Parkinsonian Motor Deficits Are Reflected by Proportional A9/A10 Dopamine Neuron Degeneration in the Rat

In a model of Parkinson's disease (PD), amphetamine, a dopamine (DA)-releasing drug, fails to induce ipsilateral drug rotations in a proportion of rats with complete unilateral 6-hydroxydopamine (6-OHDA) lesions of the medial forebrain bundle and DA neurons of the substantia nigra. To investigate this phenomenon, individual 6-OHDA lesions (measured by tyrosine hydroxylase immunohistochemistry) in the substantia nigra pars compacta (A9), ventral tegmental area (A10), and striatum were examined in conjunction with outcomes of four behavioral tests. The behavioral tests were skilled paw reaching, a head-turning test, and apomorphine (0.05 mg/kg) and amphetamine (4 mg/kg) drug-induced rotations. Four weeks postlesion, ipsilateral side bias measured by the head-turning test correlated strongly with extent of A9 DA neuronal lesion. Additional A10 neuronal DA lesions did not substantially improve the model fit, indicating that the head-turning bias was primarily A9 dependent. In contrast, total head-turning activity increased monotonically with lesions of A10 striatal DA fibers. Skilled paw-reaching accuracy decreased with increased lesion of both A9 and A10 DA neuronal systems. Associating amphetamine-induced rotations with extent of A9 DA lesion generated a second-order polynomial model, y = -11.1x + 0.20 x(2) + 208.7 (R(2) = 0.73), with an overall F ratio (df = 2,21) of 28.4 (P < 0.0001). This model predicts that an A9 DA lesion of about 50% is required to induce an ipsilateral turning bias, after which rotations increase with the degree of A9 DA neuronal lesion. No further change in rotational behavior was seen until an additional A10 DA lesion reached 60%, after which the rotational response decreased. This analysis provides tests that differentiate between A9 DA degeneration and combined A9/A10 lesions in animal models and in addition allows predictive testing of PD therapeutic intervention at a preclinical level.

[1]  K. Fuxe,et al.  Functional role of the nigro-neostriatal dopamine neurons. , 2009, Acta pharmacologica et toxicologica.

[2]  O. Isacson,et al.  Immunophilin Ligands and GDNF Enhance Neurite Branching or Elongation from Developing Dopamine Neurons in Culture , 2000, Experimental Neurology.

[3]  Ornella Rimoldi,et al.  Dopamine release from nigral transplants visualized in vivo in a Parkinson's patient , 1999, Nature Neuroscience.

[4]  L. Ryan,et al.  Subthalamic nucleus lesions induce deficits as well as benefits in the hemiparkinsonian rat , 1999, The European journal of neuroscience.

[5]  M. Radeke,et al.  Compartmental expression of trkB receptor protein in the developing striatum , 1999, Neuroscience.

[6]  P. Chaturvedi,et al.  A Novel Immunophilin Ligand: Distinct Branching Effects on Dopaminergic Neurons in Culture and Neurotrophic Actions after Oral Administration in an Animal Model of Parkinson's Disease , 1998, Neurobiology of Disease.

[7]  Anders Björklund,et al.  Characterization of Behavioral and Neurodegenerative Changes Following Partial Lesions of the Nigrostriatal Dopamine System Induced by Intrastriatal 6-Hydroxydopamine in the Rat , 1998, Experimental Neurology.

[8]  L. Annett,et al.  Behavioural effects of subthalamic nucleus lesions in the hemiparkinsonian marmoset (Callithrix jacchus) , 1998, The European journal of neuroscience.

[9]  T. Deacon,et al.  Xenotransplantation of Porcine Fetal Ventral Mesencephalon in a Rat Model of Parkinson's Disease: Functional Recovery and Graft Morphology , 1996, Experimental Neurology.

[10]  A. Björklund,et al.  Dopaminergic neuronal degeneration and motor impairments following axon terminal lesion by intrastriatal 6-hydroxydopamine in the rat , 1996, Neuroscience.

[11]  O. Isacson,et al.  Extensive axonal and glial fiber growth from fetal porcine cortical xenografts in the adult rat cortex. , 1995, Cell transplantation.

[12]  John W. Thomas,et al.  A 6-Hydroxydopamine-Induced Selective Parkinsonian Rat Model: Further Biochemical and Behavioral Characterization , 1994, Experimental Neurology.

[13]  R. Ridley,et al.  Behavioral Assessment of the Effects of Embryonic Nigral Grafts in Marmosets with Unilateral 6-OHDA Lesions of the Nigrostriatal Pathway , 1994, Experimental Neurology.

[14]  D. Gash,et al.  Effect of bilateral 6-OHDA lesions of the substantia nigra on locomotor activity in the rat , 1994, Brain Research.

[15]  Greg A. Gerhardt,et al.  Correlation of apomorphine- and amphetamine-induced turning with nigrostriatal dopamine content in unilateral 6-hydroxydopamine lesioned rats , 1993, Brain Research.

[16]  S B Dunnett,et al.  Behavioural analysis of unilateral monoamine depletion in the marmoset. , 1992, Brain : a journal of neurology.

[17]  P. V. Domburg,et al.  The Human Substantia Nigra and Ventral Tegmental Area: A Neuroanatomical Study With Notes on Aging and Aging Diseases , 1991 .

[18]  S. Dunnett,et al.  The “staircase test”: a measure of independent forelimb reaching and grasping abilities in rats , 1991, Journal of Neuroscience Methods.

[19]  G. Lahoste,et al.  Nigral D1 and striatal D2 receptors mediate the behavioral effects of dopamine agonists , 1990, Behavioural Brain Research.

[20]  L. Sebastiani,et al.  Injections of 6-hydroxydopamine in the substantia nigra of the rat brain: Morphological and biochemical effects , 1990, Behavioural Brain Research.

[21]  M. Moal,et al.  Effects of intra-accumbens dopaminergic grafts on behavioral deficits induced by 6-OHDA lesions of the nucleus accumbens or A10 dopaminergic neurons: A comparison , 1988, Behavioural Brain Research.

[22]  A. Björklund,et al.  Striatal grafts in rats with unilateral neostriatal lesions—III. Recovery from dopamine-dependent motor asymmetry and deficits in skilled paw reaching , 1988, Neuroscience.

[23]  M. Papp,et al.  Separation of the motivational and motor consequences of 6-hydroxydopamine lesions of the mesolimbic or nigrostriatal system in rats , 1987, Behavioural Brain Research.

[24]  M. Papp,et al.  Motivational versus motor impairment after haloperidol injection or 6-OHDA lesions in the ventral tegmental area or substantia nigra in rats , 1986, Physiology & Behavior.

[25]  G. Di Chiara,et al.  D-1 receptor supersensitivity in the rat striatum after unilateral 6-hydroxydopamine lesions. , 1986, European journal of pharmacology.

[26]  A. J. Bradbury,et al.  The neurotoxic actions of 6-hydroxydopamine infused into the rat substantia nigra , 1986, Neuroscience Letters.

[27]  S. Iversen,et al.  Effect of injections of 6-OHDA into either nucleus accumbens septi or frontal cortex on spontaneous and drug-induced activity , 1983, Neuropharmacology.

[28]  G. Koob,et al.  Hyperactivity and hypoactivity produced by lesions to the mesolimbic dopamine system , 1981, Behavioural Brain Research.

[29]  Douglas L. Jones,et al.  From motivation to action: Functional interface between the limbic system and the motor system , 1980, Progress in Neurobiology.

[30]  R. Wurtman,et al.  Partial lesions of the dopaminergic nigrostriatal system in rat brain: biochemical characterization , 1980, Brain Research.

[31]  S. Iversen,et al.  The effect of morphine applied locally to mesencephalic dopamine cell bodies on spontaneous motor activity in the rat , 1979, Neuroscience Letters.

[32]  H. Simon,et al.  Behavioral effects of lesions in the A10 dopaminergic area of the rat , 1977, Brain Research.

[33]  B. Costall,et al.  The relationship between striatal and mesolimbic dopamine dysfunction and the nature of circling responses following 6-hydroxydopamine and electrolytic lesions of the ascending dopamine systems of rat brain , 1976, Brain Research.

[34]  K. E. Moore,et al.  Mesolimbic dopaminergic neurones in the rotational model of nigrostriatal function , 1976, Nature.

[35]  S. Iversen,et al.  Amphetamine and apomorphine responses in the rat following 6-OHDA lesions of the nucleus accumbens septi and corpus striatum , 1975, Brain Research.

[36]  U. Ungerstedt,et al.  Postsynaptic supersensitivity after 6-hydroxy-dopamine induced degeneration of the nigro-striatal dopamine system. , 1971, Acta physiologica Scandinavica. Supplementum.

[37]  U. Ungerstedt.  Striatal dopamine release after amphetamine or nerve degeneration revealed by rotational behaviour. , 1971, Acta physiologica Scandinavica. Supplementum.

[38]  U. Ungerstedt,et al.  Quantitative recording of rotational behavior in rats after 6-hydroxy-dopamine lesions of the nigrostriatal dopamine system. , 1970, Brain research.

[39]  U. Ungerstedt,et al.  6-Hydroxy-dopamine induced degeneration of central monoamine neurons. , 1968, European journal of pharmacology.

[40]  T. Hökfelt,et al.  Evidence for dopamine receptor stimulation by apomorphine , 1967, The Journal of pharmacy and pharmacology.

[41]  M. Abercrombie.  Estimation of nuclear population from microtome sections , 1946, The Anatomical record.

[42]  M. Youdim,et al.  Mechanism of 6-hydroxydopamine neurotoxicity. , 1997, Journal of neural transmission. Supplementum.

[43]  H. T. ten Donkelaar,et al.  The human substantia nigra and ventral tegmental area. A neuroanatomical study with notes on aging and aging diseases. , 1991, Advances in anatomy, embryology, and cell biology.

[44]  G. Paxinos,et al.  The Rat Brain in Stereotaxic Coordinates , 1983 .

[45]  J. V. van Rossum,et al.  Effects of chemical stimulation of the mesolimbic dopamine system upon locomotor activity. , 1976, European journal of pharmacology.

[46]  K. E. Moore,et al.  Supersensitivity to dopamine agonists following unilateral, 6-hydroxydopamine-induced striatal lesions in mice. , 1975, The Journal of pharmacology and experimental therapeutics.

[47]  T. Ljungberg,et al.  Dopaminergic supersensitivity in the striatum. , 1975, Advances in neurology.

[48]  T. Ljungberg,et al.  Behavioral, physiological, and neurochemical changes after 6-hydroxydopamine-induced degeneration of the nigro-striatal dopamine neurons. , 1974, Advances in neurology.