Mechanisms of dysregulation of dopamine neurotransmission by cholinesterase-inhibitors: implications for Gulf War Illness

Details

• Personal Author:
  Bibb JA ; Goldberg M ; Haley RW ; O'Callaghan JP ; Torres-Altoro M
• Description:
  Rationale: Gulf War Illness (GWI) is linked epidemiologically with exposure to acetylcholinesterase (AChE)-inhibiting chemicals. In comparisons of ill and well GW veterans, magnetic resonance spectroscopy found metabolite abnormalities in basal ganglia associated with increased central dopamine turnover, and cholinergic challenge with physostigmine caused abnormal cholinergic response in caudate, putamen and globus pallidus. From these findings, we hypothesized that Gulf War Illness (GWI) involves dysregulation of dopamine neurotransmission in the mesocorticolimbic reward and motor circuitry of the basal ganglia, which contributes emotional and visceral nervous system processing. Methods and Results: In an animal model of GWI mice were repetitively exposed to the AChE inhibitors chorpyrifos (CP) and/or pyridostigmine bromide (PB). Repetitive CP exposure increased striatal PKA-dependent phosphorylation of the D1 dopamine receptor downstream effector Ser845 of the GluR1 subunit of the AMPA receptor. Treatment of striatal slices with CP induced a dose-dependent increase in phospho-Ser845 GluR1 and phospho-Thr34 DARPP-32, which was blocked by a D1 antagonist. These effects were also induced by PB. Activation of the D1 dopamine receptor/cAMP/PKA cascade is regulated by the neuronal protein kinase, Cdk5. Interestingly, brain slice treatment with CP induced calpain-dependent conversion of the Cdk5 activating cofactor p35 to p25, a neuronal injury marker. Systemic exposure to PB for 10 days followed by a 4-week delay caused p25 formation in the prefrontal cortex. Finally, treatment of mice with a chronic low-dose combination of CP and PB reduced concentrations of dopamine and its metabolites DOPAC and HVA, and increased dopamine turnover, in the olfactory bulb. Conclusion: Repetitive exposure to AChE-inhibitors causes dopamine neurotransmission abnormalities, possibly contributing to brain dysfunction in GWI. [Description provided by NIOSH]
• Subjects:
  Animals Laboratories Occupational Health Safety
• Keywords:
  Acetylcholinesterase Animal Studies Author Keywords: Anticholinesterase Pesticides Brain Dopamine Central Nervous System Central Nervous System Disorders Gulf War Laboratory Animals
• ISSN:
  1096-6080
• Document Type:
  Text
• Genre:
  Abstract or Summary
• Place as Subject:
  OSHA Region 3 ; OSHA Region 6 ; Texas ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  114
• Issue:
  1
• NIOSHTIC Number:
  nn:20049411
• Citation:
  Toxicologist 2010 Mar; 114(1)(Abstract Suppl):2251
• Federal Fiscal Year:
  2010
• Peer Reviewed:
  False
• Source Full Name:
  The Toxicologist. Society of Toxicology 50th Annual Meeting and ToxExpo, March 6-10, 2011, Washington, DC
• Supplement:
  Abstract
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:dd616e56fe0cdeaa9f8b674125d0abb05de111293ce095242c1358017a84e078d4d9fbe78f0f51cb6958d28cef05acf6870309648f5fb47964822a672a30af4f
• Download URL:
  https://stacks.cdc.gov/view/cdc/203861/cdc_203861_DS1.pdf
• File Type:
  [PDF - 5.34 MB ]