Acid Transport System X-AG / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001640:Bicuculline / Q000494:pharmacology; D015153:Blotting, Western / Q000379:methods; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D050491:Glutamate Plasma Membrane Transport Proteins; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology* / Q000187:drug effects; D007150:Immunohistochemistry / Q000379:methods; D015640:Ion Channel Gating / Q000187:drug effects; D007473:Ion Channels / Q000187:drug effects*; D008564:Membrane Potentials / Q000187:drug effects / Q000528:radiation effects; D018613:Microscopy, Confocal / Q000379:methods; D009474:Neurons / Q000187:drug effects* / Q000528:radiation effects; D018408:Patch-Clamp Techniques / Q000379:methods; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012997:Solvents / Q000494:pharmacology; D027981:Symporters / Q000494:pharmacology; D013997:Time Factors; D014050:Toluene / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism / Q000494:pharmacology
D027322:Amino Acid Transport System X-AG; D018690:Excitatory Amino Acid Agonists; D018756:GABA Antagonists; D050491:Glutamate Plasma Membrane Transport Proteins; D007473:Ion Channels; C409466:NR1 NMDA receptor; C120997:NR2A NMDA receptor; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; D012997:Solvents; D027981:Symporters; D014050:Toluene; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; C010739:ifenprodil; D001640:Bicuculline