Date of Award


Document Type


Degree Name

Doctor of Philosophy (PhD)




College of Graduate Studies

First Advisor

Gary Aston-Jones

Second Advisor

Jacqueline F. McGinty

Third Advisor

Howard Becker

Fourth Advisor

Thomas Jhou

Fifth Advisor

Colleen A. Hanlon


Chronic relapse is a tremendous obstacle in battling addiction. Animal models of relapse (e.g. reinstatement of extinguished lever pressing) are critical for uncovering the neural substrates of addiction. Understanding the neurocircuitry of relapse may provide potentially viable targets to reduce relapse rates and treat addiction. Elucidating the circuits involved in stimulus-induced reinstatement is of particular importance because drug-associated stimuli (e.g. discrete or contextual drug-associated cues) evoke drug craving and perpetuate drug seeking. Nucleus accumbens (NAc) and lateral septum (LS) are two subcortical structures known to contribute to drug addiction and relapse behaviors. However, NAc and LS afferents recruited during stimulus-induced reinstatement of extinguished cocaine seeking have not been fully characterized. Here, we used self-administration paradigms combined with retrograde tracers, Fos immunohistochemistry, pharmacology, and chemogenetics to elucidate NAc and LS afferents involved in stimulus-induced reinstatement of cocaine seeking. In the first set of experiments, we found that neurons in the prelimbic cortex, basolateral amygdala, and ventral subiculum that project to NAc core, but not to NAc shell, showed enhanced neural activation during cue-induced reinstatement compared to extinguished cocaine seeking behavior. However, only activation of the prelimbic-NAc core pathway positively correlated with cocaine seeking behavior. Furthermore, activation of these circuits was specific to cocaine-, but not sucrose-seeking. In the second set of experiments, we found that dorsal hippocampus, LS, and dorsal hippocampal inputs to LS showed enhanced neural activation during context-induced compared to cue-induced reinstatement of cocaine seeking. In support of these results, chemogenetic-mediated inhibition of the dorsal hippocampal-LS pathway attenuated context-, but not cue-induced reinstatement. However, pharmacological inhibition of LS attenuated both context- and cue-induced reinstatement. We then examined if ventral hippocampal neurons may drive cue-induced reinstatement via LS. We found that ventral hippocampal inputs to LS were activated during context- and cue-induced reinstatement, but chemogenetic-mediated inhibition of the circuit did not attenuate either reinstatement modality. Together these data elucidate multiple excitatory inputs to NAc or LS during stimulus-induced reinstatement of cocaine seeking, and indicate distinct neural circuits mediating various reinstatement modalities. The results provide greater insight into the neurocircuitry of relapse that may lead to new therapeutics to treat drug addiction.


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