Gulf War Syndrome: A role for organophosphate induced plasticity of locus coeruleus neurons

Gulf War deployment has been associated with an increased prevalence of psychological symptoms, such as anxiety and depression, substance use, mental disorders and a lower quality of life beginning during the war and persisting a decade later. In 2008, a US Government panel concluded and validated that “Gulf War syndrome” (GWS) a!icted about 25% of the 700,000 deployed US veterans1. Epidemiological studies indicate that repetitive low-level exposure to organophosphate chemicals, including the insecticide, chlorpyrifos (CP) was one probable causative factor in GWS2. CP was frequently used as an insecticide applied to bedding and clothing during the Gulf War. Since the Gulf War the use of CP has been banned for household use in the US, but use and exposure remains high in agricultural communities and developing countries. Epidemiological data from agricultural communities that use CP regularly also report GWS-like symptoms. Lasting developmental delays in children exposed to CP have been con"rmed along with a 50-75% increase in the prevalence of Attention De"cit Hyperactivity Disorder (ADHD) per 10 fold increase in urinary metabolites of CP.1,3 CP is metabolized and excreted in urine as the toxic metabolite chlorpyrifos oxon (CPO). CPO is several fold more potent than CP as a neurotoxin due to its irreversible inhibition of acetylcholinesterase (AChE) activity, a similar mechanism to the neurotoxin, Sarin4,5. Given the lack of a direct connection between CPO and changes in neuronal function we developed an ex vivo rodent brain slice preparation to assess the e#ects of acute and prolonged exposure e#ects of CPO on the excitability of noradrenergic neurons within the LC. $e LC provides the sole source of noradrenaline in the brain and has a well-established role in mediating arousal, attention, anxiety and stress response1.