Abstract
The neurotoxin 6-hydroxydopamine (6-OHDA), following pretreatment with the norepinephrine transport inhibitor desipramine, selectively destroys dopaminergic neurons. When given to rats, neonatal 6-OHDA (n6-OHDA) crosses the blood–brain barrier to destroy 90–99% of dopaminergic nerves in pars compacta substantia nigra (SNpc). The n6-OHDA-lesioned rat is posed as a reasonable animal model for PD: (a) the magnitude of dopaminergic neuronal destruction is expansive, (b) mapping of dopaminergic denervation has been defined, (c) effects on dopamine (DA) receptor alterations have been elucidated (d) as well as changes in receptor sensitivity status, (e) reactive sprouting of serotoninergic innervation (i.e. hyperinnervation) has been mapped, and (f) interplay between serotoninergic and dopaminergic systems is characterized. (g) A broad range of locomotor and stereotyped behaviors has been assessed and (h) large numbers of neurochemical assessments have been attained. (i) n6-OHDA-lesioned rats survive 6-OHDA lesioning and (j) the rat is behaviorally indistinguishable from controls. Dopaminergic destruction in early ontogeny rather in adulthood is a ‘treatment liability’ of this model, yet other animal models have liability issues of a serious nature—the initial one being use of a neurotoxin to produce the animal model of PD. The n6-OHDA-lesioned rat is proposed as a PD model for its value in associating the SNpc dopaminergic lesion with behavioral outcomes, also for replicability of dopaminergic destruction, and the accompanying neuronal adaptations and interplay between neuronal phenotypes in brain—which provide a means to better define and understand the range of deficits and neuronal adaptations that are likely to occur in human PD.
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Abbreviations
- α-Syn:
-
Alpha-synuclein
- 5-HT:
-
5-Hydroxytryptamine, serotonin
- 5,7-DHT:
-
5,7-Dihydroxytryptamine
- 6-OHDA:
-
6-Hydroxydopamine
- n6-OHDA:
-
Neonatally administered 6-OHDA
- ADHD:
-
Attention deficit hyperactivity disorder
- AMPH:
-
Amphetamine
- APO:
-
Apomorphine
- BBB:
-
Blood–brain barrier
- CNS:
-
Central nervous system
- DA:
-
Dopamine
- DAR:
-
Dopamine receptor
- DAT:
-
Dopamine transporter
- GI:
-
Gastrointestinal
- i.vtr.:
-
Intracerebroventricular
- l-DOPA:
-
L-3,4-Dihydroxyphenylalanine
- mCPP:
-
M-Chlorophenylpiperazine
- MPP+ :
-
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridinium ion
- MPTP:
-
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
- n6-OHDA:
-
Neonatally administered 6-hydroxydopamine
- NE:
-
Norepinephrine
- NET:
-
Norepinephrine transporter
- PCA:
-
Parachloroamphetamine
- PD:
-
Parkinson’s disease
- PFFs:
-
Pre-formed fibrils
- R:
-
Receptors
- ROS:
-
Reactive oxygen species
- SNpc:
-
Substantia nigra pars compacta
- VCMs:
-
Vacuous chewing movements
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Acknowledgements
Research supporting experimental work by the author was funded by the Parkinson Foundation, March of Dimes, Scottish Rite Schizophrenia Research Program, John E. Fogarty Foundation International Center grants and NINDS NS 39272 and NS 29505.
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Kostrzewa, R.M. Neonatal 6-hydroxydopamine lesioning of rats and dopaminergic neurotoxicity: proposed animal model of Parkinson’s disease. J Neural Transm 129, 445–461 (2022). https://doi.org/10.1007/s00702-022-02479-4
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DOI: https://doi.org/10.1007/s00702-022-02479-4