Intrastriatal grafts of fetal ventral mesencephalon in rats with unilateral 6-hydroxydopamine lesions can reduce and even reverse rotational behavior in response to direct and indirect dopamine agonists. These grafts can ameliorate deficits on simple spontaneous behaviors, but do not improve complex behaviors that require the skilled integration of the use of both paws. We report here that rats with grafts into the DA-depleted substantia nigra, that receive cyclosporine A, can experience recovery on spontaneous behaviors that mimic those observed in Parkinson's disease. Specific cyclosporine A treatment conditions can differentially affect whether intranigral grafts normalize paw use during initiation or termination of a movement sequence. These findings may have important implications for the treatment of Parkinson's disease.
AppletonR.E.; FarrellK.; TealP.; HashimotoS.A.; WongP.K.Complex partial status epilepticus associated with cyclosporin A therapy.J. Neurol. Neurosurg. Psychiatry52: 1068–1071; 1989.
2.
BadianiA.; BrowmanK.E.; RobinsonT.E.Influence of novel versus home environments on sensitization to the psychomotor stimulant effects of cocaine and amphetamine.Brain Res.674: 291–298; 1995.
3.
BadianiA.; MoranoM.I.; AkilH.; RobinsonT.E.Circulating adrenal hormones are not necessary for the development of sensitization to the psychomotor activating effects of amphetamine [published erratum appears in Brain Res. 1995 Apr 24;678(1-2): 269].Brain Res.673: 13–24; 1995.
BeneckeR.; RothwellJ.C.; DickJ.P.; DayB.L.; MarsdenC.D.Disturbance of sequential movements in patients with Parkinson's disease.Brain361–379; 1987.
6.
BeneckeR.; RothwellJ.C.; DickJ.P.; DayB.L.; MarsdenC.D.Simple and complex movements off and on treatment in patients with Parkinson's disease.J. Neurol. Neurosurg. Psychiatry50: 296–303; 1987.
7.
BirdG.L.; MeadowsJ.; GokaJ.; PolsonR.; WilliamsR.Cyclosporin-associated akinetic mutism and extrapyramidal syndrome after liver transplantation.J. Neurol. Neurosurg. Psychiatry53: 1068–1071; 1990.
8.
BjorklundA.; LindvallO.Dopamine in dendrites of substantia nigra neurons: Suggestions for a role in dendritic terminals.Brain Res.83: 531–537; 1975.
9.
BjorklundA.; SteneviU.; SchmidtR.H.; DunnettS.B.; GageF.H.Intracerebral grafting of neuronal cell suspensions. II. Survival and growth of nigral cell suspensions implanted in different brain sites.Acta Physiol. Scand. Suppl.522: 9–18; 1983.
10.
BlackJ.E.; IsaacsK.R.; AndersonB.J.; AlcantaraA.A.; GreenoughW.T.Learning causes synaptogenesis, whereas motor activity causes angiogenesis, in cerebellar cortex of adult rats.Proc. Natl. Acad. Sci. USA87: 5568–5572; 1990.
11.
BorlonganC.V.; FreemanT.B.; ScorciaT.A.; ShermanK.A.; OlanowW.C.; CahillD.W.; SanbergP.R.Cyclosporine-A increases spontaneous and dopamine agonist-induced locomotor behavior in normal rats.Cell Transplant.4: 65–73; 1995.
12.
BuonamiciM.; CerviniM.A.; RossiA.C.; SebastianiL.; RaffaelliA.; BagnoliP.Injections of 6-hydroxydopamine in the substantia nigra of the rat brain: Morphological and biochemical effects.Behav. Brain Res.38: 83–95; 1990.
13.
BuonamiciM.; MajR.; PaginiF.; RossiA.; KhazanN.Tremor at rest episodes in unilaterally 6-OHDA-induced substantia nigra lesioned rats: EEG-EMG and behavior.Neuropharmacology25: 323–325; 1986.
14.
CarliM.; EvendenJ.L.; RobbinsT.W.Depletion of unilateral striatal dopamine impairs initiation of contralateral actions and not sensory attention.Nature313: 679–682; 1985.
15.
CheramyA.; LevielV.; GlowinskiJ.Dendritic release of dopamine in the substantia nigra.Nature289: 537–542; 1981.
DunnettS.B.; BjorklundA.; SchmidtR.H.; SteneviU.; IversenS.D.Intracerebral grafting of neuronal cell suspensions.IV. Behavioural recovery in rats with unilateral 6-OHDA lesions following implantation of nigral cell suspensions in different forebrain sites. Acta Physiol. Scand. Suppl.522: 29–37; 1983.
18.
DunnettS.B.; WhishawI.Q.; RogersD.C.; JonesG.H.Dopamine-rich grafts ameliorate whole body motor asymmetry and sensory neglect but not independent limb use in rats with 6-hydroxydopamine lesions.Brain Res.415: 63–78; 1987.
19.
FriedmanS.; AderR.Adrenocortical response to novelty and noxious stimulation.Neuroendocrinology2: 209–212; 1967.
20.
GreenoughW.T.; AndersonB.J.Cerebellar synaptic plasticity. Relation to learning versus neural activity.Ann. NY Acad. Sci.627: 231–247; 1991.
21.
HavenM.C.; SobeskiL.M.; EarlR.A.; MarkinR.S.Cyclosporine concentrations in blood after liver transplantation: Correlation of immunoassay results with clinical events [published erratum appears in Clin. Chem. 1989: Nov;35(11): 2257].Clin. Chem.35: 564–568; 1989.
22.
HeftiF.; MelamedE.; SahakianB.J.; WurtmanR.J.Circling behavior in rats with partial, unilateral nigro-striatal lesions: Effect of amphetamine, apomorphine, and DOPA.Pharmacol. Biochem. Behav.12: 185–188; 1980.
23.
HeftiF.; MelamedE.; WurtmanR.J.Partial lesions of the dopaminergic nigrostriatal system in rat brain: Biochemical characterization.Brain Res.195: 123–137; 1980.
24.
HennessyJ.W.; KingM.G.; McClureT.A.; LevineS.Uncertainty, as defined by the contingency between environmental events, and the adrenocortical response of the rat to electric shock.J. Comp. Physiol. Psychol.91: 1447–460; 1977.
25.
HennessyM.; LevineS.Effects of various habituation procedures on pituitary-adrenal responsiveness in the mouse.Physiol. Behav.18: 799–802; 1977.
26.
JohnstonR.; BeckerJ. in preparation.
27.
JonesT.A.; SchallertT.Use-dependent growth of pyramidal neurons after neocortical damage.J. Neurosci.14: 2140–2152; 1994.
28.
LaHosteG.J.; MarshallJ.F.Nigral D1 and striatal D2 receptors mediate the behavioral effects of dopamine agonists.Behav. Brain Res.38: 233–242; 1990.
29.
MarsdenC.D.The mysterious motor function of the basal ganglia: The Robert Wartenberg Lecture.Neurology32: 514–539; 1982.
30.
MontoyaC.P.; AstellS.; DunnettS.B.Effects of nigral and striatal grafts on skilled forelimb use in the rat.Prog. Brain Res.82: 459–466; 1990.
31.
NikkhahG.; BentlageC.; CunninghamM.G.; BjorklundA.Intranigral fetal dopamine grafts induce behavioral compensation in the rat Parkinson model.J. Neurosci.14: 3449–3361; 1994.
32.
NikkhahG.; CunninghamM.G.; McKayR.; BjorklundA.Dopaminergic microtransplants into the substantia nigra of neonatal rats with bilateral 6-OHDA lesions. II. Transplant-induced behavioral recovery.J. Neurosci.3562–3570; 1995.
33.
OorschotD.Total number of neurons in the neostriatal, pallidal, subthalamic, and substantia nigral nuclei of the rat basal ganglia: A stereological study using the Cavalieri and optical dissector methods.J. Comp. Neurol.366: 580–599; 1996.
34.
PaulsonP.E.; RobinsonT.E.Relationship between circadian changes in spontaneous motor activity and dorsal versus ventral striatal dopamine neurotransmission assessed with on-line microdialysis.Behav. Neurosci.108: 624–635; 1994.
35.
PoltorakM.; FreedW.J.Immunological reactions induced by intracerebral transplantation: Evidence that host microglia but not astroglia are the antigen-presenting cells.Exp. Neurol.103: 222–233; 1989.
RobertsonG.S.; FineA.; RobertsonH.A.Dopaminergic grafts in the striatum reduce D1 but not D2 receptor-mediated rotation in 6-OHDA-lesioned rats.Brain Res.539: 304–311; 1991.
38.
RobinsonT.E.; BeckerJ.B.The rotational behavior model: Asymmetry in the effects of unilateral 6-OHDA lesions of the substantia nigra in rats.Brain Res.264: 127–131; 1983.
39.
RubinA.M.; KangH.Cerebral blindness and encephalopathy with cyclosporin A toxicity.Neurology37: 1072–1076; 1987.
40.
SchallertT.; HallS.‘Disengage’ sensorimotor deficit following apparent recovery from unilateral dopamine depletion.Behav. Brain Res.30: 15–24; 1988.
41.
SchultzW.Depletion of dopamine in the striatum as an experimental model of Parkinsonism: Direct effects and adaptive mechanisms.Prog. Neurobiol.18: 121–166; 1982.
42.
StelmachG.E.; WorringhamC.J.; StrandE.A.The programming and execution of movement sequences in Parkinson's disease.Int. J. Neurosci.36: 55–65; 1987.
43.
ThierryA.M.; TassinJ.P.; BlancG.; GlowinskiJ.Selective activation of mesocortical DA system by stress.Nature263: 242–244; 1976.
44.
UngerstedtU.6-Hydroxy-dopamine induced degeneration of central monoamine neurons.Eur. J. Pharmacol.5: 107–110; 1968.
45.
WeinerW.; LangA.An introduction to movement disorders and the basal ganglia. In: WeinerW.; LangA., eds. Movement disorders: A comprehensive survey.Mount Kisco, NY: Futura Publishing;1989: 1–22.
46.
WestermannK.H.; StaibA.H.Nigrostriatally induced motor reactions in the rat. I. Rotational behavior and posture asymmetry after intracerebral injection of apomorphine and dopamine.Acta Biol. Med. Ger.35: 773–780; 1976.
47.
WictorinK.; BrundinP.; SauerH.; LindvallO.; BjorklundA.Long distance directed axonal growth from human dopaminergic mesencephalic neuroblasts implanted along the nigrostriatal pathway in 6-hydroxydopamine lesioned adult rats.J. Comp. Neurol.323: 475–494; 1992.
48.
WidnerH.; BrundinP.Immunological aspects of grafting in the mammalian central nervous system. A review and speculative synthesis.Brain Res.472: 287–324; 1988.
