SEX-DIFFERENCES FOLLOWING PHARMACOLOGICAL MANIPULATION OF THE CHOLINERGIC SYSTEM BY DFP AND PHILOCARPINE

A series of seven experiments was designed to investigate the mechanism(s) responsible for sex differences in the effects of DFP, an irreversible anticholinesterase, on behavioural and physiological variables. It was found that female (Sprague-Dawley) rats were more resistant than males to the effects of DFP: decreases in body temperature and water intake were significantly less in the females. These effects were related to less inhibition of brain acetylcholinesterase (AChE) in female than in male animals. Of the five isoenzymes of AChE separated from homogenates of brain, one was relatively insensitive to the effects of DFP, but all were inhibited to a greater extent in male animals. In contrast to the effects of DFP, female rats were more sensitive to the hypothermic effects of pilocarpine, a directly acting muscarinic agonist, indicating that the resistance of females to the hypothermic effects of DFP could not be attributed to decreased sensitivity of muscarinic cholinergic receptors. Measurement of the degree of radioactivity in brain homogenates following the peripheral administration of {P32}-DFP indicated that the uptake of DFP into the brain was less for female than for male rats. A final experiment confirmed that the females had higher baseline levels of serum cholinesterase activity. It was also found that DFP produced a greater degree of inhibition of this enzyme in females. These experiments suggest that female rats may be less sensitive to the effects of DFP because they have higher levels of serum cholinesterase, which can bind to DFP administered peripherally and reduce the amount available for penetration into the brain. The results also support the hypothesis that the behavioural and physiological effects of DFP are related to the anticholinesterase properties of the agent. © 1979 Springer-Verlag.