Parkinsonian motor deficits are reflected by proportional A9/A10 dopamine neuron degeneration in the rat

A E Moore, F Cicchetti, J Hennen, O Isacson
Experimental Neurology 2001, 172 (2): 363-76
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.

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