olanzapine and tetrahydrodeoxycorticosterone

Olanzapine and fluoxetine elevate the GABAergic neuroactive steroid allopregnanolone to physiologically relevant concentrations in rodent cerebral cortex. It is unknown if these agents also alter pregnenolone or deoxycorticosterone. Since olanzapine and fluoxetine in combination have clinical utility and may demonstrate synergistic effects, we investigated neuroactive steroid alterations following olanzapine, fluoxetine or coadministration. Male rats received IP vehicle, olanzapine, fluoxetine or the combination of both agents in higher-dose (0, 10, 20 or 10/20 mg/kg, respectively) and lower-dose (0, 5, 10 or 5/10 mg/kg, respectively) experiments. Pregnenolone and allopregnanolone levels in hippocampus were determined by gas chromatography/mass spectrometry. Peripheral deoxycorticosterone and other steroid levels were determined by radioimmunoassay. Olanzapine, fluoxetine or the combination increased hippocampal pregnenolone and serum deoxycorticosterone in both higher- and lower-dose experiments, and elevated hippocampal allopregnanolone in higher-dose conditions. No synergistic effects on pregnenolone or allopregnanolone were observed following olanzapine and fluoxetine coadministration compared to either compound alone. Pregnenolone and its sulfate enhance learning and memory in rodent models, and therefore pregnenolone elevations may be relevant to cognitive changes in psychotic and affective disorders. Since pregnenolone decreases have been linked to depression, it is possible that olanzapine- and fluoxetine-induced pregnenolone elevations may contribute to the antidepressant actions of these agents.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Chromatography, High Pressure Liquid; Corticosterone; Desoxycorticosterone; Dose-Response Relationship, Drug; Drug Synergism; Fluoxetine; Gas Chromatography-Mass Spectrometry; Hippocampus; Male; Olanzapine; Pregnanolone; Pregnenolone; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Selective Serotonin Reuptake Inhibitors

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.. 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.. 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.. 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.

Topics: Analysis of Variance; Animals; Behavior, Animal; Benzodiazepines; Corticosterone; Desoxycorticosterone; Dose-Response Relationship, Drug; Female; Infusion Pumps; Mesencephalon; Olanzapine; Ovariectomy; Posture; Progesterone; Radioimmunoassay; Rats; Rats, Long-Evans; Selective Serotonin Reuptake Inhibitors; Sexual Behavior, Animal; Ventral Tegmental Area