A major focus of drug abuse research is understanding the molecular adaptations caused by drugs of abuse that lead to addiction. Recent studies have focused attention on the important role that long-lasting aversive consequences of drug withdrawal play in this process. As immediate early genes play a critical role in mediating enduring forms of synaptic plasticity,we have initiated studies aimed at assessing whether one of these, Narp, may be involved in the long-lasting effects induced by drug exposure or withdrawal. We have chosen Narp for study because in vitro studies indicate that it is involved in clustering AMPA receptors and synapse formation, which have been implicated in several drug-induced adaptations. In preliminary studies we have found that Narp is selectively induced in the extended amygdala in response to opiate withdrawal. As the extended amygdala plays a key role in the aversive consequences of drug withdrawal, we plan to test the hypothesis that Narp mediates acquisition of this learned behavior. Accordingly, we will: (a) Determine whether suppressing Narp expression or action alters the aversive effects of opiate withdrawal, (b) Determine if Narp mediates synapse remodeling after opiate withdrawal. An improved understanding of the molecular mechanisms subserving drug addiction will help direct a more rational approach to looking for effective treatments. We have identified a putative mediator (a protein known as Narp) of drug withdrawal, a dysphoric state that helps sustain addiction. Using genetically-engineered Narp-deficient mice and viral vectors that suppress Narp expression we plan to evaluate Narp's role in this process.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA016303-03
Application #
7382589
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Pollock, Jonathan D
Project Start
2006-04-01
Project End
2009-06-30
Budget Start
2008-03-01
Budget End
2009-06-30
Support Year
3
Fiscal Year
2008
Total Cost
$312,118
Indirect Cost
Name
Johns Hopkins University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Chang, Andrew D; Vaidya, Punit V; Retzbach, Edward P et al. (2017) Narp Mediates Antidepressant-Like Effects of Electroconvulsive Seizures. Neuropsychopharmacology :
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

Showing the most recent 10 out of 12 publications