Bender, Brooke
(2023)
Evaluating the differential effects of cue extinction on goal-directed and habitual cocaine-seeking behavior.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Several types of maladaptive learning and memory contribute to substance use disorders (SUDs). Pavlovian associations form between the drug and contextual and discrete stimuli, or cues, and later exposure to these cues can trigger drug cravings and promote relapse. Cue exposure therapy, the repeated exposure to cues in the absence of drugs to extinguish drug-cue associations, has been proposed as a behavioral treatment to reduce cue-induced cravings. Cue extinction, a preclinical model of cue exposure therapy, reduces cue-induced drug seeking in rats through the depotentiation of thalamo-lateral amygdala synapses. Initial experiments utilized protocols that promote goal-directed drug seeking that relies on the dorsomedial striatum (DMS) and the association between cocaine and the drug-seeking behavior, but certain conditions facilitate habitual behavior that relies on the dorsolateral striatum (DLS) and the association between cues and the drug-seeking behavior. An imbalance of goal-directed and habitual control may also contribute to compulsive drug-seeking behavior that persists despite punishment. Additionally, whereas goal-directed behavior is reduced by inhibition of the basolateral amygdala (BLA), where cue extinction has its effects, habitual behavior is not impacted by BLA inhibition, which suggests that cue extinction may not impact habitual drug seeking. Therefore, in the work presented in this dissertation, we examine how cue extinction differentially affects goal-directed and habitual drug seeking and the dorsal striatum. We find that both habitual and punishment-resistant drug seeking is dependent on DLS dopamine, and habitual drug seeking results in different patterns of protein expression and in vivo calcium and dopamine activity in the DLS and DMS compared to goal- directed drug seeking. Additionally, cue extinction reduces goal-directed, but not habitual, drug seeking unless goal-directed control is pharmacologically restored in rats previously behaving habitually. Cue extinction also reduces dopamine and calcium activity during drug seeking in the DMS, but has no effects on the DLS. Together, these findings indicate that extinction of drug-cue associations does not affect habitual behavior or the underlying neural circuitry involve in promoting habitual behavior and suggest that different methods may be required to target habitual and compulsive aspects of drug-seeking behavior in the treatment of SUDs.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
4 October 2023 |
| Date Type: |
Publication |
| Defense Date: |
28 April 2023 |
| Approval Date: |
4 October 2023 |
| Submission Date: |
1 May 2023 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
225 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Neurobiology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
cocaine, cue extinction, dorsal striatum, drug-associated memory, habitual behavior, goal-directed behavior |
| Date Deposited: |
04 Oct 2023 16:07 |
| Last Modified: |
04 Oct 2023 16:07 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/44826 |
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