The traditional therapy of organophosphorus anticholinesterase (OP) intoxication focuses on acute signs of toxicity mediated by the accumulation of synaptic acetylcholine levels in the nervous system. While substantial evidence indicates that non-cholinergic signaling is "recruited" following acetylcholinesterase inhibition and plays a role in long-term neurological deficits, involvement of other signaling pathways is essentially not considered in the treatment regimen. We propose that early accumulation of another neurotransmitter, serotonin, in the hippocampus (a brain region implicated in affective disorders) following OP exposure leads to subsequent, long-term changes in serotonergic signaling and the expression of persistent neuropsychological deficits. Endocannabinoids (eCBs) are endogenous neuromodulators produced by depolarized neurons that retrogradely inhibit the release of a variety of neurotransmitters at the presynaptic terminal. We hypothesize that acute OP exposure initially elicits excessive hippocampal serotonergic signaling that later leads to persistent neurochemical and behavioral changes, and that early enhancement of eCB signaling by pharmacological blockade of eCB hydrolyzing enzymes reduces both acute and long-term neurological consequences of OP intoxication. Aim 1 will determine the persistence of depressive-like behavioral changes following exposure to the prototype OP di-isopropylflourophosphate (DFP) and its correlation with inhibition and recovery of acetylcholinesterase activity. Aim 2 will evaluate the effects of inhibitors of eCB-degrading enzymes (given either immediately after or 30 min after DFP) on acute and persistent signs of toxicity as well as study the possible interaction between the standard antidote atropine and inhibitors of eCB degradation on expression of toxicity. Aim 3 will study short- and long-term changes in serotonergic signaling in the hippocampus and the dorsal raphe nucleus, the origin of extensive serotonergic innervation to the hippocampus. Findings from the proposed studies could shift the emphasis of clinical management of OP intoxication to incorporate measures for counteracting non-cholinergic signaling changes and their influence on acute and persistent neurological consequences following acute exposures. The long-term objectives of this project are to define conditions under which eCB signaling decreases acute and chronic toxicity following acute OP exposure, to understand the neurochemical basis for such neuroprotection, and to use this knowledge to develop an effective therapeutic countermeasure to improve public health. PUBLIC HEALTH RELEVANCE: Exposure to organophosphorus chemicals (OPs) can lead to life-threatening acute toxicity as well as persistent neuropsychological disturbances lasting years after intoxication. We propose that early treatment with a drug which blocks the breakdown of endocannabinoids, endogenous chemicals that reduce nervous system hyperactivity by decreasing neurotransmitter release, can reduce both short- term and long-term consequences of OP exposure. Knowledge gained from the proposed studies could improve therapeutic management of acute intoxication and limit the debilitating, persistent adverse health consequences that follow.