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Contribution of Nucleus Accumbens to Reward-Seeking Behaviors: Role of Dopamine-Mediated ERK Signaling

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posted on 2015-01-01, 00:00 authored by Merissa Lynn Remus

Exposure to environmental cues that have been associated with rewards tend to increase behaviors that serve to procure the reward. The excitatory modulation that so-called conditioned cues exert over reward seeking depends on the nucleus accumbens (NAc). A critical molecular step within the NAc in this behavioral phenomenon is activation of extracellular signal-regulated kinase (ERK) in the NAc. The first set of experiments served to investigate the subregional pattern of ERK activation within the NAc during cue-potentiation of reward seeking and the contribution of different elements in the behavioral situation to the distribution of ERK signaling in the NAc of rats. We found that the occurrence of rewardseeking behavior did not affect ERK activation in either the core or the shell of the NAc. In contrast, presentation of the conditioned cue caused a significant increase in ERK activation in both subregions of the NAc. Different from the pattern evoked by the cue, presentation of the reward itself had no effect on ERK activation in the core but caused a pronounced increase in ERK activation in the shell. Taken together, these results demonstrate that ERK signaling in the NAc during cue-evoked reward seeking involves both the core and the shell and is driven by the conditioned cue irrespective of whether or not the situation permits engagement in reward-seeking behavior. Furthermore, the results show that the subregional distribution of ERK signaling in the NAc evoked by rewards differs from that evoked by cues that predict them. The second set of experiments served to determine the contribution of NAc dopamine type 1 (D1) versus type 2 (D2) receptors to cue-evoked NAc ERK activation, and to identify the phenotype of NAc cell in which cue-evoked ERK activation occurs. We found that NAc D1 receptor antagonism markedly blunted the cue-evoked increase in ERK signaling in both the core and the shell, whereas NAc D2 receptor antagonism had no effect on ERK signaling. In addition, we found that every cell in the NAc of rats exhibiting cuepotentiated reward seeking that stained immunopositive for active ERK also stained for prodynorphin, a neuropeptide that in the NAc is expressed selectively by D1 receptorcontaining medium spiny neurons. These results demonstrate that conditioned cue-evoked ERK activation is mediated by D1 receptors and takes place in D1 receptor expressing NAc projection cells. Taken together with findings that D1 receptor antagonism abrogates the ability of conditioned cues to potentiate reward seeking, the results point to a molecular mechanism through which dopamine mediates enhanced reward seeking in the presence of reward-predictive cues. Furthermore, the results suggest that inputs to and projection targets of D1 receptor-expressing NAc output cells are candidate elements of the neural circuit underlying cue-potentiation of reward seeking. Collectively, the findings may lead to the development of targeted interventions for the treatment of conditions characterized by maladaptive reward seeking, such as drug addiction and obesity.

History

Date

2015-01-01

Degree Type

  • Dissertation

Department

  • Biological Sciences

Degree Name

  • Doctor of Philosophy (PhD)

Advisor(s)

Floh Thiels

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