Effects of aromatase inhibitor letrazole on monoaminergic neurotransmitters, ncam levels and cognitive functions in female rats

It is well-known that estrogen influences the learning and memory, especially spatial memory. Expression of aromatase which synthesizes estrogen has been demonstrated in neurons and astrocytes. However, letrazole strongly inhibits this enzyme in a reversible manenr. In this study, we aimed to investigate effecte of letrazol on spatial learning, memory perfomances, neural cell adhesion molecules (NCAM) in different brain regions and the catecholaminergic neurotransmitter levels and their relationship. In intact model, 32 adult Sprague-Dawley rats with regular oestrous cycles were divided into four groups (n=8). Rats in control group received saline alone. Letrazole was administered to the animals in the second and third groups by daily oral gavage at 0.2 and 1 mg/kg doses, respectively, for six weeks. Another group of letrazole (1mg/kg)-treated rats were allowed to recover for two weeks. In the second model, 32 rats were divided into four groups after bilateral ovariectomy. The first group served as control and received saline alone. Letrazole (1 mg/kg) was administered to second group for six weeks. Ovariectomized (ovx) rats in the third group were administered letrazole (1 mg/kg) and daily estradiol (E2, 10 ?g/rat). The rats in the last group were administered letrazole (1 mg/kg) and E2, (10 ?g/rat) on alternate days. At the end, all rats were subjected to a spatial version of Morris water maze. Then, the animals were decapitated and the brains rapidly removed and seperated into regions. Catecholamine concentrations were determined by HPLC-ECD. NCAM 180, 140 and 120 isoforms were detected by Western blotting. Levels of serum E2 were determined by ELISA. Uterine weights were significantly reduced by letrazole in a dose-dependent manner (p<0.01) which returned to control values following two weeks of recovery (p<0.05). Serum E2 levels followed a similar course (p<0.01). Although improvement in spatial learning performance of letrazole-treated rats was not statistically significant, high-dose letrazole-treated group remained significantly longer in the target quadrant compared to the control in probe trial performance test (p<0.05). Administration of letrazole to ovx animals significantly reduced the latency (p<0.001) and increased the probe trial performance compared to ovx controls (p<0.05). The learning performance was rather insuficient in rats treated with daily E2 compared to all of the others groups, but it was better with E2 on alternate days than treated with daily E2 animals (p<0.05). Letrazole increased expressions of NCAM 180 and NCAM 140 in both hippocampus and cortex of intact rats (p<0.01 and p<0.001, respectively). In the cortex samples of ovx animals, NCAM 180 was overall lower than the intact control values (p<0.05). Concentrations of catecholaminergic neurotransmitters differed according to the brain region and types of catecholaminergic neurotransmitters studied. It appears that inhibition of estrogen synthesis in the brain may have beneficial effects on spatial memory. We suggest that structural changes such as NCAM expression and catecholaminergic neurotransmitters in the hippocampus and prefrontal cortex may be the neural basis for estrogen-dependent alterations in cognitive functions. Moreover, the method for estrogen administration to ovx rats may affect the learning performance and catecholamine levels.