SHAM SURGERY DOES NOT AMELIORATE MPTP-INDUCED BEHAVIORAL DEFICITS IN MONKEYS

Parkinsonism has been reported to improve following transplantation of fetal mesencephalic tissue into the striatum of MPTP-exposed monkeys and humans and in patients with idiopathic Parkinson's disease. While there is good evidence for the survival of grafted tyrosine hydroxylas e (TH)-positive cells in animals studies, it is not known whether they produce neuronal effects that account for behavioral improvement afte r transplantation or whether spontaneous or graft-induced changes in t he host striatum are at least partly responsible. Are neuronal synapti c connections and dopamine release necessary, or would ''toenails and talcum powder'' do the job equally well? We have addressed geries, inc luding sham surgery, the implantation of cerebellar tissue, and the im plantation of mesencephalic TH-positive fetal tissue of various gestat ional ages into the striatum. Adult male African green monkeys receive d systemic MPTP administration (cumulative doses of 2.0-2.5 mg/kg) pri or to these stereotaxic surgical manipulations. Subjects were matched for quantitative behavioral deficits prior to surgery. Subjects were e xamined and assessments made by ''blinded'' observers who scored indiv idual spontaneous and elicited behaviors. Observers were trained and t ested repeatedly for inter-rater reliability. A ''parkinsonian summary score'' derived and determined using a principal component factor ana lysis of a large sample of data from MPTP-treated and normal montem br ain tissue was prepared for biochemical analysis of dopamine concentra tions and TH immunohistochemical studies. The most dramatic improvemen t was seen in monkeys with ''early'' (<4 cm fetal crown rump length) s urviving substantia nigra grafts in the caudate nucleus. Some behavior al improvements were seen MPTP-treated sham-operated monkeys, cerebell ar-grafted monkeys, and ''later'' (> 14 cm fetal crown rump length) su bstantia nigra-grafted monkeys. These changes in monkeys which did not have surviving dopamine-producing grafts probably represent the recov ery capacity of MPTP-treated host brain during this time interval sinc e un-operated subjects showed similar changes. More variable effects w ere seen with substantia nigra grafts in the putamen. The most consist ent correlate of behavioral improvement in all experimental groups was elevation in dopamine concentrations near the grafts compared with a distant striatal location which is believed to represent the depletion without the effects of the grafts. While these data do not establish the precise mechanism of action, they point to a hierarchy of factors which provide increasingly large restorative effects, including sprout ing of host neurons and increased dopamine production by grafted fetal dopamine neurons. Sham surgery appears to be significantly less effec tive than early fetal mesencephalic tissue which survives and releases dopmaine.