Inhibiting subthalamic d5 receptor constitutive activity alleviates abnormal electrical activity and reverses motor impairment in a rat model of parkinson’s disease
Journal of Neuroscience. 2013-09-11; 33(37): 14840-14849
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1. J Neurosci. 2013 Sep 11;33(37):14840-9. doi: 10.1523/JNEUROSCI.0453-13.2013.
Inhibiting subthalamic D5 receptor constitutive activity alleviates abnormal
electrical activity and reverses motor impairment in a rat model of Parkinson’s
Chetrit J(1), Taupignon A, Froux L, Morin S, Bouali-Benazzouz R, Naudet F, Kadiri
N, Gross CE, Bioulac B, Benazzouz A.
(1)Université Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, CNRS,
Institut des Maladies Neurodégénératives, UMR 5293, and CNRS, Institut
Interdisciplinaire des Neurosciences, UMR 5297, F-33000 Bordeaux, France.
Burst firing has been reported as a pathological activity of subthalamic nucleus
(STN) neurons in Parkinson’s disease. However, the origin of bursts and their
causal link with motor deficits remain unknown. Here we tested the hypothesis
that dopamine D5 receptors (D5Rs), characterized by a high constitutive activity,
may contribute to the emergence of burst firing in STN. We tested whether
inhibiting D5R constitutive activity depresses burst firing and alleviates motor
impairments in the 6-OHDA rat model of Parkinson’s disease. Intrasubthalamic
microinjections of either an inverse agonist of D5Rs, flupenthixol, or a D2R
antagonist, raclopride, were applied. Behavioral experiments, in vivo and in
vitro electrophysiological recordings, and ex vivo functional neuroanatomy
studies were performed. Using [(5)S]GTPγ binding autoradiography, we show that
application of flupenthixol inhibits D5R constitutive activity within the STN.
Furthermore, flupenthixol reduced evoked burst in brain slices and converted
pathological burst firing into physiological tonic, single-spike firing in 6-OHDA
rats in vivo. This later action was mimicked by calciseptine, a Cav1 channel
blocker. Moreover, the same treatment dramatically attenuated motor impairment in
this model and normalized metabolic hyperactivity in both STN and substantia
nigra pars reticulata, the main output structure of basal ganglia in rats. In
contrast, raclopride as well as saline did not reverse burst firing and motor
deficits, confirming the selective action of flupenthixol on D5Rs. These results
are the first to demonstrate that subthalamic D5Rs are involved in the
pathophysiology of Parkinson’s disease and that administering an inverse agonist
of these receptors may lessen motor symptoms.
PMID: 24027284 [Indexed for MEDLINE]