The AS/AGU rat: a spontaneous model of disruption and degeneration in the nigrostriatal dopaminergic system.

The AS/AGU rat provides an alternative to experimentally produced laboratory models of basal ganglia disorders. This mutant is characterised by disturbances of movement including clumsy gait, whole body tremor, rigidity and difficulty in initiating movement. From an early age, there is a profound depletion of extracellular dopamine in the dorsal caudate-putamen as measured via in vivo microdialysis; levels are only 10-20% of those found in the parent Albino Swiss (AS) strain. Subsequently a depletion of whole tissue dopamine levels occurs and, later still, loss of dopaminergic cells in the substantia nigra pars compacta. The dysfunction in movement and the nigrostriatal dopaminergic system are clearly linked, since movement can be ameliorated by L-DOPA administration. Furthermore, there are depletions in glucose utilisation in several regions of the basal ganglia circuitry, including the substantia nigra pars compacta, the subthalamic nucleus and the ventrolateral thalamus. The AS/AGU rat represents a unique opportunity to investigate the intrinsic factors controlling the integrity of dopaminergic systems and the recent successful positional cloning of the agu gene will allow the molecular mechanisms underlying this interesting phenotype to be analysed.

Macrophages of the sperm granuloma 3 months after vasectomy in the Albino Swiss rat.

This study documents the appearance and arrangement of the macrophages of the sperm granuloma 3 months after vasectomy in the Albino Swiss rat. We found, as have others, that the macrophages form a distinct layer in the granuloma wall, external to the central mass of extravasated spermatozoa. Those closest to the spermatozoa showed much phagocytosis. Many had two, three, or more nuclei. The largest macrophages, giant cells of the foreign body and Langhans types, were generally farther from the sperm mass, but retained evidence of phagocytic activity in the form of sperm fragments. Macrophages, either mono- or multinucleate, frequently showed numerous surface microridges that interdigitated with those of neighboring cells. The microridges varied in length, but were of uniform thickness and cytoplasmic content and were rarely branched. Monocytes were frequently observed, indicating continuing significant recruitment of cells of the macrophage series to the granuloma. We also noted mononucleate cells in the connective tissue external to the macrophage layer. Their cytology suggested they were macrophages, but they showed much less phagocytic activity than those of the main macrophage layer and had distinctive aggregations of moderately electron-dense droplets.

Effect of vasectomy on the seminiferous tubule boundary zone in the Albino Swiss rat.

The boundary zone of a seminiferous tubule consists of the basement membrane of the seminiferous epithelium, its myoid cells, and their basal laminae. This study examines the boundary zones of seminiferous tubules in healthy and degenerated testes following long-term, left-sided vasectomy in the rat and compares them to those of sham-operated controls and adult rats exposed in utero to the antiandrogen, flutamide. Degenerated tubular profiles showed similar changes, irrespective of whether the degeneration was ipsilateral or bilateral. In transverse tubular profiles, the basal laminae of the seminiferous epithelium and the myoid cells became more undulating, that of seminiferous epithelium showing complex folding. The collagen layer of the boundary zone, which lies between the basal laminae of the seminiferous epithelium and the myoid cells, thickened and its fibers became irregularly orientated. Rather than being flattened as in controls, the region of the myoid cell near the nucleus and the nucleus itself developed triangular profiles in the transversely sectioned tubules. Similar features were also seen in the degenerated tubules of rats exposed to flutamide. The changes in the boundary zone are not specific for vasectomy and probably reflect reduction in the cross-sectional area of tubular profiles and possibly in their length. We also noted occasional leukocytes infiltrating the boundary zone; they may have increased in number in those tubules that showed degeneration following vasectomy.

Observations on multiple sperm granulomas in the rat epididymis following vasectomy.

Seven epididymides of long-term vasectomized rats showing multiple sperm granulomas were studied in serial histological sections. Despite the presence of the multiple granulomas, only two rats showed continuity of the epididymal duct with the central sperm mass of a granuloma. A further three specimens showed breaks in the epididymal epithelium at sites of local distension in the epididymal tail. Granulomas in the epididymal body seem to receive spermatozoa only transiently. The spermatozoa at the center of granulomas in continuity with the epididymal duct showed evenly distributed sperm heads. A number of others showed clumping of spermatozoa, attributed to stagnation of flow and fluid resorption. In many granulomas, folds in the macrophage layer with a connective tissue core rich in lymphocytes and plasma cells projected into the central sperm mass. We conclude that the sperm granuloma is a dynamic structure that shows changes with age and that the sperm granuloma closest to the testis must not be assumed to be the one that is draining the spermatozoa.

Degenerated tubules in the guinea pig testis after long-term vasectomy or sham operation.

The testes of eight unilaterally vasectomized and six sham-operated Dunkin Hartley guinea pigs were examined 3 years after operation by wax and resin histology and transmission electron microscopy. Degenerated tubules are reported that were common on the side of vasectomy but also found in the contralateral testes and in the controls. A central accumulation of macrophages, rich in phagocytosed debris including spermatozoal fragments, was surrounded by attenuated Sertoli cells, a markedly thickened basement membrane and myoid cells. At some sites macrophages impinged directly on the basement membrane. They probably represented highly degenerated seminiferous tubules. The study suggests that the response to injury of seminiferous tubules may show species variations. Macrophages did not feature in the degenerated seminiferous tubules we reported following vasectomy in the rat. However, the rat showed striking changes in the morphology of the basal laminae and myoid cells which did not occur in the guinea pig. Pathological changes have been reported in the human testis following vasectomy but their etiology is unclear. Studies in the guinea pig are enhancing understanding of the mechanisms and features of testicular damage.

Effect of long-term vasectomy on seminiferous tubules in the guinea pig.

The little previous work on the influence of vasectomy on the guinea pig testis has given controversial results. One group reports that the guinea pig suffers autoimmune orchitis while others claim damage may be mechanical. To clarify the issue, this study compares the morphology of seminiferous tubules 3 years after left unilateral vasectomy (8 guinea pigs) and control sham operation (6 animals). Grossly, left and right testes following left-sided vasectomy were similar to controls and not significantly different in weight. On histology, left and right experimental testes and the control material showed various degrees of seminiferous tubular degeneration, including intraepithelial vesicle formation, loss of germ cells and intraluminal macrophages. Although vesicle formation was striking in most testes, quantitative analysis indicated that it was more frequent in the ipsilateral testis following unilateral vasectomy. It seems that vasectomy had exacerbated an age-related phenomenon. Lymphocytic infiltration was seen in five of the left testes following vasectomy, in two of the corresponding right testes, but in none of the controls. Two vasectomized left testes, however, showed atrophic changes but no lymphocytic invasion. The results suggest that autoimmune orchitis follows vasectomy but that it may not be the primary cause of degeneration. Attempts to gain positive evidence for mechanical damage, however, were inconclusive.

Local cerebral glucose utilization in the AS/AGU rat: a mutant with movement disorders.

The AS/AGU mutant rat is characterized by a wide staggering gait and a movement disorder of the hindlimbs. Local cerebral glucose utilization in the brain was investigated using the [14C]2-deoxyglucose autoradiographic technique to map any functional alterations in the mutant AS/AGU (agu/agu) compared with Albino Swiss controls (+/+). Locomotor tests were also performed to confirm the phenotypic assignment of the animals. Statistically significant reductions in glucose utilization were apparent in 12 of the 44 regions examined in the AS/AGU animals. The regions showing the most significant differences (P < 0.01) from the control AS strain were the substantia nigra pars compacta (-23%) and medial geniculate body (-17%). Statistically significant decreases (P < 0.05 and P < 0.02) in glucose utilization ranging from -15 to -26% were also displayed in the superior colliculus superficial layer, auditory cortex, ventroposterior nucleus of the thalamus, molecular layer of the hippocampus, dentate gyrus, medial amygdaloid nucleus, median raphe nucleus, subthalamic nucleus, medial preoptic area of the hypothalamus and anterior hypothalamus. In no region studied was the mean value of glucose use in the AS/AGU rat greater than in the control animals. The results of this study complement previous behavioural and neurochemical characterization studies of this mutant, confirm that the disorder involves functional disturbances of the basal ganglia, and demonstrate the involvement of the limbic system and some sensory systems.

The effects of pre- and postnatal exposure to the nonsteroidal antiandrogen flutamide on testis descent and morphology in the Albino Swiss rat.

Exposure of male Albino Swiss rats to the nonsteroidal antiandrogen flutamide during the period from gestational day (d) 10 to birth resulted in feminisation of the external genitalia and the suppression of growth of the male reproductive tract. In adulthood, testes were found to be located in diverse positions. True cryptorchidism occurred in 10% of cases, whereas 50% of testes descended to the scrotum and 40% were located in a suprainguinal ectopic region. Varying degrees of tubule abnormality were seen in the testes of flutamide-treated animals, ranging from completely normal tubules with full spermatogenesis (and the expected frequency of the stages of spermatogenesis) to severely abnormal tubules lined with Sertoli cells only. For each individual testis, the overall severity of tubule damage was strongly correlated with its adult location, with intra-abdominal testes worst affected and scrotally-located testes least; only the latter contained normal tubules. Similarly, intra-abdominal testes were the smallest in weight and contained the least testosterone. By contrast, postnatal treatment of male rats with flutamide from birth to postnatal d 14 did not impair development of the external genitalia, the process of testicular descent or adult spermatogenesis. These findings confirm that androgen blockade during embryonic development interferes with testicular descent but also demonstrate that (1) prenatal flutamide treatment per se has a detrimental effect on adult testis morphology but (2) the degree of abnormality of the testes is strongly influenced by location.

Changes in the testes following vasectomy in the rat.

Six months and more after unilateral vasectomy in the rat, ipsilateral (same side) and bilateral testicular atrophy are common; this paper investigates their etiology. Ipsilateral atrophy is associated with the presence of a sperm granuloma in the head of the corresponding epididymis and appears to be pressure-mediated. That sperm granulomas at the epididymal head fail to relieve intraluminal pressure in the epididymal duct of the rat was supported by a study of the effects of ligation of that region. No histological evidence was found to indicate that bilateral atrophy was the result of an immune response. A radiological study does not support the idea that compression or displacement of testicular blood vessels by sperm granulomas is responsible for bilateral atrophy.

Cell recruitment to the sperm granuloma which follows vasectomy in the rat.

Sperm granulomas are chronic inflammatory lesions at sites of extravasation of spermatozoa from the reproductive tract. Using light and transmission electron microscopy, monocytes were identified in the wall of the early granuloma of the vasectomized rat. Some young macrophages contained sperm fragments and scanning electron microscopy showed them to wrap around, and partially engulf, spermatozoa. T-lymphocytes predominated over B-lymphocytes in the granuloma wall, helper cells being more numerous than suppressor/cytotoxic cells. The percentage of lymphocytes of all classes among the cells of the granuloma wall was higher at 3 months than at 3 weeks and 6 months after vasectomy, reflecting the high immunological activity known to occur at this interval after vasectomy in the rat.

Effects of androgens on sexual behaviour and somatic variables in the male golden hamster.

Comparisons were made of the sexual behaviour of sham-operated male hamsters and castrated males receiving testosterone, dihydrotestosterone or androstenedione (1-5 mg/week), or oil alone. Tests of short duration (10 min) were conducted at Week 3 (when the animals were sexually naive), Week 6 and Week 9. Sham-operated males showed marked increases in many elements of behaviour between Weeks 3 and 9, while castrated males receiving no androgen replacement showed marked decreases. Males receiving each of the three androgens showed marked increases in behaviour, but androstenedione-treated males showed less facilitation of sexual behaviour than controls. Dihydrotestosterone was as effective as testosterone. The three androgens were comparable in maintaining seminal vesicle weight after castration and in preventing the customary rise in pituitary and body weights. These data suggest that, unlike the situation in the rat, aromatization of androgens is unnecessary for the display of sexual behaviour in the hamster.