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

Hanna Iderberg, Natallia Maslava, Analisa D. Thompson, Michael Bubser, Colleen M. Niswender, Corey R. Hopkins, Craig W. Lindsley, P. Jeffrey Conn, Carrie K. Jones, M. Angela Cenci

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article number5768
Pages (from-to)121-129
Number of pages9
JournalNeuropharmacology
Volume95
DOIs
StatePublished - Aug 2015

Fingerprint

Dyskinesias
Parkinson Disease
Pharmacology
Catalepsy
Aptitude
Oxidopamine
Haloperidol
Basal Ganglia
gamma-Aminobutyric Acid
Glutamic Acid
Animal Models
metabotropic glutamate receptor 4
N-(3-chlorophenyl)picolinamide
LSP1 2111

Keywords

  • Dopamine
  • Dyskinesias
  • Glutamate
  • Metabotropic receptor
  • Movement disorders
  • Parkinson's disease
  • Plasticity

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience

Cite this

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; Maslava, Natallia; Thompson, Analisa D.; Bubser, Michael; Niswender, Colleen M.; Hopkins, Corey R.; Lindsley, Craig W.; Conn, P. Jeffrey; Jones, Carrie K.; Cenci, M. Angela.

In: Neuropharmacology, Vol. 95, 5768, 08.2015, p. 121-129.

Research output: Contribution to journalArticle

Iderberg, Hanna ; Maslava, Natallia ; Thompson, Analisa D. ; Bubser, Michael ; Niswender, Colleen M. ; Hopkins, Corey R. ; Lindsley, Craig W. ; Conn, P. Jeffrey ; Jones, Carrie K. ; Cenci, M. Angela. / 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. In: Neuropharmacology. 2015 ; Vol. 95. pp. 121-129.
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AU - Bubser, Michael

AU - Niswender, Colleen M.

AU - Hopkins, Corey R.

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AB - 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.

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