Earlier versions of this R01 grant focused on the role of neurotrophic signaling pathways in the neural plasticity induced in the ventral tegmental area (VTA) nucleus accumbens (NAc) reward circuit by chronic exposure to stimulant or opiate drugs of abuse, with a particular focus on the molecular mechanisms by which these drugs alter the morphology of VTA and NAc neurons. In this renewal application, we propose to focus on one major aspect of this effort: stimulant and opiate regulation of the morphology of NAc medium spiny neurons (MSNs). While there has been considerable work on this topic, major questions persist, given different laboratories' use of contingent vs. noncontingent drug exposure and of different methods to quantify dendritic morphology, and their focus on different times after drug withdrawal and on different subregions of NAc (core vs. shell). A further complicating factor is that few studies have considered different effects of drug exposure on the two main subtypes of NAc MSNs, those expressing predominantly the D1 vs. D2 dopamine receptor. The goal of this grant is to characterize, in a comprehensive cell type and subregion specific manner, the effect of cocaine or heroin self-administration, over the life cycle of self-administration behavior (acquisition, withdrawal, extinction, and relapse), on the number and morphology of NAc dendritic spines. We will also gain insight into input specificity of such dendritic plasticity as ell as the postsynaptic strength of spines under control and drug self-administration conditions by use of optogenetic and 2 photon imaging approaches. In parallel, we will continue our innovative studies that have provided novel insight into the molecular basis by which chronic drug self-administration induces this postsynaptic plasticity of NAc MSN dendritic spines. This work, in concert with ongoing studies in many other laboratories focused largely on complementary aspects of glutamatergic synaptic plasticity in drug abuse models, will help establish the ways in which such dendritic plasticity contributes to a state of addiction. As well, these studies will hep us capitalize on our improved understanding of drug-induced dendritic plasticity in NAc MSNs by identifying target genes suitable for future drug discovery efforts.

Public Health Relevance

The objective of this grant is to study the detailed molecular and cellular mechanisms by which chronic exposure to drugs of abuse alters the structure and function of neurons within the brain's reward circuitry. These studies will provide new information concerning how drugs of abuse cause a state of addiction as well as identify novel leads toward the development of improved diagnostic tests and treatments.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA014133-17
Application #
9059056
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Sorensen, Roger
Project Start
2000-09-01
Project End
2020-03-31
Budget Start
2016-04-01
Budget End
2017-03-31
Support Year
17
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Neurosciences
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
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Cahill, M E; Walker, D M; Gancarz, A M et al. (2018) The dendritic spine morphogenic effects of repeated cocaine use occur through the regulation of serum response factor signaling. Mol Psychiatry 23:1474-1486
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Calipari, Erin S; Godino, Arthur; Peck, Emily G et al. (2018) Granulocyte-colony stimulating factor controls neural and behavioral plasticity in response to cocaine. Nat Commun 9:9
Cahill, Michael E; Browne, Caleb J; Wang, Junshi et al. (2018) Withdrawal from repeated morphine administration augments expression of the RhoA network in the nucleus accumbens to control synaptic structure. J Neurochem 147:84-98
Mul, Joram D; Soto, Marion; Cahill, Michael E et al. (2018) Voluntary wheel running promotes resilience to chronic social defeat stress in mice: a role for nucleus accumbens ?FosB. Neuropsychopharmacology 43:1934-1942
Yu, Jun; Yan, Yijin; Li, King-Lun et al. (2017) Nucleus accumbens feedforward inhibition circuit promotes cocaine self-administration. Proc Natl Acad Sci U S A 114:E8750-E8759
Anderson, Ethan M; Wissman, Anne Marie; Chemplanikal, Joyce et al. (2017) BDNF-TrkB controls cocaine-induced dendritic spines in rodent nucleus accumbens dissociated from increases in addictive behaviors. Proc Natl Acad Sci U S A 114:9469-9474
Ceglia, Ilaria; Lee, Ko-Woon; Cahill, Michael E et al. (2017) WAVE1 in neurons expressing the D1 dopamine receptor regulates cellular and behavioral actions of cocaine. Proc Natl Acad Sci U S A 114:1395-1400
Calipari, Erin S; Juarez, Barbara; Morel, Carole et al. (2017) Dopaminergic dynamics underlying sex-specific cocaine reward. Nat Commun 8:13877

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