nACfiR upregulation by ciironic exposure to nicotine and ottier nicotinic drugs The Overall Progress Report and Overall Description sections provide the logic and background for the study of receptor upregulation by candidate drugs. Upregulation in 2 pathways related to nicotine addiction Cellular and circuit-level research on nAChRs is governed by the fact that only a handful of papers present believable eEPSCs, sEPSCs, or mEPSCs associated with nAChR activation by ACh in the brain. Investigators believe that most HS nicotinic receptors are on presynaptic terminals, where they control transmitter release (and therefore pose challenges for detailed study) (MacDermott et al., 1999). Many studies also reveal the presence of somatodendritic HS nAChRs (mostly a4B2* and a6*). Little or no evidence shows that these somatodendritic receptors respond to circulating or released ACh. But there is much evidence that these nAChRs do respond to nicotine with both activation and, in some cases, desensitization, primarily because nicotine is not hydrolyzed by acetylcholinesterase.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19DA019375-08
Application #
8380398
Study Section
Special Emphasis Panel (ZMH1-ERB-C)
Project Start
Project End
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
8
Fiscal Year
2012
Total Cost
$261,174
Indirect Cost
$99,955
Name
California Institute of Technology
Department
Type
DUNS #
009584210
City
Pasadena
State
CA
Country
United States
Zip Code
91125
Henderson, Brandon J; Wall, Teagan R; Henley, Beverley M et al. (2016) Menthol Alone Upregulates Midbrain nAChRs, Alters nAChR Subtype Stoichiometry, Alters Dopamine Neuron Firing Frequency, and Prevents Nicotine Reward. J Neurosci 36:2957-74
Henderson, Brandon J; Lester, Henry A (2015) Inside-out neuropharmacology of nicotinic drugs. Neuropharmacology 96:178-93
Wieskopf, Jeffrey S; Mathur, Jayanti; Limapichat, Walrati et al. (2015) The nicotinic α6 subunit gene determines variability in chronic pain sensitivity via cross-inhibition of P2X2/3 receptors. Sci Transl Med 7:287ra72
Marks, Michael J; O'Neill, Heidi C; Wynalda-Camozzi, Kelly M et al. (2015) Chronic treatment with varenicline changes expression of four nAChR binding sites in mice. Neuropharmacology 99:142-55
Wang, Yuexiang; Lee, Jang-Won; Oh, Gyeon et al. (2014) Enhanced synthesis and release of dopamine in transgenic mice with gain-of-function *6* nAChRs. J Neurochem 129:315-27
Eaton, J Brek; Lucero, Linda M; Stratton, Harrison et al. (2014) The unique *4+/-*4 agonist binding site in (*4)3(*2)2 subtype nicotinic acetylcholine receptors permits differential agonist desensitization pharmacology versus the (*4)2(*2)3 subtype. J Pharmacol Exp Ther 348:46-58
Wageman, Charles R; Marks, Michael J; Grady, Sharon R (2014) Effectiveness of nicotinic agonists as desensitizers at presynaptic *4*2- and *4*5*2-nicotinic acetylcholine receptors. Nicotine Tob Res 16:297-305
Henderson, Brandon J; Srinivasan, Rahul; Nichols, Weston A et al. (2014) Nicotine exploits a COPI-mediated process for chaperone-mediated up-regulation of its receptors. J Gen Physiol 143:51-66
Marks, Michael J (2013) Genetic matters: thirty years of progress using mouse models in nicotinic research. Biochem Pharmacol 86:1105-13
O'Neill, Heidi C; Laverty, Duncan C; Patzlaff, Natalie E et al. (2013) Mice expressing the ADNFLE valine 287 leucine mutation of the Î’2 nicotinic acetylcholine receptor subunit display increased sensitivity to acute nicotine administration and altered presynaptic nicotinic receptor function. Pharmacol Biochem Behav 103:603-21

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