Student Research: Barbara E. Fitzgerald

MS, , 1991
Faculty Advisor: Lucio G. Costa

Modulation of Muscarinic Receptor Subtypes in Rat Brain and T-lymphocytes Following Prolonged Exposure to Organophosphate


Organophosphate insecticides account for a large percentage of inseciticides currently in use. They are generally less likely to bioaccumulate than the organochlorines they largely replaced. Many organophosphates are highly acutely toxic to humans, however, and numerous documented cses of poisoning in pesticide applicators and field workers have been attributed to accidental overexposure.

Although down-regulation of muscarinic receptors in the CNS has been shown in laboratory animals to correlate with the development of tolerance and spatial memory deficits, moduclation of central msucarinic receptors during human response to chronic exposure to organophosphates has not been evaluated. A peripheral, easily accesible biological marker for muscarinic receptors would allow the study of changes in receptor densities in chronically exposed persons. Therefore, this project had the following aims:

1. Extend previous work by determining how closely lymphocyte muscarinic receptor density reflects the level of brain muscarinic receptors over time in response to prolonged organophosphate exposure. The ultimate goal is to establish a peripheral biomarker for investigation of human central muscarinic receptor changes following repeated exposure to organophosphates.
2. Implement binding assays for 3H-telenzepine and 3H-AFDX 384 (two recently developed, subtype-specific ligands) in rat brain, and utilize these radioligands to monitor M1 and M2 subtype response in brain over the time-course of organophosphate exposure and recovery. Determination of M1 and M2 receptor subtype modulation should yield insight into their respective roles in mediating the behavioral effects of repeated organophosphate exposure.

Taken from the beginning of thesis.