Comparison of the effects of tamoxifen and toremifene on liver and kidney tumor promotion in female rats.

Female rats were subjected to a 70% partial hepatectomy and administered either diethylnitrosamine (10 mg/kg) or the solvent, trioctanoin. After a 2 day recovery from the surgery, the rats were placed on basal diet alone or containing phenobarbital (500 mg/kg diet), mestranol (0.2 mg/kg diet), tamoxifen (250 or 500 mg/kg diet) or toremifene (250, 500 or 750 mg/kg diet) for 6 or 18 months prior to killing. The liver and kidneys were prepared for pathological diagnoses. In addition, sections of liver from the 6 month killing were frozen and serially sectioned. The sections were stained for expression of the placental isozyme of glutathione S-transferase (GST), gamma glutamyl transpeptidase (GGT), canalicular ATPase (ATP) and glucose 6-phosphatase (G6P) and scored by quantitative stereology for number and volume fraction of liver occupied by altered hepatic foci (AHF) with alterations in these markers individually and combined (ANY). Each of the agents increased the volume fraction of liver occupied by AHF when the ANY category was used. Statistical increases in both the GGT-positive and G6P-deficient AHF populations were observed in the spontaneously as well as DEN-initiated groups treated with tamoxifen or toremifene. After 18 months of administration, the highest concentration of tamoxifen increased the incidence of malignant hepatic neoplasms in non-DEN-initiated rats. Toremifene, at the highest tested dose, increased the incidence of hepatocellular carcinomas in the DEN-initiated groups to a level one-third that observed with tamoxifen administration to DEN-initiated rats. Both tamoxifen and toremifene increased the incidence of hypernephromas in previously DEN-initiated rats. While both tamoxifen and toremifene are effective promoting agents for DEN-initiated lesions, tamoxifen is more potent than toremifene in the induction of rat hepatocarcinogenesis.

Behavioral effects of intraventricularly administered (-)-nicotine on fixed ratio schedules of food presentation in rats.

The behavioral effects of intraventricularly (IVT) administered (-)-nicotine on food-maintained behavior were studied. Rats responded by pressing a lever under various fixed ratio (FR) schedules. Infusion of 5 microgram of (-)-nicotine suppressed responding under an FR 16 schedule for 11-13 min. The effect was inversely related to the ratio size (16, 32, 64 responses per food delivery), but it was directly related to the infused (-)-nicotine dose (0.312, 0.624, 1.25, 2.5, 5.0, 10.0 microgram) when ratio size was held constant. Responses rates following the (-)-nicotine-induced suppression were similar to those obtained prior to infusion. The behavioral effects of (-)-nicotine were blocked, in a dose-related manner, by the centrally acting nicotinic-cholinergic antagonist, mecamylamine (0.05-3.0 mg/kg) but not by ther peripherally acting antagonist, hexamethonium (0.5-3.0 mg/kg), suggesting that the behavioral effects of IVT infusions of (-)-nicotine are mediated by central nicotine-cholinergic receptors.