The anticonvulsant effect of citalopram on El mice,and the levels of tryptophan and tyrosine and their metabolites in the brain

Serotonin (5-HT) plays an important role in the seizures of El mice since the seizure threshold of El mice correlates with the 5-HT concentration in the central nervous system. In this study, the anticonvulsant effect of a 5-HT reuptake blocker, citalopram, was evaluated behaviorally and biochemically. El mouse convulsions were inhibited by oral administration of citalopram for 2 weeks. Citalopram increased tryptophan and tyrosine amounts, and decreased the 5-HT, 5-hydroxy-indoleacetic acid, kynurenine, and dopamine amounts in the brain. These findings show that citalopram depresses monoaminergic metabolism. Given the known convulsant effect of kynurenine, it is suggested that its decrease by citalopram may involve attenuation of El mice seizures.     

Resynchronization of the Circadian Corticosterone Rhythm After a Light/Dark Shift in Juvenile and Adult Mice

Most of the extensive literature concerning the resynchronization of circadian rhythms after a Zeitgeber shift is devoted to the dependence of resynchronization on the mode of the shift and the strength of the Zeitgeber, as well as on the circadian function investigated. Ontogenetic influences have rarely been investigated. Therefore, we studied the resynchronization of several circadian rhythms in juvenile and adult female laboratory mice. We present here the results concerning the corticosterone rhythm. The daily rhythms were determined as transverse profiles (2-h intervals) before as well as 3, 7, and 14 days after an 8-h phase delay of the light/dark cycle produced by a single prolongation of dark time. The corticosterone concentration in serum was determined radioimmunologically. In the control animals the daily patterns were bimodal, with main maxima at the end of the light time and secondary ones just after lights on. Ontogenetic differences were small. In adult mice the amplitude was slightly increased due to an increase in the maximum values, and the time of highest hormone concentrations was slightly phase advanced. In juvenile mice, a distinct daily pattern with a phase position in relation to the light/dark cycle corresponding to that of control animals was present on the 3rd day after the Zeitgeber shift. The daily mean as well as the minimum and maximum values increased initially and reached the values of control animals during the second week. In adult animals, a pronounced daily rhythm with the normal phase position was present only at the 7th postshift day. The amplitude, daily mean, and maximum values were decreased, and the minimum values were increased. The initial values were not reached even after 2 weeks. The results show that resynchronization was faster in juvenile mice compared with adult mice. As a possible cause for the observed age-related differences, a not yet stabilized phase-coupling between various circadian rhythms is supposed.     

Systemic amyloidosis in transgenic mice carrying the human mutant transthyretin (Met 30) gene

To analyze the pathologic processes of amyloid deposition in type I familial amyloidotic polyneuropathy (FAP), mice were made transgenic by introducing the human mutant transthyretin (TTR) gene(MT-hMet 30). An inbred strain of mouse, C57 BL/6, was chosen. Transgenic mice were killed using ether anesthesia at 3-mo intervals up to 24 mo after birth. In these transgenic mice, amyloid deposition started in the gastrointestinal tract, cardiovascular system, and kidneys and extended to various other organs and tissues with advancing age. The pattern of amyloid deposition was similar to that observed in human autopsy cases of FAP, except for its absence in the choroid plexus and in the peripheral and autonomic nervous systems. We extracted the amyloid fibrils from kidneys of these mice with a human mutant TTR gene and analyzed them immunochemically and electronmicroscopically. Deposited amyloid was shown to be composed of human mutant TTR and mouse serum amyloid P component. Amyloid fibril from transgenic mice was morphologically and immunohistochemically similar to that of human FAP. The most striking pathologic feature of the transgenic mice was the absence of amyloid deposition in the peripheral and autonomic nervous tissues. Thus, other intrinsic factors may be involved in amyloid deposition in the nervous tissues of human FAP.     

The radiosensitivity of spermatogonial stem cells in C3H/101 F1 hybrid mice

The radiosensitivity of spermatogonial stem cells of C3H/HeH × 101/H F₁ hybrid mice was determined by counting undifferentiated spermatogonia at 10 days after X-irradiation. During the spermatogenic cycle, differences in radiosensitivity were found, which were correlated with the proliferative activity of the spermatogonial stem cells. In stage VIII_irr, during quiescence, the spermatogonial stem cells were most radiosensitive with a D₀ of 1.4 Gy. In stages XI_irr−V_irr, when the cells were proliferatively active, the D₀ was about 2.6 Gy. Based on the D₀ values for sensitive and resistant spermatogonia and on the D₀ for the total population, a ratio of 45:55% of sensitive to resistant spermatogonial stem cells was estimated for cell killing.

When the present data were compared with data on translocation induction obtained in mice of the same genotype, a close fit was obtained when the translocation yield (Y; in % abnormal cells) after a radiation dose D was described by Y = e^τD, with τ = 1 for the sensitive and τ = 0.1 for the resistant spermatogonial stem cells, with a maximal e^τD of 100.     

Genetic control of retroviral disease in aging wild mice

Different populations of wild mice (Mus musculus domesticus) in Los Angeles and Ventura Counties were observed over their lifespan in captivity for expression of infectious murine leukemia virus (MuLV) and murine mammary tumor virus (MMTV) and for the occurrence of cancer and other diseases. In most populations of feral mice these indigenous retroviruses were infrequently expressed and cancer seldom occurred until later in life (>2 years old). MMTV was found in the milk of about 50% of wild mice, but was associated with only a low incidence (>1%) of breast cancer after one year of age. By contrast, in several populations, most notably at a squab farm near Lake Casitas (LC), infectious MuLV acquired at birth via milk was highly prevalent, and the infected mice were prone to leukemia and a lower motor neuron paralytic disease after one year of age. These two diseases were both caused by the same infectious (ecotropic)strain of MuLV and were the principal cause of premature death in these aging LC mice. A dominant gene called FV-4^R restricting the infection with ecotropic MuLV was found segregating in LC mice. Mice inheriting this FV-4^R allele were resistant to the ecotropic MuLV associated lymphoma and paralysis. The FV-4^R allele represents a defective endogenous MuLV provirus DNA segment that expresses an ecotropic MuLV envelope-related glycoprotein (gp70) on the cell surface. This FV-4^R encoded gp70 presumably occupies the receptor for ecotropic MuLV and blocks entry of the virus. The FV-4^R gene was probably acquired by the naturally occurring crossbreeding of LC feral mice with another species of feral mice (Mus castaneus) from Southeast Asia. The FV-4^R gp70 does not block entry of the amphotropic MuLV that uses a separate cell surface receptor. Therefore LC mice continued to be susceptible to the highly prevalent but weakly lymphogenic and nonparalytogenic amphotropic strain of MuLV. The study points out the potential of feral populations to reveal genes associated with specific disease resistance.     

Evolution of aging: Testing the theory usingDrosophila

Evolutionary explanations of aging (or senescence) fall into two classes. First, organisms might have evolved the optimal life history, in which survival and fertility late in life are sacrificed for the sake of early reproduction or high pre-adult survival. Second, the life history might be depressed below this optimal compromise by the influx of deleterious mutations; since selection against late-acting mutations is weaker, deleterious mutations will impose a greater load on late life. We discuss ways in which these theories might be investigated and distinguished, with reference to experimental work withDrosophila. While genetic correlations between life history traits determine the immediate response to selection, they are hard to measure, and may not reflect the fundamental constraints on life history. Long term selection experiments are more likely to be informative. The third approach of using experimental manipulations suffers from some of the same problems as measures of genetic correlations; however, these two approaches may be fruitful when used together. The experimental results so far suggest that aging inDrosophila has evolved in part as a consequence of selection for an optimal life history, and in part as a result of accumulation of predominantly late-acting deleterious mutations. Quantification of these effects presents a major challenge for the future.