Although significant advances in the treatment of opiate addiction have been made, relapse to opiate use after abstinence continues to impede successful treatment, highlighting the need for efforts to dissect the mechanism of opiate-dependent changes in brain function. Long-lasting associations between opiates and the context in which they are taken result in cues that lead to drug craving and ultimately relapse. The hippocampus has traditionally been recognized for its role in learning and memory but recent evidence has shown its critical role in the behavioral effects of opiates, probably via activation of hippocampal excitatory inputs to the reward pathway (i.e. Nucleus Accumbens, NAc). Several lines of evidence suggest that drug- induced contextual/cue memories are associated with molecular changes in hippocampal function and that these changes may be necessary for some behavioral effects of opiates. Results from our laboratory have revealed that AMPAR and NMDAR play a crucial role in opiate-induced contextual learning. In addition SK2 channels, which are functionally linked to NMDAR, are critically involved in coding contextual memories. Furthermore, we have recently found that context-dependent sensitization to morphine leads to the activation of SK2 channels in the hippocampus. SK2-mediated functional effects on activated spines may be responsible for the expression and reinstatement of morphine place preference behavior. We also have preliminary data showing that the intrahippocampal administration of the SK2 blocker, apamin, following conditioning training, blocks the expression of morphine CPP. However, there are no reports dissecting how SK2 channels influence learning for opiate-paired contextual/cue behavior. Our central hypothesis is that enhancement of SK2 function, via increased Ca2+ influx through NMDAR, in the hippocampus plays a critical role in the formation of the association between the drug reward experience and the context/cue. Our overall objective is to uncover the cellular mechanisms underlying morphine-induced activation of SK2 channels, and to investigate how the activation of hippocampal SK2 channels are integral for morphine-induced contextual/cue learned associations, using both the CPP and i.v. drug self-administration models.
In Aim 1, we will determine the mechanisms by which SK2 channel function is increased following morphine contextual/cue associations.
In Aim 2, we will define the requirement for enhanced SK2 channel function in the expression and reinstatement of morphine contextual/cue associations in vivo.
In Aim 3, we will determine whether hippocampal excitatory inputs to the NAc are enhanced during morphine-contextual/cue associations and to measure the underlying SK2-mediated changes in hippocampal pyramidal neuronal networks. Studies proposed here offer potentially novel drug addiction treatments in targeting SK2 channels to prevent drug-context/cue associations and thus prevent relapse to opiate use.

Public Health Relevance

In this study we propose that the functional cross-talk between SK2 channels and NMDAR in the hippocampus is a key modulator in the mechanisms underlying morphine-induced contextual/cue learning. These mechanistic studies will ultimately provide critical information for the potential development of novel pharmacotherapeutics for treating opiate addiction.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA042499-03
Application #
9632801
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Sorensen, Roger
Project Start
2017-05-01
Project End
2022-01-31
Budget Start
2019-02-01
Budget End
2020-01-31
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Washington University
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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