Summary
In vivo voltammetry was used to monitor dopamine (DA) neuron activity during the course of reinnervation of the initially denervated caudateputamen by grafted mesencephalic neurons. Fetal DA neurons were implanted as a cell suspension into the depth of the caudate-putamen in adult 6-hydroxydopamine-lesioned recipient rats. Recordings were performed over a period of 2.5–4 months, starting within a week after transplantation, using chronically implanted surface-treated multifiber carbon electrodes. The voltammetric method used in this study has generated considerable discussion centred on the ability of the multifiber electrodes to measure DA alone in vivo, but the results of previous studies have led to the conclusion that changes in the voltammetric signal most probably reflect dopaminergic terminal activity. It seems therefore possible to follow the time-course of changes in the voltammetric signal amplitude during the process of dopaminergic reinnervation of the host striatum from the grafts. A 6-hydroxydopamine lesion of the mesostriatal dopamine pathway caused a substantial (> 80%) reduction of the voltammetric signal within 8–10 days, and the low residual signal remained essentially unchanged for time periods up to at least 5 months in the non-grafted control rats. In 7 of 11 rats with DA-rich grafts there was a recovery of the signal amplitude to levels within, or close to, the range recorded from the striatum of normal intact rats. The increase was observed 6–8 weeks after grafting in the rats which had received the largest transplants, and at about 13–14 weeks after grafting in the rats which had received the smallest ones. The recovery of the signal amplitude, from baseline to maximal response, was quite rapid and typically developed between two or three recording sessions, i.e. over a period of one to two weeks. In contrast to the intact striatum, the recovered signal in the graft-reinnervated striata showed a progressive decline within one hour of sampling time at high sampling frequencies (1 per min to 1 per 3 min). Grafted striata also showed a larger response to systemically administered amphetamine than did intact striata. Since the changes in the voltammetric signal recorded with the multifiber electrode mainly reflect dopaminergic terminal activity, the results provide evidence that the intrastriatal DA-rich grafts are spontaneously active, and that the grafted DA neurons can restore DA neuro-transmission in the reinnervated part of the host caudate-putamen to levels which are within the normal range. From the time-course of changes in the voltammetric signal it can be estimated that the outgrowing DA fibers, after an initial maturation period, expand from the graft into the host striatum at a maximum rate of about 0.1 mm per week, and that the advancing front of graft-derived fibers may be capable of saturating the area around the electrode tip with new terminals within a time period of about 1–2 weeks. The characteristics of the signal seem compatible with the view that the activity of the individual grafted DA neurons is greater than that of the mesostriatal DA neurons in situ.
Similar content being viewed by others
References
Abercrombie M (1946) Estimation of nuclear population from microtome sections. Anat Rec 94: 239–247
Arbuthnott G, Dunnett SB, MacLeod N (1985) Electrophysiological recording from nigral transplants in the rat. Neurosci Lett 57: 205–210
Björklund A, Dunnett SB, Stenevi U, Lewis ME, Iversen SD (1980) Reinnervation of the denervated striatum by substantia nigra transplants: functional consequences as revealed by pharmacological and sensorimotor testing. Brain Res 199: 307–333
Björklund A, Stenevi U, Schmidt RH, Dunnett SB, Gage FH (1983a) Intracerebral grafting of neuronal cell suspensions. I. Introduction and general methods of preparation. Acta Physiol Scand, Suppl 522: 1–9
Björklund A, Stenevi U, Schmidt RH, Dunnett SB, Gage FH (1983b) 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
Björklund A, Lindvall O, Isacson O, Brundin P, Wictorin K, Strecker RE, Clarke DJ, Dunnett SB (1987) Mechanisms of action of intracerebral neural implants: studies of nigral and striatal grafts to the lesioned striatum. Trends Neurosci 10: 509–516
Brundin P, Björklund A (1987) Survival, growth and function of dopamine neurons grafted to the brain. In: Seil FJ, Herbert E, Carlson B (eds) Neural regeneration. Progress in Brain Research Vol 71. Elsevier, Amsterdam, pp 293–307
Brundin P, Isacson O, Björklund A (1985) Monitoring of cell viability in suspensions of embryonic CNS tissue and its use as a criterion for intracerebral graft survival. Brain Res 331: 251–259
Cespuglio R, Rious F, Buda M, Faradji H, Gonon F, Jouvet M (1980) Mesure in vivo par voltamétrie impulsionelle différentielle du 5HIAA dans le striatum du rat. C R Acad Sci (Paris) 290: 901–906
Dunnett SB, Björklund A, Gage FH, Stenevi U (1985) Transplantation of mesencephalic dopamine neurons to the striatum of adult rats. In: Björklund A, Stenevi U (eds) Neural grafting in the mammalian CNS. Elsevier, Amsterdam, pp 451–469
Dunnett SB, Björklund A, Schmidt RH, Stenevi U, Iversen SD (1983) Intracerebral grafting of neuronal cell suspensions. IV. Behavioural recovery in rats with unilateral 6-OHDA lesions following implantation of nigral cell suspensions in different brain sites. Acta Physiol Scand, Suppl 522: 29–37
El Ganouni S, Forni C, Nieoullon A (1987) In vitro and in vivo characterization of the properties of multifiber carbon electrode allowing long-term electrochemical detection of dopamine in freely moving animals. Brain Res 404: 239–256
Forni C (1982) Realization of a new multifiber electrochemical device allowing continuous in vivo measurements of neuromediators. J Neurosci Methods 5: 167–171
Forni C, Nieoullon A (1984) Electrochemical detection of dopamine release in the striatum of freely moving hamsters. Brain Res 297: 11–20
Freund TF, Bolam JP, Björklund A, Stenevi U, Dunnett SB, Powell JF, Smith AD (1985) Efferent synaptic connections of grafted dopaminergic neurons reinnervating the host neostriatum: a tyrosine hydroxylase immunocytochemical study. J Neurosci 5: 603–616
Gonon F, Buda M, Cespuglio R, Jouvet M, Pujol JF (1980) In vivo electrical detection of catechols in the rat neostriatum: dopamine or DOPAC? Nature 286: 902–904
Gonon F, Buda M, Cespuglio R, Jouvet M, Pujol JF (1981) Voltammetry in the striatum of chronic freely moving rats: detection of catechols and ascorbic acid. Brain Res 223: 69–80
Groves PM, Rebec GV (1976) Biochemistry and behavior: some central actions of amphetamine and antipsychotic drugs. Ann Rev Psychol 27: 91
Herman JP, Choulli K, Le Moal M (1985) Hyper-activity to amphetamine in rats with dopaminergic grafts. Exp Brain Res 60: 521–526
Kuhr WG, Wightman RM (1986) Real-time measurement of dopamine release in rat brain. Brain Res 381: 168–171
Loren I, Björklund A, Falck B, Lindvall O (1980) The aluminiumformaldehyde (ALFA) method for improved visualization of catecholamines and indoleamines. I. A detailed account of methodology for central nervous tissue, using paraffin, cryostat or vibratome sections. J Neurosci Methods 2: 277–300
Mahalik TJ, Finger TE, Strömberg I, Olson L (1985) Substantia nigra transplants into denervated striatum of the rat: ultrastructure of graft and host interconnections. J Comp Neurol 240: 60–70
Marsden CA, Joseph MH, Kruk ZL, Maidment NT, O'Neill RD, Schenk JO, Stamford JA (1988) In vivo voltammetry: present electrodes and methods. Neuroscience 25: 389–400
Nieoullon A, Forni C, El Ganouni S (1986) Contribution to the study of nigrostriatal dopaminergic neuron activity using electrochemical detection of dopamine release in the striatum of freely moving animals. Ann NY Acad Sci 473: 126–139
Rose G, Gerhardt G, Strömberg I, Olson L, Hoffer B (1985) Monoamine release from dopamine depleted caudate-nucleus by substantia nigra transplants: an in vivo electrochemical study. Brain Res 341: 92–100
Schmidt RH, Björklund A, Stenevi U, Dunnett SB, Gage FH (1983) Intracerebral grafting of neuronal cell suspensions. III. Activity of intrastriatal nigral suspension implants as assessed by measurements of dopamine synthesis and metabolism. Acta Physiol Scand, Suppl 522: 19–28
Schmidt RH, Ingvar M, Lindvall O, Stenevi U, Björklund A (1982) Functional activity of substantia nigra grafts reinnervating the striatum: neurotransmitter metabolism and 14C2- deoxy-D-glucose autoradiography. J Neurochem 38: 737–748
Sharp T, Maidment NT, Brazell MP, Zetterström T, Ungerstedt U, Bennett GW, Marsden CA (1985) Parallel changes in monoamine metabolites measured by simultaneous in vivo differential pulse voltammetry and intracerebral dialysis. Neuroscience 12: 1213–1221
Stamford JA, Kruk ZL, Millar J (1986) Sub-second striatal dopamine release measured by in vivo voltammetry. Brain Res 381: 351–355
Strecker RE, Sharp T, Brundin P, Zetterström T, Ungerstedt U, Björklund A (1987) Autoregulation of dopamine release and metabolism by intrastriatal nigral grafts as revealed by intracerebral dialysis. Neuroscience 22: 169–178
Zetterström T, Sharp T, Marsden CA, Ungerstedt U (1983) In vivo measurement of dopamine and its metabolites by intracerebral dialysis: changes after D-amphetamine. J Neurochem 41: 1769–1773
Zetterström T, Brundin P, Gage FH, Sharp T, Isacson O, Dunnett SB, Ungerstedt U, Björklund A (1986) Spontaneous release of dopamine from intrastriatal nigral grafts as monitored by the intracerebral dialysis technique. Brain Res 362: 344–349
Wuerthele SM, Freed WJ, Olson L, Mohirisa J, Spoor L, Wyatt RJ, Hoffer BJ (1981) Effect of dopamine agonists and antagonists on the electrical activity of substantia nigra neurons transplanted into the lateral ventricle of the rat. Exp Brain Res 44: 1–10
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Forni, C., Brundin, P., Strecker, R.E. et al. Time-course of recovery of dopamine neuron activity during reinnervation of the denervated striatum by fetal mesencephalic grafts as assessed by in vivo voltammetry. Exp Brain Res 76, 75–87 (1989). https://doi.org/10.1007/BF00253625
Received:
Revised:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00253625