Pharmacological stimulation of metabotropic glutamate receptor type 4 in a rat model of Parkinson's disease and l-DOPA-induced dyskinesia: Comparison between a positive allosteric modulator and an orthosteric agonist.
Iderberg, Hanna LU ; Maslava, Natallia LU ; Thompson, Analisa D ; Bubser, Michael ; Niswender, Colleen M ; Hopkins, Corey R ; Lindsley, Craig W ; Conn, P Jeffrey ; Jones, Carrie K and Cenci Nilsson, Angela LU
(2015)
In Neuropharmacology
95.
p.121-129
- Abstract
- Metabotropic glutamate receptor 4 (mGlu4) negatively modulates GABA and glutamate release in the 'indirect pathway' of the basal ganglia, and has thus been proposed as a potential target to treat motor symptoms in Parkinson's disease. Here, we present an extensive comparison of the behavioural effects produced by the mGlu4 positive allosteric modulator (PAM), VU0364770, and the mGlu4 orthosteric agonist, LSP1-2111, in rats with unilateral 6-OHDA lesions. The compounds' activity was initially assessed in a test of haloperidol-induced catalepsy in intact rats, and effective doses were then evaluated in the hemiparkinsonian animal model. Neither of the two compounds modified the development of dyskinetic behaviours elicited by chronic... (More)
- Metabotropic glutamate receptor 4 (mGlu4) negatively modulates GABA and glutamate release in the 'indirect pathway' of the basal ganglia, and has thus been proposed as a potential target to treat motor symptoms in Parkinson's disease. Here, we present an extensive comparison of the behavioural effects produced by the mGlu4 positive allosteric modulator (PAM), VU0364770, and the mGlu4 orthosteric agonist, LSP1-2111, in rats with unilateral 6-OHDA lesions. The compounds' activity was initially assessed in a test of haloperidol-induced catalepsy in intact rats, and effective doses were then evaluated in the hemiparkinsonian animal model. Neither of the two compounds modified the development of dyskinetic behaviours elicited by chronic treatment with full doses of l-DOPA. When given together with l-DOPA to rats with already established dyskinesias, neither VU0364770 nor LSP1-2111 modified the abnormal involuntary movement scores. VU0364770 potentiated, however, the motor stimulant effect of a subthreshold l-DOPA dose in certain behavioural tests, whereas LSP1-2111 lacked this ability. Taken together, these results indicate that a pharmacological stimulation of mGlu4 lacks intrinsic antidyskinetic activity, but may have DOPA-sparing activity in Parkinson's disease. For the latter indication, mGlu4 PAMs appear to provide a better option than orthosteric agonists. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/5265041
- author
- Iderberg, Hanna
LU
; Maslava, Natallia
LU
; Thompson, Analisa D
; Bubser, Michael
; Niswender, Colleen M
; Hopkins, Corey R
; Lindsley, Craig W
; Conn, P Jeffrey
; Jones, Carrie K
and Cenci Nilsson, Angela
LU
- organization
- publishing date
- 2015
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Neuropharmacology
- volume
- 95
- pages
- 121 - 129
- publisher
- Elsevier
- external identifiers
-
- pmid:25749357
- wos:000357349100012
- scopus:84925389242
- pmid:25749357
- ISSN
- 1873-7064
- DOI
- 10.1016/j.neuropharm.2015.02.023
- language
- English
- LU publication?
- yes
- id
- c84b1e32-ba0d-4c2c-8de1-354609a6624a (old id 5265041)
- alternative location
- http://www.ncbi.nlm.nih.gov/pubmed/25749357?dopt=Abstract
- date added to LUP
- 2016-04-01 10:06:39
- date last changed
- 2022-05-13 05:29:04
@article{c84b1e32-ba0d-4c2c-8de1-354609a6624a,
abstract = {{Metabotropic glutamate receptor 4 (mGlu4) negatively modulates GABA and glutamate release in the 'indirect pathway' of the basal ganglia, and has thus been proposed as a potential target to treat motor symptoms in Parkinson's disease. Here, we present an extensive comparison of the behavioural effects produced by the mGlu4 positive allosteric modulator (PAM), VU0364770, and the mGlu4 orthosteric agonist, LSP1-2111, in rats with unilateral 6-OHDA lesions. The compounds' activity was initially assessed in a test of haloperidol-induced catalepsy in intact rats, and effective doses were then evaluated in the hemiparkinsonian animal model. Neither of the two compounds modified the development of dyskinetic behaviours elicited by chronic treatment with full doses of l-DOPA. When given together with l-DOPA to rats with already established dyskinesias, neither VU0364770 nor LSP1-2111 modified the abnormal involuntary movement scores. VU0364770 potentiated, however, the motor stimulant effect of a subthreshold l-DOPA dose in certain behavioural tests, whereas LSP1-2111 lacked this ability. Taken together, these results indicate that a pharmacological stimulation of mGlu4 lacks intrinsic antidyskinetic activity, but may have DOPA-sparing activity in Parkinson's disease. For the latter indication, mGlu4 PAMs appear to provide a better option than orthosteric agonists.}},
author = {{Iderberg, Hanna and Maslava, Natallia and Thompson, Analisa D and Bubser, Michael and Niswender, Colleen M and Hopkins, Corey R and Lindsley, Craig W and Conn, P Jeffrey and Jones, Carrie K and Cenci Nilsson, Angela}},
issn = {{1873-7064}},
language = {{eng}},
pages = {{121--129}},
publisher = {{Elsevier}},
series = {{Neuropharmacology}},
title = {{Pharmacological stimulation of metabotropic glutamate receptor type 4 in a rat model of Parkinson's disease and l-DOPA-induced dyskinesia: Comparison between a positive allosteric modulator and an orthosteric agonist.}},
url = {{http://dx.doi.org/10.1016/j.neuropharm.2015.02.023}},
doi = {{10.1016/j.neuropharm.2015.02.023}},
volume = {{95}},
year = {{2015}},
}