The broad objective of this proposal is to elucidate the calcium- dependent mechanisms of nicotinic receptor function. It was recently shown that neuronal nicotinic receptors (nAChRs) have a high Ca2+ permeability and our initial studies indicate that changes in calcium homeostasis and Ca2+/calmodulin-dependent protein kinase (CaM- Kinase II) can modulate nicOtine's pharmacological effects and are involved in neuroadaptative processes after chronic exposure to nicotine in the animal. In this project we plan to study calcium-dependent intracellular mechanisms and their modulation after short and long-term activation of nAChRs. We will assess the potential role of CaM-kinase II activatiOn in the behavioral effects of nicOtine using pharmacological, biochemical and genetic approaches. Tolerance to nicotine's effects could involve an adaptation in the calcium signaling system activated by nicotine leading to a decrease in in CaM-kinase II activity. Such a hypothesis will be investigated by measuring quantitative and qualitative changes in Ca2+-calmodulin-dependent signaling in in vitro and ex-vivo preparations during long-term exposure to nicotine. Finally, we will attempt to modulate tolerance to nicotine's effects by administering drugs that alter calcium entry. In vivo studies with calcium channel modulators and CaM-Kinase II inhibitors as well as NMDA receptor antagonists will be conducted in animals chronically infused with nicotine. The proposed studies will elucidate the calcium-dependent processes involved in nicotine's actions in the brain as well as the neuroadaptation 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 #
5R01DA012610-02
Application #
6497822
Study Section
Special Emphasis Panel (ZRG1-IFCN-1 (01))
Program Officer
Lin, Geraline
Project Start
2001-02-01
Project End
2004-01-31
Budget Start
2002-02-01
Budget End
2003-01-31
Support Year
2
Fiscal Year
2002
Total Cost
$181,250
Indirect Cost
Name
Virginia Commonwealth University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
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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