Electronic nicotine device systems (ENDS)-induced alterations in glutamate homeostasis: Effects on seizure susceptibility

Project Summary
There have been several reported cases of seizures in youths following electronic nicotine delivery systems
(ENDS) use, prompting an investigation by the Federal Drug Administration. Although reports show that ENDS
aerosols contain fewer numbers and lower levels of toxicants than conventional cigarettes, there is evidence of
adverse biological effects in humans, and the long-term effects of ENDS exposure with nicotine (NIC) and
flavorings such as menthol on seizure susceptibility are unknown. The reports of illnesses associated with ENDS
challenge the concept that they are a healthier alternative to traditional cigarettes and underscore the urgent
need for studies to elucidate the health effects of ENDS. Seizures are linked to smoking through genetic
mutations and by exposure to high levels of nicotine, but the effects of NIC exposure via ENDS use is unknown.
Using our rodent-validated vapor inhalation system, our preliminary data indicates that inhalation of NIC leads
to changes in body weight, locomotor activity, and somatic signs of dependence and causes profound changes
in glutamate regulatory proteins, suggesting increased neuronal activity. The central hypothesis of the current
proposal is that exposure to ENDS disrupts neuronal function and increases seizure susceptibility via alteration
in glutamate homeostasis. This hypothesis will be tested by pursuing two Specific Aims: 1) To test the hypothesis
that exposure to ENDS with menthol increases seizure susceptibility and 2) To test the hypothesis that ENDS
with menthol exposure increases neuronal hyperexcitability. Given the dramatic increase in ENDS use, the need
for fundamental research on its health effects is imperative. The proposed research will lead to a greater
understanding of the fundamental effects of ENDS use with nicotine on neuronal hyperexcitability and seizure
susceptibility. These data will provide critical first step towards understanding the effect of ENDS use, which will
help guide individuals and policy makers in making informed decisions about ENDS use.

Grant Number: 1R21NS131301-01A1
NIH Institute/Center: NIH
Principal Investigator: Susan Campbell