RT Journal Article
SR Electronic
T1 Inhibiting Subthalamic D<sub>5</sub> Receptor Constitutive Activity Alleviates Abnormal Electrical Activity and Reverses Motor Impairment in a Rat Model of Parkinson's Disease
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 14840
OP 14849
DO 10.1523/JNEUROSCI.0453-13.2013
VO 33
IS 37
A1 Jonathan Chetrit
A1 Anne Taupignon
A1 Lionel Froux
A1 Stephanie Morin
A1 Rabia Bouali-Benazzouz
A1 Frédéric Naudet
A1 Nabila Kadiri
A1 Christian E. Gross
A1 Bernard Bioulac
A1 Abdelhamid Benazzouz
YR 2013
UL http://www.jneurosci.org/content/33/37/14840.abstract
AB 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 [5S]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.