The role of nucleus accumbens dopamine in incubation of cocaine craving
Creators: name: Weber, Sophia
name: Kawa, Alex
name: Moutier, Alana
name: Beutler, Madelyn
name: Koyshman, Lara
name: Moreno, Cloe
name: Westlake, Jonathan
name: Driscoll, Gillian
name: Kuhn, Hayley
name: Wolf, Marina
Publisher: name: Oregon Health and Science University
Year: 2024
Subjects: subject: Behavior, Addictive
subject: Oregon
subject: dopamine
subject: incubation of drug craving
subject: fiber photometry
subject: behavioral pharmacology
subject: cocaine

description: The nucleus accumbens plays a key role in guiding motivated behavior by integrating glutamate inputs, the major driver of neuronal activation, and dopamine (DA) inputs, a critical source of neuronal modulation. Therefore, it is important to understand how glutamate and DA transmission interact, particularly in reward-seeking behavior. In this dissertation, I use fiber photometry to extend our understanding of this interaction during two reward-seeking tasks. 
 Substance use disorder (SUD) is a brain disease in which reward-seeking becomes dysregulated. One hallmark of SUD is relapse despite desire or attempts to stop drug use, and this represents the most challenging aspect of treating this disorder. To better understand the persistent craving and relapse vulnerability seen in humans, in Chapter 1 I used the incubation of drug craving model, in which cue-induced drug seeking in rats progressively increases (incubates) during forced abstinence and then remains high for long periods of time. This phenomenon has also been demonstrated in humans. Previously, our lab and others demonstrated that expression of incubated cocaine seeking requires strengthening of glutamatergic synaptic transmission in the nucleus accumbens core. However, little was known about DA transmission in this model. To address this gap, I recorded DA transients in the nucleus accumbens core of male and female rats during cue-induced cocaine seeking. The magnitude of DA transients time-locked to responding did not differ when measured during early abstinence (prior to incubation) versus late abstinence (after incubation has plateaued). To test the functional relevance of these transients, I injected DA receptor antagonists into the nucleus accumbens core just before the seeking test. Blockade of either D1 or D2 DA receptors reduced cue-induced cocaine seeking after but not before incubation. These results suggest that DA contributes to incubated cocaine seeking but the emergence of this role reflects changes in postsynaptic responsiveness to DA rather than presynaptic alterations.
Dopamine and glutamate signaling in the nucleus accumbens core are also implicated in seeking natural rewards such as food. Work using the classical extinction-reinstatement model has demonstrated that suppression of neuronal activity as well as blockade of DA signaling in the nucleus accumbens (core versus shell not specified) reduces reinstatement to food seeking. In Chapter 2, I further explored a role for both neuronal activity and DA using sensor multiplexing, a fiber photometry technique enabling simultaneous recording of changes in DA and calcium (a proxy for neuronal activation). DA transients time-locked to responding for food significantly increased with food self-administration training, while neuronal calcium transients showed a decrease from basal activity that became more pronounced with training. In the first session of extinction, I report a blunted DA increase from baseline and a blunted decrease in calcium. By the last extinction session, there were no detectable deflections from baseline in either trace. Rats then underwent a reinstatement test, a test of reward seeking, and showed increases from baseline time-locked to the lever-press in both DA and calcium recordings. These experiments support glutamate and DA acting cooperatively in the nucleus accumbens core during food reinstatement and validate sensor multiplexing in a model of motivated behavior.