Dopamine (DA) depletion modifies the firing pattern of neurons in the substantia nigra pars reticulata (SNr) shifting their mostly tonic firing towards irregularity and bursting, traits of pathological firing underlying rigidity and postural instability in Parkinson's disease (PD) patients and animal models of Parkinsonism (PS). Drug induced Parkinsonism (DIP) represents about 20-40% of clinical cases of PS becoming a problem for differential diagnosis, still not well studied with physiological tools. It may co-occur with tardive dyskinesia. Here we use in vitro slice preparations including the SNr to observe drug induced pathological firing by using drugs that most likely produce it: DA receptors antagonists (SCH23390 plus sulpiride), to compare with firing patterns found in DA-depleted tissue. The hypothesis being that SNr firing would be similar under both conditions, a prerequisite to propose a similar preparation to test other DIP producing drugs. Firing was analyzed with three complementary metrics, showing similarities between DA-depletion and acute DA-receptors blockade. Moreover, blockade of either nonselective cationic channels (NSCC) or Ca3-type calcium channels hyperpolarized the membrane, abolished bursting and irregular firing, silencing SNr neurons in both conditions. Therefore, currents generating firing in control conditions are in part responsible for pathological firing. Haloperidol, a DIP producing drug, reproduced DA-receptors antagonists firing modifications. Since acute DA-receptor blockade induces SNr neurons firing similar to that found in the 6-OHDA model of PS, output basal ganglia neurons may play a role in generating DIP. Therefore, this study opens the way to test other DIP producing drugs.
Última actualización: 17/06/2019