Reconstruction of the nigrostriatal dopamine pathway by intracerebral nigral transplants

Abstract

Surgical or neurotox~c lesions of the mgrostriatal dopamme (DA) pathway produce a denervation of the striatum that leads to severe and long-lasting motor disturbances ~,3,'~,6.~1,12 and, if the lesion is bilateral and complete, fatal deficits in consummatory behavlourl,lt, 13. With substantial lesions of the nigrostriatal DA pathway the denervation will persist and functional recovery is very hmited ~0. We here report that transplants of embryonic substantia nigra, implanted into the parietal cortex m adult rats, are able to establish a new dopamlnerglc input to the previously denervated neostrlatum, and that th~s newly-formed 'nigrostHatal' DA pathway may compensate for at least some aspects of the lesion-induced motor disturbances. The ventral mesencephalic tegmentum (containing the developing dopamine-contaming-neurones of the substantla nigra -- A l0 cell system) was dissected out from 1619-day-old rat embryos (crown rump length 15-33 mm) and transplanted into a cavity in the parietal cortex, using a modification s of a previously published transplantation technique 9. The recipients were adult, female, Sprague-Dawley rats (180-200 g body weight) that underwent the following sequence of operations. First, a unilateral destruction of the DA neurones of the substantia mgra was made by two Injections of 6-hydroxydopamine (6-OHDA) into the right substantia nigra. Each injection contained 8/zg of 6-OHDA (free base) in 4/~1 of saline. 0.2 mg/ml of ascorbic acid was added as an anti-oxidant. After 1-2 weeks, a 2 / 3 mm w~de cavity was made through the anterior parietal cortex and the corpus callosum lpsllateral to the 6-OHDA lesion, exposing the dorsal surface of the head of the caudate-putamen. The cavity was made by suction under visual control; it was filled with gel-foam and the wound was closed. Some weeks later the transplant was inserted into the cawty, as shown in Fig 1. The rats were allowed to survive for 1.5 (8 rats), 3.5 (10 rats) and 7 months (5 rats). The ammals in the 3.5 month group were tested repeatedly, before and after transplantation, for amphetamine-reduced circling behaviour (5 mg/kg metamphetamine, i.p.) according to Ungerstedt10,12. All rats in this group responded to the amphetamine injection with at least 10 turns/rain in the direction of the lesion side before transplantation. After sacrifice, all brains were processed for monoamme fluorescence hlstochemistry 7. Microscopy was made in serial sections of the mesencephalon and the