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Injection of quinolinic acid in the rat striatum mimics neurochemical changes observed in Huntington's disease. We previously demonstrated that intrastriatal transplantation of fetal striatum or gelfoam protects against toxicity induced by a subsequent intrastriatal injection of quinolinic acid performed one week later. Herein, we examined whether fetal striatum or sham transplantation provides protection against quinolinic acid that lasts up to four weeks. Intrastriatal quinolinic acid injection produces neuronal loss and gliosis in Nissl staining, loss of cytochrome oxidase histochemical staining, decrease in autoradiographic binding of [3H]SCH 23390-labeled dopamine D1 and [3H]CGS 21680-labeled adenosine A2 receptors, and increase in autoradiographic binding of [3H]PK 11195-labeled peripheral benzodiazepine binding sites. None of these changes was observed in rats transplanted with fetal striatum one, two or four weeks before quinolinic acid injection. In animals transplanted with fetal striatal tissue, Nissl staining showed healthy grafts located in normal appearing striata. Although sham transplantation performed one week before quinolinic acid injection also protected against histological, histochemical and binding changes, sham transplantation performed two or four weeks before quinolinic acid injection was less effective in attenuating quinolinic acid-induced striatal toxicity. Thus, sham transplantation provides transient protection against quinolinic acid-induced striatal toxicity, whereas implantation of tissue such as fetal striatum seems to be required for long-lasting protection. Our study suggests that intracerebral transplantation may also act through other mechanisms than restoration of deficient neurotransmitters or damaged pathways, a finding which may have significant clinical implications in assessing the potential benefit of this approach for the treatment of neurodegenerative disorders such as Huntington's disease.

The non-human primate models of Parkinson's disease which have been developed using the neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine) have proven to be either unstable or variable, or to display only a limited subset of parkinsonian features. The present study examined a new two-stage lesion approach in which MPTP was administered via the carotid arteries. The first infusion through one artery produced a hemiparkinsonian state and was followed several months later by a second MPTP infusion into the contralateral carotid artery to induce bilateral parkinsonism. Animals receiving lesions were evaluated using a battery of tests which included a monkey parkinsonism rating scale, a movement time-task and continuous monitoring of home cage activity. All animals monitored showed significant decreases in activity levels of up to 95% following the second lesion. These decreased activity levels remained stable throughout the observation period of up to 12 months postlesion. In addition to the decreased home cage activity, bilaterally lesioned animals displayed bilateral parkinsonian features including akinesia, bradykinesia, rigidity, tremor and balance and gait disturbances which were stable, following an acute period of up to 45 days, for the remainder of the study. Administration of levodopa increased activity levels and reduced motor dysfunctions. Thus, a two-stage bilateral lesion approach, utilizing the neurotoxin MPTP, appears to provide a less variable and relatively stable model of bilateral Parkinson's disease in nonhuman primates. Treated animals display the cardinal features of parkinsonism and respond appropriately to the standard antiparkinsonian drug, levodopa.

Amitotic [3H]thymidine-labeled C6 glioma cells, which are known to produce neurotrophic factor(s), were grafted alone and with adrenal chromaffin cells in an attempt to improve chromaffin cell survival and phenotypic differentiation. Long-Evans rats with unilateral 6-hydroxydopamine-induced lesions of the nigrostriatal pathway were divided into four groups: (1) those receiving adrenal medullary cells co-transplanted with C6 glioma cells; (2) those receiving adrenal medullary graft alone; (3) those receiving C6 glioma grafts alone; and (4) those serving as a vehicle control group. All rats were killed one month after transplantation. Immunohistochemical, neurochemical, and autoradiographic methods were used to identify and characterize the grafted cells. Tyrosine hydroxylase-immunoreactive cells were found in all animals that received grafts of the adrenal medulla alone or of adrenal medulla co-transplanted with C6 glioma cells. The cograft recipients had more tyrosine hydroxylase-immunoreactive cells than the hosts receiving just adrenal chromaffin cells (P less than 0.05). Additionally, more grafted chromaffin cells formed processes in the former group. All three tissue recipient groups (adrenal medullary, C6 glioma cell, and cografted animals) had a significant reduction (P less than 0.05) in ipsilateral rotations after amphetamine (0.5 mg/kg i.p.) injections as compared to the control vehicle recipient group. Moreover, the reduction in rotation was more marked in the cografted hosts than in the other two implanted groups (P less than 0.05). Significantly higher dopamine levels were found in the transplant sites of both cograft and adrenal medullary graft recipients than in sham grafted control animals.

Developing retinas from 13-18-day fetuses and 2-day neonatal Long-Evans rats transplanted into the anterior chamber of adult eyes of the same or different strain (Lewis) survive and differentiate. Light and electron microscopic studies show that the transplants undergo histogenetic differentiation, resulting in the development of neurons and Müller glial cells and formation of nuclear and plexiform layers. Vascular connections develop between the host iris and the retinal transplant. Vessels and nerves, presumably of iridal origin, were seen on the surface of some transplants. Possible manifestations of graft rejection were monitored; signs of tissue rejection in transplants performed in the Long-Evans rats, an outbred strain, were rare and if present they were mild, at least during the survival periods of up to 91 days allowed in these experiments. Transplants into the eyes of Lewis rats were also well tolerated during the survival period. These observations indicate that retinal transplantation to the adult eye of a genetically different host can be successfully achieved and that both embryonic and perinatal retinas are suitable as donor tissue for ocular transplants. The procedure offers ample opportunities for the study of problems related to retinal plasticity.

The purpose of this study was to determine whether cells of the human neuroblastoma line, LA-N-2, are capable of establishing functional synapses in culture. We used a coculture system in which striated muscle cells from the rat served as postsynaptic targets for the cholinergic LA-N-2 cells. By recording postsynaptic responses from muscle cells, differentiated LA-N-2 cells were found to innervate muscle cells, releasing acetylcholine spontaneously at LA-N-2-muscle synapses. A subpopulation of the LA-N-2 cells forming synapses with the muscle cells also developed the ability to release acetylcholine in response to stimulation. This, coupled with results obtained from experiments examining the time course of synapse formation, led us to propose that the extent to which LA-N-2 cells in our coculture system are differentiated may vary and that this variation may underlie the degree to which they express neuron-like transmission properties.

Previously it was found that grafts of supraoptic plus paraventricular areas from 19-day-old foetal normal rats survived in the third ventricle of the brain of 4- to 6-day-old, vasopressin-deficient Brattleboro pups, but could not alleviate their polyuria. In the present series, factors important in graft development were analysed. Again using day-19 fetuses as donors, anterohypothalamus grafts as well as grafts placed near a crushed median eminence survived relatively poorly, but showed the presence of vasopressin neurons immunocytochemically one month post-grafting. Homotopic grafting in the supraoptic nucleus, however, even failed to show surviving vasopressin neurons. Graft survival was improved by the use of donor tissue of fetuses younger than day 19. Parvocellular vasopressin cells were frequently seen, organized into clusters resembling the normal suprachiasmatic nucleus. However, magnocellular neurons, as normally seen in supraoptic and paraventricular nuclei, only survived grafting when taken between days 11 and 15 of fetal age. It was concluded that only immature vasopressin neurons survived grafting under the condition employed. Magnocellular neurons had a limited fiber outgrowth into the host brain and median eminence. Most large neurons only stained with non-specific neurophysin antiserum, not with specific vasopressin-associated neurophysin antiserum. Thin fibers of the parvocellular vasopressin neurons provided only occasional and sparse innervation of the host median eminence and lateral septum (one case), but several examples of massive fiber bundles running dorsally from graft into host brain were observed. These fibers terminated in the thalamic periventricular area, a nucleus that is normally innervated by the vasopressin neurons of the suprachiasmatic nucleus. The failure of the grafts to provide adequate vasopressinergic innervation of the host median eminence probably explains why none of the nearly 200 Brattleboro neonates operated upon showed any sign of relief of their diabetes insipidus. It suggests, however, that the present procedures might be useful in restoring central vasopressinergic functions in the developing Brattleboro rat.