Different analyses of neuronal activity in primate models of Parkinson's disease (PD) have resulted in two different views on the effects of dopamine depletion. The first is based on the higher firing rate and bursty firing pattern, and assumes that dopamine depletion results in a hyperactivity of basal ganglia (BG) output structures. The second is based on the less-specific responses to passive joint manipulation and the excessive correlations between neuronal discharges, and assumes that dopamine depletion results in a loss of functional segregation in cortico-BG circuits. The aim of the present study was to test out the predictions of these two different views on thalamic neuronal activity. Three male vervet monkeys (Cercopithecus aethiops) were progressively intoxicated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Neuronal activities were characterized using standard analyses (firing rates and patterns, receptive fields, and cross-correlations) and compared between the normal, asymptomatic (before the stabilization of motor symptoms), and parkinsonian (with persistent akinesia and rigidity) stages of MPTP intoxication. The pallidonigral thalamus (receiving projections from the BG) was characterized in both the asymptomatic and parkinsonian states by (1) an unchanged firing rate and pattern and (2) a proliferation of nonspecific neurons and correlated pairs. In contrast, the cerebellar thalamus (receiving projections from the cerebellum), was characterized by no change (asymptomatic state) or minor changes (symptomatic state). Thus the major dysfunction after dopamine depletion appeared to be the loss of functional segregation within cortico-BG circuits, which could also be at the heart of parkinsonian pathophysiology.

Reduction of A 2A receptor expression is one of the earliest events occurring in both Huntington's disease (HD) patients and mice overexpressing the N-terminal part of mutated huntingtin. Interestingly, increased activity of A 2A receptors has been found in striatal cells prone to degenerate in experimental models of this neurodegenerative disease. However, the role of A 2A receptors in the pathogenesis of HD remains obscure. In the present study, using A 2A Ϫ/Ϫ mice and pharmacological compounds in rat, we demonstrate that striatal neurodegeneration induced by the mitochondrial toxin 3-nitropropionic acid (3NP) is regulated by A 2A receptors. Our results show that the striatal outcome induced by 3NP depends on a balance between the deleterious activity of presynaptic A 2A receptors and the protective activity of postsynaptic A 2A receptors. Moreover, microdialysis data demonstrate that this balance is anatomically determined, because the A 2A presynaptic control on striatal glutamate release is absent within the posterior striatum. Therefore, because blockade of A 2A receptors has differential effects on striatal cell death in vivo depending on its ability to modulate presynaptic over postsynaptic receptor activity, therapeutic use of A 2A antagonists in Huntington's as well as in other neurodegenerative diseases could exhibit undesirable biphasic neuroprotective-neurotoxic effects.

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