Smith, Dana
(2023)
Role of dopamine signaling in the lateral amygdala in mediating associative learning with relevance to substance use disorders.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
In classical conditioning, a form of associative learning, repeatedly pairing a neutral stimulus with a biologically significant unconditioned stimulus (US) results in an association between the two stimuli. The neutral stimulus becomes a conditioned stimulus (CS) and presentation of it alone elicits a conditioned response (CR) that mirrors the unconditioned response. Associative learning can promote maladaptive behaviors including drug abuse. Environmental cues paired with repeated drug use acquire strong incentive value such that exposure to them alone can trigger craving and relapse.
Initially weak afferents carrying CS information and strong afferents carrying US information converge in the lateral amygdala (LA) and through plasticity mechanisms, there is enhancement at the excitatory synapses carrying CS information. Evidence suggests that the ventral tegmental area (VTA) dopamine projection to the LA participates in encoding reinforcing effects that act as a US in conditioned cue reward-seeking as dopamine released in the amygdala is important for emotional and behavioral functions. In the context of drugs of abuse, dopamine in the LA has been shown to be necessary for maintenance of drug-cue associations, regulation of drug-seeking behavior, and reinstatement of drug-seeking.
In this dissertation, through a combination of fiber photometry, chemogenetics, and behavioral techniques, we found that dopamine activity in the LA is necessary for cue-mediated reward-seeking. During conditioning, as learning occurs, dopamine activity develops responses to reward-predictive cues. Dopamine activity in the LA is associated with cue-related events as release is unchanged by reward or instrumental action. We also found that inhibiting dopaminergic input to the LA during cocaine self-administration slowed acquisition and weakened the ability of the previously cocaine-paired cue to elicit cocaine-seeking. Conversely, exciting the projection during self-administration boosted the salience of the cocaine-paired cue as indicated by enhanced responding during cue-induced reinstatement. Importantly, interfering with dopamine input to the LA has no impact on the ability of cocaine to elicit a place preference or induce reinstatement in response to a priming cocaine injection. Together, this work indicates that manipulation of projections underlying dopamine signaling in the LA may be useful for developing therapeutic interventions for substance use disorders (SUD).
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
29 September 2023 |
| Date Type: |
Publication |
| Defense Date: |
21 March 2023 |
| Approval Date: |
29 September 2023 |
| Submission Date: |
26 March 2023 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
187 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Psychiatry |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
classical conditioning, cocaine self-administration, fiber photometry, chemogenetics |
| Date Deposited: |
29 Sep 2023 14:17 |
| Last Modified: |
29 Sep 2023 14:17 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/44329 |
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