Neural substrates of cocaine-cue extinction learning and consolidation in rats
Szalay, Jonathan J.
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Memory system circuitry may regulate how cues associated with cocaine are extinguished. One goal of this dissertation was to investigate whether the dorsal subiculum (dSUB) region of the hippocampus and the rostral aspect of the basolateral amygdala (rBLA) were involved in acquisition of cocaine-cue extinction learning in rats (Experiment 1). Using lidocaine, rats underwent bilateral or asymmetric inactivation of the dSUB and rBLA. Following intravenous cocaine self-administration training with light and sound cues present, behavior was assessed during cue extinction tests (cues present, no cocaine available). Results demonstrated that pre-test inactivation of dSUB and rBLA, bilaterally or asymmetrically, deterred extinction. Rats maintained elevated levels of cocaine-seeking behavior, despite the absence of cocaine. Control studies in Experiment 1 showed that unilateral or ipsilateral inactivation of dSUB and rBLA prior to extinction tests were unable to deter extinction. Rats reduced cocaine-seeking behavior in the absence of cocaine. Thus, acquisition of cocaine-cue extinction learning required the dSUB and rBLA to be functionally active simultaneously in at least one brain hemisphere. These results suggest that a serial circuit within each hemisphere mediates acquisition of cocaine-cue extinction learning. A second goal was to investigate whether the dSUB, rBLA and infralimbic prefrontal cortex (IL) were involved in the consolidation of cocaine-cue extinction learning in rats (Experiment 2). The protein-synthesis inhibitor anisomycin was infused bilaterally into the dSUB, rBLA or IL. Post-test inhibition of protein synthesis in dSUB deterred extinction following a single session, whereas inhibition in rBLA disrupted extinction only following multiple sessions. Post-test manipulation of IL did not modify responding. Studies in Experiment 2 to control for the time-dependency of consolidation processes showed that bilateral protein-synthesis inhibition in dSUB and rBLA six hours after extinction sessions was unable to deter extinction. Thus, consolidation processes regulated by dSUB and rBLA occur within a critical window of time immediately following extinction sessions. Collectively, these findings suggest that neural substrates for cocaine-cue extinction interact serially during acquisition of learning but have temporally distinct roles during consolidation. Understanding the contribution of individual substrates may help guide therapeutic treatment strategies when implementing cue exposure therapy for drug relapse prevention.
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