L-DOPA is the main pharmacological
therapy for
Parkinson's disease. However, long-term exposure to
L-DOPA induces
involuntary movements termed
dyskinesia. Clinical trials show that
dyskinesia is attenuated by
metabotropic glutamate receptor type 5 (mGluR5) antagonists. Further, the onset of
dyskinesia is delayed by
nicotine and mGluR5 expression is lower in smokers than in non-smokers. However, the mechanisms by which mGluR5 modulates
dyskinesia and how mGluR5 and
nicotine interact have not been established. To address these issues, we studied the role of mGluR5 in D1R-containing neurons in
dyskinesia and examined whether
nicotine reduces
dyskinesia via mGluR5. In the
aphakia mouse model of
Parkinson's disease, we selectively knocked down mGluR5 in D1R-containing neurons (aphakia-mGluR5KD-D1). We found that genetic downregulation of mGluR5 decreased
dyskinesia in
aphakia mice. Although chronic
nicotine increased the
therapeutic effect of
L-DOPA in both
aphakia and aphakia-mGluR5KD-D1 mice, it caused a robust reduction in
dyskinesia only in
aphakia, and not in aphakia-mGluR5KD-D1 mice. Downregulating mGluR5 or
nicotine treatment after
L-DOPA decreased ERK and
histone 3 activation, and FosB expression. Combining
nicotine and mGluR5 knockdown did not have an added antidyskinetic effect, indicating that the effect of
nicotine might be mediated by downregulation of mGluR5 expression. Treatment of aphakia-mGluR5KD-D1 mice with a negative allosteric modulator did not further modify
dyskinesia, suggesting that mGluR5 in non-D1R-containing neurons does not play a role in its development. In conclusion, this work suggests that mGluR5 antagonists reduce
dyskinesia by mainly affecting D1R-containing neurons and that the effect of
nicotine on dyskinetic signs in
aphakia mice is likely via mGluR5.