NMDA receptor antagonists attenuate the proconvulsant effect of juvenile social isolation in male mice.

Abstract

Experiencing psychosocial stress in early life, such as social isolation stress (SIS), is known to have negative enduring effects on the development of the brain and behavior. In addition to anxiety and depressive-like behaviors, we previously showed that juvenile SIS increases susceptibility to pentylenetetrazole (PTZ)-induced seizures in mice through enhancing the nitrergic system activity in the hippocampus. In this study, we investigated the possible involvement of N-methyl-D-aspartate (NMDA) receptors in proconvulsant effects of juvenile SIS. Applying 4 weeks of SIS to juvenile male mice at postnatal day 21-23, we observed an increased susceptibility to PTZ as well as anxiety and depressive-like behaviors in adult mice. Intraperitoneal (i.p.) administration of NMDA receptor antagonists, MK-801 (0.05 mg/kg) and ketamine (0.5mg/kg), reversed the proconvulsant effects of SIS in Isolated (and not social) housed animals. Co-administration of non-effective doses of nitric oxide synthase (NOS) inhibitors, 7NI (25mg/kg) and L-NAME (10mg/kg), with NMDA receptor antagonists, MK-801 (0.01 mg/kg) and ketamine (0.1mg/kg) attenuated the proconvulsant effects of juvenile SIS only in isolated housed mice. Also, using real time RT-PCR, we showed that hippocampal upregulation of NR2B subunit of NMDA receptor may play a critical role in proconvulsant effects of juvenile SIS by dysregulation of NMDA/NO pathway. In conclusion, results of present study revealed that experiencing SIS during adolescence predisposes the co-occurrence of seizure disorders with psychiatric comorbidities and also, alteration of NMDA receptor structure and function in hippocampus plays a role in proconvulsant effects of juvenile SIS through enhancing the NMDA/NO pathway.

• Authors: Shayan Amiri, Arya Haj-Mirzaian, Hossein Amini-khoei, Majid Momeny, Armin Shirzadian, Maryam Rahimi-Balaei, Ghazaleh Zarrinrad, Mahmoud Ghazi-Khansari, Romina Azizi, Ahmad Reza Dehpour, Shahram Ejtemaei Mehr
• Journal: Brain research bulletin (Brain Res Bull) Vol. 121 Pg. 158-68 (03 2016) ISSN: 1873-2747 [Electronic] United States
• PMID: 26836272 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 Elsevier Inc. All rights reserved.

Chemical References

• Enzyme Inhibitors
• Excitatory Amino Acid Antagonists
• Indazoles
• RNA, Messenger
• Receptors, N-Methyl-D-Aspartate
• Ketamine
• Dizocilpine Maleate
• 7-nitroindazole
• NG-Nitroarginine Methyl Ester
• Pentylenetetrazole

Topics

• Age Factors
• Animals
• Animals, Newborn
• Disease Models, Animal
• Dizocilpine Maleate (therapeutic use)
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (pharmacology)
• Excitatory Amino Acid Antagonists (therapeutic use)
• Immobility Response, Tonic (drug effects)
• Indazoles
• Ketamine (therapeutic use)
• Male
• Maze Learning (drug effects)
• Mice
• Motivation (drug effects)
• NG-Nitroarginine Methyl Ester (pharmacology)
• Pentylenetetrazole (toxicity)
• RNA, Messenger (metabolism)
• Receptors, N-Methyl-D-Aspartate (genetics, metabolism)
• Seizures (chemically induced, drug therapy)
• Social Isolation (psychology)
• Statistics, Nonparametric
• Swimming (psychology)
• Time Factors