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 towards 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.

Impact of juvenile chronic stress on adult cortico-accumbal function: Implications for cognition and addiction

“…Decreases in markers of glutamatergic signaling and dampened PFC excitability are also noted (Ishikawa et al, 2015; Novick et al, 2016; Ver Hoeve et al, 2014; Zhao et al, 2009). Given the requirement of NMDA receptor-mediated activity within PFC circuits during cognitive tasks (Arnsten & Rubia, 2012), this would presumably result in less recruitment of the PFC as required for effective top-down control.…”

Stress-altered synaptic plasticity and DAMP signaling in the hippocampus-PFC axis; elucidating the significance of IGF-1/IGF-1R/CaMKIIα expression in neural changes associated with a prolonged exposure therapy

“…In this respect, the goal of fear extinction learning is to retrain the brain to prevent the retrieval of aversive memories associated with the post-traumatic stress condition. However, the effectiveness of PET depends on multiple cellular mechanisms such as inflammation, neurotransmitter systems, and synaptic modifications in neural circuits associated with fear memory retrieval (Abraham et al, 2016; Novick et al, 2016). …”

Role of NMDA and AMPA glutamatergic receptors in the effects of social defeat on the rewarding properties of MDMA in mice

“…Furthermore, Novick et al . () reported that repeated social defeat during adolescence produced long‐term changes in the expression of NMDA receptors in several brain areas (increases in the CA3 and decreases in the infralimbic PFC and central amygdala) but not in others (CA1, nucleus accumbens, caudate‐putamen, prelimbic and cingulate cortex, and basolateral amygdala). Finally, Stelly et al .…”

“…A single experience of defeat increased the ratio NMDA/AMPA binding in the CA3 area of the hippocampus (Krugers et al, 1993) and repeated episodic defeats enhanced the GluR1 AMPA subunit protein expression in the ventral tegmental area (VTA) . Furthermore, adolescent social defeat increased the NMDA receptor expression in CA3 in adulthood, although this expression decreased in the central amygdala and the infralimbic prefrontal cortex (PFC) (Novick et al, 2016). Sensitisation to the motor effects of amphetamine induced by the exposure to repeated social defeat was blocked by NMDA and metabotropic glutamate (mGlu5) receptor antagonists (Yap et al, 2005).…”

“…In addition, the changes in NMDA and AMPA receptor membrane expression induced by social defeat were evaluated in the hippocampus and striatum. These brain areas were chosen because of their involvement in the effects of social defeat and drug reward (Krugers et al, 1993;Covington et al, 2010;Bagot et al, 2015;Novick et al, 2016;Yashiro & Seki, 2017;Li et al, 2018). Based on the results obtained with other psychostimulants, our hypothesis is that the NMDA and AMPA receptors will be involved in the effects of social defeat on the rewarding properties of MDMA.…”