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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)
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author
organization
publishing date
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
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
2015-04-02 15:41:33
date last changed
2017-10-01 03:07:46
@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},
  volume       = {95},
  year         = {2015},
}