Effects of Nerve Agent Analogs on Memorial, Attentional, and Interoceptive Processes: Insights into the Cognitive Consequences of Chemical Warfare

Abstract ID 96747 Poster Board 109 As one of the most toxic forms of chemical warfare agents, nerve agents cause death just minutes after exposure by irreversibly inhibiting acetylcholinesterase (AChE) activity in the central and peripheral nervous system thus preventing the breakdown of the neurotransmitter acetylcholine (ACh). In doing so, AChE inhibitors increase the concentration of the neurotransmitter in the synapse and lead to prolonged stimulation of nicotinic and muscarinic ACh receptors. To aid in the Defense Threat Reduction Agency's (Department of Defense) understanding of the impact of nerve agent exposure on cognition, studies were conducted to examine the effects of chemical weapon analogs on sustained attention and short-term memory as well as their interoceptive effects. Touchscreen-based psychomotor vigilance, delayed matching-to-position, and discrimination performance were assessed in female and male rats after administration of the chemically-diverse centrally- and peripherally-acting AChE inhibitors donepezil, rivastigmine, physostigmine, galantamine, and tacrine, the peripherally-restricted AChE inhibitor neostigmine, as well as drugs that act on nicotinic and/or muscarinic receptors (e.g., nicotine, arecoline). All five AChE inhibitors produced dose-dependent performance impairments in both the memorial and attentional tasks and these effects were greater than those of nicotine, arecoline, and neostigmine. Performance decrements in the psychomotor vigilance task were more sensitive to rivastigmine, physostigmine, galantamine, and tacrine possibly due to the time course of these drugs. Donepezil produced greater impairment in the delayed matching-to-position task than the psychomotor vigilance task. Interestingly, results also showed differences in potency between the AChE inhibitors wherein physostigmine and rivastigmine were more potent than donepezil and galantamine. In addition, these AChE inhibitors also differed in steepness of the dose response curves – increasing physostigmine and galantamine doses by a quarter log unit shifted performance from baseline levels to abolishing performance. To compare the interoceptive effects of the AChE inhibitors, subjects were trained to discriminate between donepezil from saline, followed by substitution testing with the other AChE inhibitors. Results thus far show that rivastigmine, galantamine, and physostigmine produced dose-dependent and full substitution for donepezil's discriminative-stimulus effects. Taken together, these data provide insights into the effects of AChE inhibitors on cognitive tasks designed to probe complex behavioral processes that are imperative to mission success of war fighters, first responders, and others affected by nerve agents. Ongoing work involves establishing how these compounds dysregulate the brain neurotransmitter function underlying sustained attention and short-term memory to provide additional mechanistic information on central nervous system risks of acute exposure to nerve agents. Supported by DTRA: HDTRA12210024