title: Adolescent social defeat alters N-methyl-D-aspartic acid receptor expression and impairs fear learning in adulthood.
abstract: Repeated social defeat of adolescent male rats results in adult mesocortical dopamine hypofunction, impaired working memory, and increased contextual anxiety-like behavior. Given the role of glutamate in dopamine regulation, cognition, and fear and anxiety, we investigated potential changes to N-methyl-D-aspartic acid (NMDA) receptors following adolescent social defeat. As both NMDA receptors and mesocortical dopamine are implicated in the expression and extinction of conditioned fear, a separate cohort of rats was challenged with a classical fear conditioning paradigm to investigate whether fear learning is altered by adolescent defeat. Quantitative autoradiography was used to measure 3H-MK-801 binding to NMDA receptors in regions of the medial prefrontal cortex, caudate putamen, nucleus accumbens, amygdala and hippocampus. Assessment of fear learning was achieved using an auditory fear conditioning paradigm, with freezing toward the auditory tone used as a measure of conditioned fear. Compared to controls, adolescent social defeat decreased adult NMDA receptor expression in the infralimbic region of the prefrontal cortex and central amygdala, while increasing expression in the CA3 region of the hippocampus. Previously defeated rats also displayed decreased conditioned freezing during the recall and first extinction periods, which may be related to the observed decreases and increases in NMDA receptors within the central amygdala and CA3, respectively. The alteration in NMDA receptors seen following adolescent social defeat suggests that dysfunction of glutamatergic systems, combined with mesocortical dopamine deficits, likely plays a role in the some of the long-term behavioral consequences of social stressors in adolescence seen in both preclinical and clinical studies.
authors.affiliation: Center for Brain and Behavior Research, Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, 414 E. Clark St., Vermillion, SD 57069, USA. Electronic address: andrew_novick@brown.edu.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Novick
authors.affiliation: Center for Brain and Behavior Research, Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, 414 E. Clark St., Vermillion, SD 57069, USA.
authors.forename: Mackenzie
authors.initials: M
authors.lastname: Mears
authors.affiliation: Center for Brain and Behavior Research, Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, 414 E. Clark St., Vermillion, SD 57069, USA.
authors.forename: Gina L
authors.initials: GL
authors.lastname: Forster
authors.affiliation: Department of Pharmaceutical Sciences, University of the Sciences in Philadelphia, 600 S 43rd St., Philadelphia, PA 19104, USA.
authors.forename: Yanlin
authors.initials: Y
authors.lastname: Lei
authors.affiliation: Department of Pharmaceutical Sciences, University of the Sciences in Philadelphia, 600 S 43rd St., Philadelphia, PA 19104, USA.
authors.forename: Shanaz M
authors.initials: SM
authors.lastname: Tejani-Butt
authors.affiliation: Center for Brain and Behavior Research, Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, 414 E. Clark St., Vermillion, SD 57069, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Watt
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D056654:CA3 Region, Hippocampal / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000493:pharmacokinetics; D018691:Excitatory Amino Acid Antagonists / Q000493:pharmacokinetics; D005239:Fear / Q000187:drug effects / Q000523:psychology*; D046352:Freezing Reaction, Cataleptic / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D007859:Learning Disabilities / Q000209:etiology*; D008297:Male; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D012919:Social Behavior; D013315:Stress, Psychological / Q000150:complications / Q000209:etiology / Q000473:pathology; D014316:Tritium / Q000493:pharmacokinetics
chemical_list: D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D014316:Tritium; D016291:Dizocilpine Maleate
keywords: Adolescence; Conditioned fear; NMDA; Social defeat; Stress