A circuit-specific role for ifenprodil in blocking cocaine-induced habits Público

Abstract

Goal-directed decision-making – i.e., performing actions based on their expected outcomes – is a critically important behavioral adaptation that requires using learned associations between actions and their outcomes or contingencies, to guide future choices. An over-reliance on inflexible habitual responding at the expense of goal-directed behavior represents a core feature of cocaine misuse. The orbitofrontal cortex (OFC), considered a part of the prefrontal cortex, is essential for updating actions based on changes to contingencies. Cocaine use impairs goal-directed behavior and eliminates dendritic spines in the OFC; these effects are more pronounced in adolescents. We have previously shown that mice that are resilient against developing escalatory cocaine seeking display decreased expression of the GluN2B subunit of NMDA receptors, a post-synaptic protein, in the OFC. Here, we show that ifenprodil, a GluN2B-selective antagonist that displays protective effects in animal models of alcohol, nicotine, and heroine relapse, preserves both goal-directed behavior and OFC dendritic spine densities in adolescent cocaine-exposed mice. Since ifenprodil prevents cocaine-induced loss of OFC dendritic spines, which are the principal post-synaptic sites of excitatory axonal projections, we hypothesized that dysregulation of inputs onto OFC neurons may be involved in the emergence of cocaine-induced habits. The OFC receives inputs from many brain regions, including major inputs from the basolateral amygdala (BLA), which plays a key role in memory consolidation in numerous memory systems. We have previously shown that chemogenetic inhibition of BLA to OFC connections during consolidation of novel contingency memories disrupts goal-directed behavior. Here, we demonstrated that ifenprodil administration failed to protect against cocaine-induced habits when BLA to OFC connections were inhibited, suggesting that the observed mechanism by which ifenprodil blocks cocaine-induced habits may act through BLA to OFC connections. It is possible that ifenprodil could prevent the emergence of durable neural adaptations in response to cocaine exposure in adolescence, that disrupt processes such as compositional changes to NMDA subunits and synaptic strengthening of BLA to OFC connections, which could impair decision-making in adulthood. These findings provide a deeper understanding of the effects of cocaine exposure on the adolescent brain and could lead to future treatment options to prevent long-term decision-making impairments.  

Table of Contents

Introduction…………………….1

           Figures 1-2

Hypotheses……………………..9

Methods……………………….10

Results…………………………15

           Figures 3-5

Discussion……………………20

Conclusion……………………25

References…………………….26

About this Honors Thesis

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School	Emory College
Department	Neuroscience and Behavioral Biology
Degree	B.S.
Submission	Honors Thesis
Language	English
Research Field	Biology, Neuroscience
Palabra Clave	basolateral amygdala orbitofrontal cortex decision making cocaine
Committee Chair / Thesis Advisor	Dr. Shannon L. Gourley, Emory University
Committee Members	Dr. Joseph R. Manns, Emory University Dr. Malavika Murugan, Emory University

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