Steroid hormones mediate sex difference in brain levels of tacrine and itshypothermic effect in the rat

Tacrine, a reversible cholinesterase (ChE) inhibitor, lowers body temperatu re by increasing cholinergic activity in the hypothalamus. Its hypothermic effect was significantly greater in female than in male rats at doses of 2. 5-12.5 mg/kg. Gonadectomy increased the maximum fall in temperature after t acrine (5 mg/ka) from 1.92 +/-0.16 to 2.59 +/-0.13 degreesC in males and fr om 2.96 +/-0.25 to 3.63 +/-0.27 degreesC in females. Testosterone (10 mg/ra t) rats significantly reduced the hypothermia in gonadectomised males and f emales and abolished the gender difference. Adrenalectomy increased the fal l in temperature after tacrine (5 mg/kg) to 2.92 +/-0.15 degreesC in males and 4.18 +/-0.24 degreesC in females. The sex difference that remained was abolished by four daily injections of corticosterone (5 mg/kg). Plasma ChE can bind tacrine thereby lowering the amount available to the brain. Ovarie ctomy decreased plasma ChE activity from 2.27 +/-0.24 to 1.66 +/-0.14, whil e adrenalectomy reduced it to 1.30 +/-0.10 (mu moles acetylthiocholine hydr olysed/ml/h). This enzyme activity was unaffected by gonadectomy and adrena lectomy in males. Brain levels of tacrine, (5 mg/kg), 1 h after injection w ere 2.41 +/-0.35 mug/gm in males and 4.97 +/-0.57 mug/gm in females. Gonade ctomy increased brain levels in males to 4.05 +/-0.51 mug/gm and testostero ne restored them to 2.64 +/-0.3 mug/gm. The hypothermic effect of tacrine w as highly correlated to its brain concentration after the hormonal manipula tions. It is concluded that steroids can reduce the pharmacological effects of tacrine by interfering with its entry into the brain. (C) 2001 Elsevier Science Ltd. All rights reserved.