Direct Evaluation of L-DOPA Actions on Neuronal Activity of Parkinsonian TissueIn Vitro

Abstract

Physiological and biochemical experiments in vivo and in vitro have explored striatal receptor signaling and neuronal excitability to posit pathophysiological models of Parkinson's disease. However, when therapeutic approaches, such as dopamine agonists, need to be evaluated, behavioral tests using animal models of Parkinson's disease are employed. To our knowledge, recordings of population neuronal activity in vitro to assess anti-Parkinsonian drugs and the correlation of circuit dynamics with disease state have only recently been attempted. We have shown that Parkinsonian pathological activity of neuronal striatal circuits can be characterized in in vitro cerebral tissue. Here, we show that calcium imaging techniques, capable of recording dozens of neurons simultaneously with single-cell resolution, can be extended to assess the action of therapeutic drugs. We used L-DOPA as a prototypical anti-Parkinsonian drug to show the efficiency of this proposed bioassay. In a rodent model of early Parkinson's disease, Parkinsonian neuronal activity can be returned to control levels by the bath addition of L-DOPA in a reversible way. This result raises the possibility to use calcium imaging techniques to measure, quantitatively, the actions of anti-Parkinsonian drugs over time and to obtain correlations with disease evolution and behavior.

Global actions of nicotine on the striatal microcircuit

“…Indeed, in comparison to our early Parkinsonian animal models (Jáidar et al, 2010), we show that the action of nicotine is almost as strong as that of L-DOPA (Plata et al, 2013). Such a strong anti-Parkinsonian action at the circuit level was certainly unexpected.…”

“…Finally, we also quantified the number of synchronization peaks per epoch: it was an average of 4.2 ± 1.7 peaks/epoch ( n = 6 slices; n = 18 epochs) in a sample of DA deprived slices and 0.3 ± 0.7 (peaks/epoch) in DA deprived slices during nicotine treatment (Figure 5F; n = 6 slices; n = 12 epochs; *** P < 0.005). In fact, the action of nicotine in this early Parkinsonian tissue is as potent as that of L-DOPA (cf., Plata et al, 2013). …”

“…Here, we tested nicotine, which has been suspected to possess anti-Parkinsonian activity for a long time. Indeed, it had an action similar to L-DOPA assayed in the same preparation (cf., Plata et al, 2013). However, both drugs were assayed in early Parkinsonian animals tested with turning behavior as a correlate of DA-deprivation.…”

“…In such a case, DA analogs, such as L-DOPA, completely restore the control activity of the circuit, dramatically and reversible, being this action a neuronal correlate of behavioral and clinical trials (Plata et al, 2013). Accordingly, one question of the present work is how much nicotinic actions approximate that of L-DOPA.…”

“…Average significance is reported. In addition, for sample comparisons of these parameters we used Wilcoxon's T statistic for paired samples and Mann-Whitney U statistic for non-paired samples (Plata et al, 2013). …”