Changes in the expression of genes encoding for mGlu4 and mGlu5 receptors and other regulators of the indirect pathway in acute mouse models of drug-induced parkinsonism.
Neuroadaptive changes involving the indirect pathway of the basal ganglia motor circuit occur in the early phases of parkinsonism. The precise identification of these changes may shed new light into the pathophysiology of parkinsonism and better define the time window of pharmacological intervention. We examined some of these changes in mice challenged with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), or with the dopamine receptor blocker, haloperidol. These two models clearly diverge from Parkinson's disease (PD); however, they allow an accurate time-dependent analysis of neuroadaptive changes occurring in the striatum. Acute haloperidol injection caused a significant increase in the transcripts of mGlu4 receptors, CB1 receptors and preproenkephalin-A at 2 and 24 h, and a reduction in the transcripts of mGlu5 and A2A receptors at 2 h. At least changes in the expression of mGlu4 receptors might be interpreted as compensatory because haloperidol-induced catalepsy was enhanced in mGlu4(-/-) mice. Mice injected with 30 mg/kg of MPTP also showed an increase in the transcripts of mGlu4 receptors, CB1 receptors, and preproenkephalin-A at 3 d, and a reduction of the transcript of A2A receptors at 1 d in the striatum. Genetic deletion of mGlu4 receptors altered the functional response to MPTP, assessed by counting c-Fos(+) neurons in the external globus pallidus and ventromedial thalamic nucleus. These findings offer the first evidence that changes in the expression of mGlu4 and mGlu5 receptors occur in acute models of parkinsonisms, and lay the groundwork for the study of these changes in models that better recapitulate the temporal profile of nigrostriatal dysfunction associated with PD.
I.R.C.C.S. Neuromed, Pozzilli, Italy.
Milena
M
Cannella
I.R.C.C.S. Neuromed, Pozzilli, Italy.
Marta
M
Motolese
I.R.C.C.S. Neuromed, Pozzilli, Italy.
Domenico
D
Bucci
I.R.C.C.S. Neuromed, Pozzilli, Italy.
Gemma
G
Molinaro
Department of Experimental Medicine, University "Sapienza", Rome, Italy.
Roberto
R
Gradini
I.R.C.C.S. Neuromed, Pozzilli, Italy; Department of Physiology and Pharmacology, University "Sapienza", Rome, Italy.
Valeria
V
Bruno
I.R.C.C.S. Neuromed, Pozzilli, Italy; Department of Physiology and Pharmacology, University "Sapienza", Rome, Italy.
Ferdinando
F
Nicoletti
I.R.C.C.S. Neuromed, Pozzilli, Italy. Electronic address: giuseppe.battaglia@neuromed.it.
Giuseppe
G
Battaglia
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000208:Acute Disease; D000818:Animals; D002375:Catalepsy / Q000378:metabolism / Q000473:pathology; D003342:Corpus Striatum / Q000378:metabolism*; D004745:Enkephalins / Q000378:metabolism; D006220:Haloperidol; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D020734:Parkinsonian Disorders / Q000378:metabolism* / Q000473:pathology; D011498:Protein Precursors / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D064529:Receptor, Metabotropic Glutamate 5 / Q000378:metabolism*; D043683:Receptors, Adenosine A2 / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D020651:Ventral Thalamic Nuclei / Q000378:metabolism
D004745:Enkephalins; C578936:Grm5 protein, mouse; D011498:Protein Precursors; D016760:Proto-Oncogene Proteins c-fos; D043884:Receptor, Cannabinoid, CB1; D064529:Receptor, Metabotropic Glutamate 5; D043683:Receptors, Adenosine A2; D018094:Receptors, Metabotropic Glutamate; C033660:preproenkephalin; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D006220:Haloperidol; C108823:metabotropic glutamate receptor 4
Haloperidol; Indirect pathway; MPTP; Metabotropic glutamate receptors; Parkinsonism