Association of social defeat stress-induced anhedonia-like symptoms with mGluR1-dependent decrease in membrane-bound AMPA-GluR1 in the mouse ventral midbrain

Abstract

Anhedonia is a core symptom of social defeat stress (SDS)-induced depression associated with the reward system. We previously reported that decreased membrane-bound AMPA-GluR1 in the reward system is associated with lipopolysaccharide-induced anhedonia-like symptoms. Since group I metabotropic glutamate receptor (mGluR) activation reduces the surface density of GluR1, we examined whether group I mGluR-dependent decrease in membrane-bound GluR1 in the reward system is involved in SDS-induced anhedonia-like symptoms. Mice exposed to SDS for 4 consecutive days had markedly decreased membrane-bound GluR1 and GluR2 in the prefrontal cortex (PFC) and membrane-bound GluR1 in the ventral midbrain (VM) along with lower sucrose preference (SP). Intra-PFC injection of the group I mGluR agonist (S)-3,5-dihydroxyphenylglycine (DHPG; 100 μmol) demonstrated decrease in membrane-bound GluR1 and GluR2 in the PFC 2 and 24 h and membrane-bound GluR1 in the VM 24 h after injection. Moreover, intra-PFC injection of DHPG decreased SP only in the second 24-h (24–48 h) period. Conversely, intra-VM injection of DHPG decreased SP in both the first and second 24-h period and decreased membrane-bound GluR1 in the VM 2 and 24 h after injection. Pre-treatment with the mGluR1 antagonist JNJ16259685 (30 mg/kg, subcutaneous) prevented SDS-decreased SP and membrane-bound GluR1 in the VM. The mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP; 10 mg/kg, subcutaneous) prevented SDS-induced decrease in membrane-bound GluR1 and GluR2 in the PFC, whereas MPEP did not affect SDS-induced decrease in SP and membrane-bound GluR1 in the VM. These results suggest that mGluR1-mediated decrease in membrane-bound GluR1 in VM is involved in SDS-induced anhedonia-like symptoms.

Keywords:

• Social defeat stress
• anhedonia
• mGluR
• reward system
• AMPA-GluR1
• synaptic plasticity

Acknowledgments

We would like to thank Miss Natsuki Kurosawa, Mr Ko Shimizu and Miss Kasumi Sato for technical supports for performing the experiments. We gratefully acknowledge the work of past and present members of our laboratory. This work was supported by a Grant for Research in the School of Pharmaceutical Science, Ohu University to K. Seki.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by a Grant for Research in the School of Pharmaceutical Science, Ohu University to K. Seki