Rationale: The progesterone metabolite and neurosteroid 5alpha-pregnane-3alpha-ol-20-one (3alpha,5alpha-THP) facilitates sexual behavior of estradiol-primed rodents through its actions in the ventral tegmental area (VTA). Olanzapine, an atypical antipsychotic, may exert some of its actions by increasing 3alpha,5alpha-THP levels.
Objective: If olanzapine has effects by increasing 3alpha,5alpha-THP levels, then olanzapine administration to the VTA should facilitate feminine sexual behavior of estradiol-primed rodents concomitant with increasing midbrain levels of 3alpha,5alpha-THP. METHODS. In experiment 1, ovariectomized rats with bilateral cannulae to the VTA were primed with estradiol at 0 h, infused with olanzapine (10 or 20 microg) or vehicle at 47 h, and tested for sexual behavior at 47.5 h. In experiment 2, estradiol-primed ovariectomized rats were infused with olanzapine (10 microg) or vehicle, tested for sexual behavior, then tissues were collected for measurement of midbrain progesterone and 3alpha,5alpha-THP, and plasma corticosterone, progesterone, and 3alpha,5alpha-THP. In experiment 3, estradiol-primed, ovariectomized rats were administered progesterone (500 microg, SC), tested for sexual behavior, then tissues were collected for midbrain and plasma progesterone and 3alpha,5alpha-THP levels.
Results: Infusions of 10 or 20 microg olanzapine to the VTA significantly increased the incidence and intensity of lordosis, and the occurrence of proceptive and aggressive behaviors. Rats infused with olanzapine to the VTA had significantly greater levels of midbrain 3alpha,5alpha-THP than did vehicle-administered rats. Olanzapine did not increase progesterone or corticosterone levels.
Conclusions: Olanzapine increases lordosis and midbrain 3alpha,5alpha-THP when infused to the VTA which suggest that olanzapine's behavioral effects may result, in part, through actions of 3alpha,5alpha-THP, independent of progesterone or corticosterone.