Autoradiographic labelling of metabotropic glutamate type 2/3 receptors in the hemi-parkinsonian rat brain

Esther Kim; Imane Frouni; Judy Shaqfah; Dominique Bédard; Philippe Huot

doi:10.1016/j.jchemneu.2024.102422

Autoradiographic labelling of metabotropic glutamate type 2/3 receptors in the hemi-parkinsonian rat brain

J Chem Neuroanat. 2024 Apr 23:138:102422. doi: 10.1016/j.jchemneu.2024.102422. Online ahead of print.

Authors

Esther Kim¹, Imane Frouni², Judy Shaqfah¹, Dominique Bédard¹, Philippe Huot³

Affiliations

¹ Neurodegenerative Disease Group, Montreal Neurological Institute-Hospital (The Neuro), Montreal, QC, Canada.
² Neurodegenerative Disease Group, Montreal Neurological Institute-Hospital (The Neuro), Montreal, QC, Canada; Département de Pharmacologie et Physiologie, Université de Montréal, Montreal, QC, Canada.
³ Neurodegenerative Disease Group, Montreal Neurological Institute-Hospital (The Neuro), Montreal, QC, Canada; Département de Pharmacologie et Physiologie, Université de Montréal, Montreal, QC, Canada; Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada; Movement Disorder Clinic, Division of Neurology, Department of Neurosciences, McGill University Health Centre, Montreal, QC, Canada. Electronic address: philippe.huot@mcgill.ca.

PMID: 38657828
DOI: 10.1016/j.jchemneu.2024.102422

Abstract

L-3,4-dihydroxyphenylalanine (L-DOPA) is the treatment of choice for Parkinson's disease (PD) motor symptoms, but its chronic use is hindered by complications such as dyskinesia. Pre-clinical studies discovered that activation of metabotropic glutamate type 2 and 3 (mGlu_2/3) receptors alleviates L-DOPA-induced dyskinesia. To gain mechanistic insight into the anti-dyskinetic activity of mGlu_2/3 activation, we performed autoradiographic binding with [³H]-LY-341,495 in brain sections from L-DOPA-treated 6-hydroxydopamine (6-OHDA)-lesioned rats that developed mild or severe dyskinesia, as well as L-DOPA-untreated 6-OHDA-lesioned and sham-lesioned animals. In the ipsilateral hemisphere, mildly dyskinetic 6-OHDA-lesioned rats showed a decrease in [³H]-LY-341,495 binding in the entopeduncular nucleus (EPN, 30 % vs sham-lesioned rats, P<0.05), globus pallidus (GP, 28 % vs sham-lesioned rats, P<0.05; 23 % vs L-DOPA-untreated 6-OHDA-lesioned rats, P<0.001), and primary motor cortex (49 % vs sham-lesioned rats, P<0.05; 45 % vs L-DOPA-untreated 6-OHDA-lesioned rats, P<0.001). Severely dyskinetic 6-OHDA-lesioned rats exhibited an increase in binding in the primary motor cortex (43 % vs mildly dyskinetic 6-OHDA-lesioned rats, P<0.05). In the contralateral hemisphere, mildly dyskinetic 6-OHDA-lesioned rats harboured a decrease in binding in the EPN (30 % vs sham-lesioned rats; 24 % vs L-DOPA-untreated 6-OHDA-lesioned rats, both P<0.05), GP (34 % vs sham-lesioned rats, P<0.05; 23 % vs L-DOPA-untreated 6-OHDA-lesioned rats, P<0.001), and primary motor cortex (50 % vs sham-lesioned rats; 44 % vs L-DOPA-untreated 6-OHDA-lesioned rats, both P<0.05). Severely dyskinetic 6-OHDA-lesioned rats presented a decrease in binding in the GP (30 % vs sham-lesioned rats; 19 % vs L-DOPA-untreated 6-OHDA-lesioned rats, both P<0.05). Abnormal involuntary movements scores of 6-OHDA-lesioned animals were positively correlated with [³H]-LY-341,495 binding in the ipsilateral striatum, ipsilateral EPN, ipsilateral primary motor cortex and contralateral primary motor cortex (all P<0.05). These results suggest that alterations in mGlu_2/3 receptor levels may be part of an endogenous compensatory mechanism to alleviate dyskinesia.

Keywords: 6-OHDA-lesioned rat; Autoradiography; Dyskinesia; Parkinson’s disease; [(3)H]-LY-341,495; mGlu(2/3) receptors.