The limited effectiveness of currently available strategies for treating drug abuse and addiction underscore the pressing need to identify the brain circuits and molecular mechanisms that mediate addiction, information needed to develop new approaches to combat this malignant disorder. Recent studies have highlighted similarities between mechanisms underlying long-term memory and those mediating drug addiction. This analogy has been quite useful in focusing attention on the role of signaling pathways implicated in enduring forms of synaptic plasticity in drug abuse and addiction. For example, immediate early genes (IEGs), such as Fos family members, Zif268 and Homer family members, linked to long-term memory, have also been found to play a key role in mediating responses to drugs of abuse. To pursue this fruitful line of research, we have undertaken a series of studies examining the role of another immediate early gene, neuronal activity regulated pentraxin, Narp, in drug abuse. This IEG is an attractive candidate for mediating the long-lasting behavioral effects of drugs of abuse because it encodes a protein that is secreted at synaptic sites and binds to the extracellular surface of AMPA receptors. Thus, by regulating clustering and/or trafficking of AMPA receptors, key effectors of synaptic plasticity, Narp is well-positioned to have a major impact on plasticity mechanisms mediating the long-lasting behavioral changes produced by drugs of abuse. As described below, we have employed Narp KO mice to evaluate the role of this protein in the long- term behavioral effects of morphine. In brief, we have found that these mice undergo normal levels of sensitization and conditioned place preference induced by repeated morphine administration. However, they show a profound defect in extinction of place preference conditioning. As exposure to environmental cues associated with the rewarding effects of drug administration provides a powerful stimulus for drug craving and relapse, there is intense interest in trying to understand how to facilitate extinction of this form of appetitive conditioning. Thus, our finding of a striking extinction deficit in Narp KO mice is of interest because it provides a valuable entryway into understanding the brain circuitry and molecular mechanisms that normally mediate extinction of conditioned effects of abused drugs. Accordingly, we plan to pursue our initial findings with a series of studies outlined below. In particular, we plan to: 1) use focal injections of a dominant negative Narp viral construct to elucidate which brain regions mediate this deficit in extinction learning, 2) determine whether decreased responsiveness to glutamate in nucleus accumbens (NAc) found in Narp KO mice mediates their extinction defect, 3) examine whether CCK antagonists reverse the extinction deficit displayed by Narp KO mice, and 4) study whether Narp suppression also blocks extinction of morphine self-administration.
An improved understanding of the molecular mechanisms subserving drug addiction will help direct a more rational approach to looking for effective treatments. We have found that a protein called Narp mediates extinction of opiate-associated memories that help sustain addiction. Using viral vectors that suppress Narp expression, we plan to pursue behavioral and biochemical studies to further elucidate Narp's role in this process.
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|Miskimon, M; Han, S; Lee, J J et al. (2014) Selective expression of Narp in primary nociceptive neurons: role in microglia/macrophage activation following nerve injury. J Neuroimmunol 274:86-95|
|Blouin, Ashley M; Lee, Jongah J; Tao, Bo et al. (2013) Narp knockout mice show normal reactivity to novelty but attenuated recovery from neophobia. Behav Brain Res 257:178-81|
|Blouin, Ashley M; Han, Sungho; Pearce, Anne M et al. (2013) Role of medial prefrontal cortex Narp in the extinction of morphine conditioned place preference. Learn Mem 20:75-9|
|Blouin, Ashley M; Stern, Anna L; Han, Sungho et al. (2013) Neuronal activity-regulated pentraxin expressed in medial prefrontal cortex neurons is not necessary for extinction of heroin self-administration. Behav Pharmacol 24:332-6|
|Reti, Irving M; Blouin, Ashley M; Worley, Paul F et al. (2011) Mediating the effects of drug abuse: the role of Narp in synaptic plasticity. ILAR J 52:321-8|
|Johnson, Alexander W; Han, Sungho; Blouin, Ashley M et al. (2010) Localized disruption of Narp in medial prefrontal cortex blocks reinforcer devaluation performance. Learn Mem 17:620-6|
|Reti, Irving M; Han, Sungho; Miskimon, Matthew et al. (2009) Nicotine and Delta(9)-tetrahydrocannabinol withdrawal induce Narp in the central nucleus of the amygdala. Synapse 63:252-5|
|Crombag, Hans S; Dickson, Mercy; Dinenna, Megan et al. (2009) Narp deletion blocks extinction of morphine place preference conditioning. Neuropsychopharmacology 34:857-66|
|Reti, I M; Miskimon, M; Dickson, M et al. (2008) Activity-dependent secretion of neuronal activity regulated pentraxin from vasopressin neurons into the systemic circulation. Neuroscience 151:352-60|
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