The broad objective of this proposal is to elucidate the calcium-dependent mechanisms of nicotine's effects and dependence. The Ca2+permeability of neuronal nicotinic receptors suggests an important role for calcium-mediated signaling cascades. Ca2+dependent kinases, in particular Ca2+calmodulin-dependent protein kinase II (CaMKII), are known to play an important role in neuronal plasticity and are therefore attractive candidates for contributing to neuronal adaptation leading to nicotine dependence. The focus of this proposal is to test the hypothesis that CaMKII activation through a4b2* nAChRs subtypes in the ventral tegmental Area (VTA) plays an important role in the rewarding effects of nicotine. In this project we will first assess the potential role of CaMKII activation in the acute response to nicotine in the VTA. Subsequent studies involving the use of various nicotinic antagonists and different nAChRs transgenic mice will be carried out in order to test the hypothesis that a4b2* nAChR subtypes mediate nicotine's effects on CaMKII activity in the VTA. Using specific inhibitors of L-type calcium channels (LCC) and NMDA receptors, we will then determine whether glutamate and LCC transmissions contribute to nicotine-induced CaMKII activity. Finally, using CaMKII inhibitors and CaMKII KO mice, we will determine if CREB is one the targets of CaMKII activation induced by nicotine in the VTA. We will next address the hypothesis that nicotine dependence may involve an adaptation of the CaMKII signaling system using conditioned place preference (CPP) in mice, an animal model of nicotine reward. Multiple approaches will be employed. We will first extend our preliminary findings by measuring changes of CaMKII activity and levels in the VTA and hippocampus during the various stages of conditioning nicotine place preference. Additionally, we will examine if CaMKII activation in the VTA and hippocampus mediate the expression of nicotine-induced CPP by performing an intra-VTA and intra-hippocampus administration of CaMKII inhibitors in CPP trained mice. Furthermore, complementary behavioral studies will utilize CaMKII Knock-out mice in nicotine-induced CPP. Results generated from acute studies (Aim 1) on CaMKII pathway will be further investigated in the CPP model. The proposed studies will help elucidate the molecular basis of nicotine dependence as well as the Ca2+ dependent neuroadaptation processes that occurs after short-and long-term exposure to this drug of abuse.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA012610-08
Application #
7899956
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Lin, Geraline
Project Start
2001-02-01
Project End
2011-07-31
Budget Start
2010-08-01
Budget End
2011-07-31
Support Year
8
Fiscal Year
2010
Total Cost
$210,552
Indirect Cost
Name
Virginia Commonwealth University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298
Kota, Dena; Alajaji, Mai; Bagdas, Deniz et al. (2018) Early adolescent nicotine exposure affects later-life hippocampal mu-opioid receptors activity and morphine reward but not physical dependence in male mice. Pharmacol Biochem Behav 173:58-64
Bagdas, D; Meade, J A; Alkhlaif, Y et al. (2018) Effect of nicotine and alpha-7 nicotinic modulators on visceral pain-induced conditioned place aversion in mice. Eur J Pain :
Jackson, Asti; Papke, Roger L; Damaj, M Imad (2018) Pharmacological modulation of the ?7 nicotinic acetylcholine receptor in a mouse model of mecamylamine-precipitated nicotine withdrawal. Psychopharmacology (Berl) 235:1897-1905
Jackson, Asti; Bagdas, Deniz; Muldoon, Pretal P et al. (2017) In vivo interactions between ?7 nicotinic acetylcholine receptor and nuclear peroxisome proliferator-activated receptor-?: Implication for nicotine dependence. Neuropharmacology 118:38-45
Arvaniti, Maria; Jensen, Majbrit M; Soni, Neeraj et al. (2016) Functional interaction between Lypd6 and nicotinic acetylcholine receptors. J Neurochem 138:806-20
Jackson, Kia J; Muldoon, Pretal P; Walters, Carrie et al. (2016) Neuronal calcium/calmodulin-dependent protein kinase II mediates nicotine reward in the conditioned place preference test in mice. Behav Pharmacol 27:50-6
Sanjakdar, Sarah S; Maldoon, Pretal P; Marks, Michael J et al. (2015) Differential roles of ?6?2* and ?4?2* neuronal nicotinic receptors in nicotine- and cocaine-conditioned reward in mice. Neuropsychopharmacology 40:350-60
Bagdas, Deniz; Targowska-Duda, Katarzyna M; López, Jhon J et al. (2015) The Antinociceptive and Antiinflammatory Properties of 3-furan-2-yl-N-p-tolyl-acrylamide, a Positive Allosteric Modulator of ?7 Nicotinic Acetylcholine Receptors in Mice. Anesth Analg 121:1369-77
Anderson, S M; Brunzell, D H (2015) Anxiolytic-like and anxiogenic-like effects of nicotine are regulated via diverse action at ?2*nicotinic acetylcholine receptors. Br J Pharmacol 172:2864-77
Papke, Roger L; Bagdas, Deniz; Kulkarni, Abhijit R et al. (2015) The analgesic-like properties of the alpha7 nAChR silent agonist NS6740 is associated with non-conducting conformations of the receptor. Neuropharmacology 91:34-42

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