Date of Award

5-2023

Document Type

Thesis campus only

Department

Neuroscience

First Advisor

Kah-Chung Leong

Second Advisor

Kimberley Phillips

Third Advisor

Gerard Beaudoin

Abstract

In addition to cocaine’s addictive properties, cocaine use may lead to heightened risk-taking behaviors in individuals despite potentially aversive consequences. One possible reason for this may be cocaine’s disruptive effect on aversive memory formation. The present study investigated the effects of cocaine on fear memory formation using a cued fear conditioning paradigm in female Sprague Dawley rats. On day 1, animals received tone-shock pairings and on day 2 (24 hours later) were returned to the fear chamber and tested for recall of fear memory. Fear was measured as percent time the animal spent freezing during the tone presentation. In Experiment 1 (n = 48), cocaine (15mg/kg; i.p.) was administered prior to or immediately after the conditioning trials to assess the effect of cocaine on fear memory acquisition and consolidation. To determine whether cocaine’s effects on memory consolidation are mediated by D2 receptors, the D2 receptor antagonist eticlopride (0.1mg/kg; i.p.) was administered concurrently with cocaine. No drugs were administered on test day. Results from Experiment 1 revealed that pre-training cocaine diminishes fear acquisition and that post-conditioning cocaine resulted in diminished fear expression during fear test. Concurrent D2 antagonism attenuated the impairing effect of cocaine on fear memory consolidation, with animals showing increased freezing relative to animals receiving cocaine alone. In Experiment 2 (n = 15), animals received direct infusions of eticlopride (0.05 μl/min) into the ventral hippocampus (VH), a structure known to be involved in cued fear conditioning and a target region of ventral tegmental area, substantia nigra, and locus coeruleus dopaminergic neurons. Intra-VH eticlopride or saline was directly infused into the VH immediately after conditioning concurrent to cocaine administration. Results from Experiment 2 suggest that the antagonism of VH D2 receptors may disrupt the impairing effects of cocaine on fear memory consolidation, suggesting the VH as a potential region mediating this effect. The present study provides evidence that acute cocaine administration impairs aversive memory formation and establishes a potential circuit through which cocaine induces its detrimental effects on fear memory consolidation. Moreover, these results provide insight into why cocaine users might engage in impulsive and risk-taking behavior that could lead to fatal consequences.

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