Acute dopamine receptor blockade in substantia nigra pars reticulata: a possible model for drug-induced Parkinsonism
Por:
Alejandra Caceres-Chavez, Veronica, Hernandez-Martinez, Ricardo, Perez-Ortega, Jesus, Arieli Herrera-Valdez, Marco, Aceves, Jose J., Galarraga, Elvira, Bargas, Jose
Publicada:
1 dic 2018
Resumen:
Dopamine (DA) depletion modifies the firing pattern of neurons in the
substantia nigra pars reticulata (SNr). shifting their mostly tonic
firing toward 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 20-40% of clinical cases of PS, becoming
a problem for differential diagnosis, and is 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-receptor antagonists (SCH23390 plus sulpiride), to compare with
firing patterns found in DA-depleted tissue. The hypothesis is that SNr
firing would be similar under both conditions. a prerequisite to the
proposal of a similar preparation to test other DIP-producing drugs.
Firing was analyzed with three complementary metrics, showing
similarities between DA depletion and acute DA-receptor blockade.
Moreover, blockade of either nonselective cationic channels or Ca(v)3
T-type calcium channels hyperpolarized the membrane and 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-receptor antagonist firing modifications. Since acute
DA-receptor blockade induces SNr neuron firing similar to that found in
the 6-hydroxydopamine 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.
NEW & NOTEWORTHY Dopamine (DA) depletion enhances substantia nigra pars
reticulata (SNr) neuron bursting and irregular firing, hallmarks of
Parkinsonism. Several drugs, including antipsychotics, antidepressants,
and calcium channel antagonists, among others, produce drug-induced
Parkinsonism. Here we show the first comparison between SNr neuron
firing after DA depletion vs. firing found after acute blockade of DA
receptors. It was found that firing in both conditions is similar,
implying that pathological SNr neuron firing is also a physiological
correlate of drug-induced Parkinsonism.
Filiaciones:
Alejandra Caceres-Chavez, Veronica:
Univ Nacl Autonoma Mexico, Div Neurociencias, Inst Fisiol Celular, Mexico City 04510, DF, Mexico
Hernandez-Martinez, Ricardo:
Univ Nacl Autonoma Mexico, Div Neurociencias, Inst Fisiol Celular, Mexico City 04510, DF, Mexico
Perez-Ortega, Jesus:
Univ Nacl Autonoma Mexico, Dept Neurobiol Desarrollo & Neurofisiol, Inst Neurobiol, Queretaro, Mexico
Arieli Herrera-Valdez, Marco:
Univ Nacl Autonoma Mexico, Dept Matemat, Fac Ciencias, Mexico City, DF, Mexico
Aceves, Jose J.:
Inst Nacl Ciencias Med & Nutr Salvador Zubiran, Mexico City, DF, Mexico
Galarraga, Elvira:
Univ Nacl Autonoma Mexico, Div Neurociencias, Inst Fisiol Celular, Mexico City 04510, DF, Mexico
Bargas, Jose:
Univ Nacl Autonoma Mexico, Div Neurociencias, Inst Fisiol Celular, Mexico City 04510, DF, Mexico
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