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.
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.
Basal Ganglia Pathophysiology Unit, Department of Experimental Medical Science, Lund University, Sweden. Electronic address: Hanna.Iderberg@med.lu.se.
Hanna
H
Iderberg
Basal Ganglia Pathophysiology Unit, Department of Experimental Medical Science, Lund University, Sweden.
Natallia
N
Maslava
Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN, USA; Department of Pharmacology, Vanderbilt University, Nashville, TN, USA.
Analisa D
AD
Thompson
Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN, USA; Department of Pharmacology, Vanderbilt University, Nashville, TN, USA.
Michael
M
Bubser
Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN, USA; Department of Pharmacology, Vanderbilt University, Nashville, TN, USA.
Colleen M
CM
Niswender
Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN, USA; Department of Pharmacology, Vanderbilt University, Nashville, TN, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA.
Corey R
CR
Hopkins
Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN, USA; Department of Pharmacology, Vanderbilt University, Nashville, TN, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA.
Craig W
CW
Lindsley
Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN, USA; Department of Pharmacology, Vanderbilt University, Nashville, TN, USA.
P Jeffrey
PJ
Conn
Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN, USA; Department of Pharmacology, Vanderbilt University, Nashville, TN, USA.
Carrie K
CK
Jones
Basal Ganglia Pathophysiology Unit, Department of Experimental Medical Science, Lund University, Sweden. Electronic address: Angela.Cenci_Nilsson@med.lu.se.
M Angela
MA
Cenci
D000613:Aminobutyrates / Q000494:pharmacology; D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology / Q000633:toxicity*; D002375:Catalepsy / Q000188:drug therapy / Q000378:metabolism; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy* / Q000378:metabolism; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology*; D006220:Haloperidol; D007980:Levodopa / Q000494:pharmacology / Q000633:toxicity*; D008297:Male; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000378:metabolism; D010721:Phosphinic Acids / Q000494:pharmacology; D010848:Picolinic Acids / Q000494:pharmacology; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000378:metabolism
D000613:Aminobutyrates; D000978:Antiparkinson Agents; D018683:Excitatory Amino Acid Agents; C555637:LSP1 2111; C571150:N-(3-chlorophenyl)picolinamide; D010721:Phosphinic Acids; D010848:Picolinic Acids; D018094:Receptors, Metabotropic Glutamate; D007980:Levodopa; D016627:Oxidopamine; D006220:Haloperidol; C108823:metabotropic glutamate receptor 4
Dopamine; Dyskinesias; Glutamate; Metabotropic receptor; Movement disorders; Parkinson's disease; Plasticity