Previous in vivo and in vitro studies demonstrate that the angiotensin type 1 receptor rapidly desensitizes after exposure to angiotensin II (AngII). Behaviorally, this likely underlies the reduced drinking observed after acute repeated central injections of AngII. To date, this phenomenon has been studied exclusively in male subjects. Because there are sex differences in the dipsogenic potency of AngII, we hypothesized that sex differences also exist in desensitization caused by AngII. As expected, when male rats were pretreated with AngII, they drank less water after a test injection of AngII than did rats pretreated with vehicle. Intact cycling female rats, however, drank similar amounts of water after AngII regardless of the pretreatment. To probe the mechanism underlying this sex difference, we tested the role of gonadal hormones in adult and developing rats. Gonadectomy in adults did not produce a male-like propensity for desensitization of water intake in female rats, nor did it produce a female-like response in male rats. To test if neonatal brain masculinization generated a male-like responsiveness, female pups were treated at birth with vehicle, testosterone propionate (TP), or dihydrotestosterone (DHT). When tested as adults, TP-treated female rats showed a male-like desensitization after repeated AngII that was not found in vehicle- or DHT-treated rats. Together, these data reveal a striking sex difference in the behavioral response to elevated AngII that is mediated by organizational effects of gonadal hormones and provide an example of one of the many ways that sex influences the renin-angiotensin-aldosterone system.
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