Repeated exposure to chlorpyrifos is associated with a dose-dependent chronic neurobehavioral deficit in adult rats.

Organophosphate (OP) chemicals include commonly used pesticides and chemical warfare agents, and mechanistically they are potent inhibitors of the cholinesterase (ChE) enzyme. Epidemiological studies report long-term neuropsychiatric issues, including depression and cognitive impairments in OP-exposed individuals. Chlorpyrifos (CPF) is one of the most widely used pesticides worldwide. Multiple laboratory studies have reported on either the long-term behavioral effect of an acute high-dose CPF (30-250 mg/kg) or studied sub-chronic behavioral effects, particularly the motor and cognitive effects of repeated low-dose CPF. However, studies are lacking on chronic mood and depression-related morbidities following repeated CPF doses that would mimic occupationally relevant OP exposures during adulthood. In this study, adult male rats were injected with CPF (1, 3, 5, or 10 mg/kg/d, s.c.) for 21 consecutive days. Dependent on the CPF dose, ChE activity was inhibited approximately 60-80% in the blood and about 20-50% in the hippocampus at 2-days after the end of CPF exposures. Following a 12-week washout period, a complete recovery of ChE activity was noted. However, CPF-treated rats exhibited a dose-dependent increase in signs related to anhedonia (sucrose preference test), anxiety (open-field and elevated plus-maze), and despair (forced swim test) at this stage. To the best of our knowledge, this could be the first laboratory study that demonstrates a cause-effect relationship between occupational-like CPF exposures in adult rats and the development of long-term depression-related outcomes and could provide an experimental system to study molecular mechanisms underlying environmental OP exposures and the elevated risk for chronic behavioral deficits.